FDA approves extended-release formulation of bipolar disorder treatment
FDA approves new indications for Abbott's arthritis treatment
Pfizer's Lipitor approved to reduce risk of heart attack and stroke
FDA approves new formulation of drug to lower intraocular pressure
Hepatitis A vaccine approved for children 12 months and older
Anticoagulant approved for use in percutaneous coronary intervention
Adjuvant chemotherapy agent approved for Dukes' C colon cancer
Sanofi vaccine approved to deter tetanus, diphtheria, whooping cough
Extended-release medication approved to treat ADHD, says Novartis
FDA approves oral disintegrating tablet to treat moderate to moderately severe pain
FDA grants full approval for Velcade as second-line multiple myeloma treatment
FDA approves angiotensin-receptor blocker to treat heart failure
FDA okays generic transdermal patches for chronic pain treatment
Oral solution of schizophrenia and bipolar disorder treatment approved
Pfizer's antifungal approved to treat bloodstream infections
FDA approves Avelox for complicated intra-abdominal infections
FDA approves new chemotherapy combination for treatment of pancreatic cancer
Pfizer's Aromasin approved as adjuvant therapy for early breast cancer
New formulation and indication for Emtriva approved by US FDA
Orally disintegrating prescription antihistamine approved in US
Treatment for Cryptosporidium-induced diarrhea approved for adults and teens
FDA approves capsule formulation of secondary hyperparathyroidism drug
Indications for Atacand include use without other ACE inhibitors
FDA approves fixed-dose combination hypertension medicine to prevent stroke
Pegasys and Copegus now approved to treat Hepatitis C and HIV coinfection
Serono's growth hormone deficiency treatment approved for adults
December 22, 2005
ST. LOUIS (MD Consult) - On December 22, 2005, Roche announced that the US Food and Drug Administration (FDA) has approved a supplemental new drug application extending the prophylaxis indication for Tamiflu (oseltamivir phosphate) to include children aged 1 to 12 years. An antiviral medication prescribed for the prevention and treatment of influenza, Tamiflu was previously approved for prophylaxis in adolescents (age 13 years and older) and adults. Tamiflu is also the only antiviral medication indicated for the treatment of influenza type A or type B infection in patients aged 1 year and older and is available in both capsule and liquid suspension formulations.
When administered within 48 hours of exposure, clinical data show that prophylaxis with Tamiflu reduced the incidence of flu from 17% (18/106) in the group not receiving Tamiflu to 3% (3/95) in the group receiving prophylaxis. The dosing for the new indication is 30 to 60 mg once daily (dependent on body weight) for a duration of 10 days. Therapy should begin within 2 days of exposure, following close contact with an infected person.
The supplemental new drug application was filed based on results from a subset of pediatric patients in a clinical study where Tamiflu was used for the management of influenza in households. The study, which included more than 1,000 patients (including adults and children), showed that postexposure prophylaxis is effective in preventing secondary spread of influenza infection and illness in households and that the protective efficacy of Tamiflu was the same in children aged 1 to 12 years as in the whole population.
Influenza is particularly dangerous for vulnerable populations including young children and infants. Children younger than 2 years old are as likely as those over the age of 65 years to be hospitalized because of influenza. It is estimated that children are 3 times more likely to get sick with influenza—on average, 1 in 10 adults is affected by influenza annually, compared with 1 in 3 children. Therefore, prevention of influenza in children can have a significant impact on the spread of influenza in the household and the whole community.
According to Roche, Tamiflu delivers:
In addition, Tamiflu is shown to provide up to 89% overall protective efficacy against clinical influenza in adults and adolescents who had been in close contact with influenza-infected patients.
In children, treatment with Tamiflu delivers:
The World Health Organization (WHO) advises that stockpiling antiviral agents in advance is presently the only way to ensure that sufficient supplies are available in the event of a pandemic. Roche, headquartered in Basel, Switzerland, has been working closely with WHO and national governments to ensure that governments are aware of the importance of stockpiling antiviral medications in the event of a pandemic situation. Roche has received and fulfilled pandemic orders for Tamiflu from approximately 50 countries worldwide. To meet this demand, Roche states that it has already significantly expanded its Tamiflu production capacity several times and will continue to do so.
Additional information about the Roche Group is available on the company's Web site.
November 30, 2005
ST. LOUIS (MD Consult) - On December 7, 2005, Abbott Laboratories announced that the US Food and Drug Administration (FDA) has approved a new indication for Depakote ER (divalproex sodium extended-release tablets) for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. Compared with Depakote (divalproex sodium delayed-release tablets), Depakote ER taken once a day helps provide more consistent levels of medication in the body.
Approximately 2.3 million American adults have bipolar disorder, also known as manic-depressive illness. Bipolar disorder is a brain disorder that causes unusual shifts in a person's mood, energy, and ability to function. The symptoms of bipolar disorder can be severe. Symptoms of acute mania may include, among others, abnormally elevated mood, irritability, marked increase in energy, grandiose thinking, and thought disorders. Mixed mania is a state of mind characterized by symptoms of both mania and depression. Patients may feel agitated, angry, irritable, and depressed all at once. Like other serious illnesses, bipolar disorder can have a negative impact on a patient's spouse, family members, friends, and coworkers. Depakote ER now provides a useful treatment option for the acute manic and mixed episodes of bipolar disorder.
The effectiveness of Depakote ER was confirmed in a randomized, double-blind, placebo-controlled parallel group, 3-week, multicenter study. The primary efficacy measurement was the Mania Rating Scale (MRS) total score evaluated on day 21 as the mean change from baseline to final evaluation (day 21). Depakote ER was significantly more effective than placebo in the reduction of the MRS total score (mean change, –11.5 vs –9.0 with placebo). The approval of Depakote ER for the treatment of acute mania associated with bipolar disorder was based in part on studies establishing the effectiveness of Depakote.
In Depakote ER acute mania trials, adverse events with a frequency of greater than 5% and at least twice as frequent as those seen with placebo were dyspepsia (23% vs 11%), vomiting (13% vs 5%), and abdominal pain (10% vs 5%).
Depakote ER is the once-daily formulation of Depakote delayed-release tablets, which was approved for the treatment of mania associated with bipolar disorder in 1995. Depakote ER is also approved as monotherapy and adjunctive therapy in the treatment of adults and children 10 years of age or older with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures. Additionally, Depakote ER is approved for migraine prevention in adults.
Valproate products should not be administered to patients with hepatic disease or significant hepatic dysfunction. Hepatic failure resulting in fatality has occurred in patients receiving valproic acid and its derivatives, usually during the first 6 months of treatment.
Valproate may produce teratogenic effects in the offspring of women receiving the drug during pregnancy. Benefits of Depakote should be weighed against the risk of injury to the fetus in women of child-bearing potential.
Cases of life-threatening pancreatitis, some rapidly progressing to death, have been reported in both adults and children receiving valproate. Valproate is contraindicated in patients with known urea cycle disorders, a group of uncommon genetic abnormalities, because of reports of sometimes fatal cases of hyperammonemic encephalopathy. Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy.
The frequency of adverse effects, particularly elevated liver enzyme levels and thrombocytopenia, may be dose related. Multiorgan hypersensitivity reactions have been reported after the initiation of valproate therapy. In a clinical trial of valproate administered to elderly patients with dementia, some patients taking valproate experienced somnolence, sometimes requiring discontinuation of the drug.
Common adverse events (>5% incidence) associated with Depakote ER or Depakote in clinical studies of patients with acute mania were somnolence, dyspepsia, nausea, vomiting, diarrhea, dizziness, pain, abdominal pain, accidental injury, asthenia, and pharyngitis.
For more details on Depakote and Depakote ER, including full prescribing information, visit depakote.com or call 1-800-633-9110.
November 30, 2005
ST. LOUIS (MD Consult) - Bayer HealthCare announced on November 30, 2005, that the US Food and Drug Administration (FDA) has approved its quinolone antibiotic Avelox (moxifloxacin) for the treatment of complicated intra-abdominal infection (cIAI). This news comes 6 months after the agency approved Avelox in complicated skin and skin structure infections and represents a further broadening of Avelox's key indications beyond respiratory tract infections.
Avelox is now the only promoted fluoroquinolone monotherapy approved by the FDA for the treatment of cIAI.
Intra-abdominal infections can be caused by conditions such as trauma, intra-abdominal surgery, or other diseases that result in spillage or spread of bacteria from the gastrointestinal tract into the abdomen. There are approximately 3.5 million cases each year in the United States.
Clinical trials demonstrated that sequential intravenous (IV) to oral Avelox therapy given once daily was as effective as IV piperacillin/tazobactam given 4 times daily followed by oral amoxicillin/clavulanic acid twice daily. A second study compared Avelox with IV ceftriaxone plus metronidazole followed by oral amoxicillin/clavulanic acid. Avelox was effective at eradicating the key pathogens in cases of cIAI including Escherichia coli and Bacteroides fragilis.
In the United States, Avelox is approved to treat acute exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired pneumonia, complicated and uncomplicated skin and skin structure infections, and cIAI. US marketing is handled by Bayer's partner Schering-Plough Corporation.
For more details, including prescribing information and indicated organisms, visit avelox.com or send an email to global.avelox@bayer.com.
November 22, 2005
ST. LOUIS (MD Consult) - On November 18, 2005, the US Food and Drug Administration (FDA) approved Effexor XR (venlafaxine hydrochloride) for the treatment of panic disorder in adults. According to Wyeth, the drug's manufacturer, this marks the first antidepressant approval for panic disorder since 2002.
Panic disorder affects 2.4 million American adults annually. It is characterized by recurrent, unexpected panic attacks; that is, a discrete period of intense fear or discomfort in the absence of real danger, where 4 of 13 specific symptoms such as accelerated heart rate, shortness of breath, trembling, or fear of dying develop abruptly, reach a peak within 10 minutes, and are followed by at least 1 month of persistent concern about having another panic attack. In one study, less than 20% of persons with panic disorder were diagnosed and treated to remission. Because this disorder is under-recognized and not always treated to remission, patients are likely to experience a chronic and cyclical course of symptoms.
The efficacy of Effexor XR as a treatment for panic disorder was established in 2 double-blind, 12-week, placebo-controlled studies. Adult patients received fixed doses of 75 or 150 mg/d in one study and 75 or 225 mg/d in the other. In these studies, Effexor XR was significantly more effective than placebo at all 3 doses.
In a long-term (26-week), double-blind study, adult patients who had responded to Effexor XR (75-225 mg/d) during an initial 12-week open-label phase were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for a 6-month double-blind treatment phase. Patients who continued to receive Effexor XR experienced a significantly longer time to relapse compared with those patients who were switched to placebo.
Panic disorder may be associated with conditions such as depression or other anxiety disorders. Effexor XR, a serotonin-norepinephrine reuptake inhibitor, is indicated not only for panic disorder but also for the treatment of major depressive disorder, generalized anxiety disorder, or social anxiety disorder in adults.
Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. Anyone considering the use of Effexor XR or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients.
Effexor XR is contraindicated in patients taking monoamine oxidase inhibitors. Adult and pediatric patients taking antidepressants can experience worsening of their depression or the emergence of suicidality. Patients should be observed closely for clinical worsening and suicidality, especially at the beginning of drug therapy or at the time of increases or decreases in dose. Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania have been reported and may represent precursors to emerging suicidality. Stopping or modifying therapy should be considered especially when symptoms are severe, abrupt in onset, or not part of presenting symptoms.
Treatment with venlafaxine is associated with sustained increases in blood pressure in some patients. Preexisting hypertension should be controlled. Regular blood pressure monitoring is recommended. Abrupt discontinuation or dose reduction has been associated with discontinuation symptoms. Patients should be counseled on possible discontinuation symptoms and should be monitored while discontinuing the drug; the dose should be tapered gradually.
The most common adverse events reported in Effexor XR short-term placebo-controlled depression, generalized anxiety disorder, or social anxiety disorder trials (incidence, ≥10% and at least twice that of placebo) were anorexia, asthenia, constipation, dizziness, dry mouth, ejaculation problems, impotence, insomnia, nausea, nervousness, somnolence, and sweating.
Full prescribing information for Effexor XR is available at effexorxr.com.
November 9, 2005
ST. LOUIS (MD Consult) - On November 2, 2005, OSI Pharmaceuticals, Inc, and Genentech, Inc, announced that the US Food and Drug Administration (FDA) has approved Tarceva (erlotinib) in combination with gemcitabine chemotherapy for the treatment of advanced pancreatic cancer in patients who have not received previous chemotherapy. Tarceva is the first drug in a phase III trial to have shown a significant improvement in overall survival when added to gemcitabine chemotherapy as initial treatment for pancreatic cancer.
The FDA based its decision for Tarceva on results from a randomized double-blind, placebo-controlled phase III clinical study of Tarceva, in combination with gemcitabine chemotherapy, in patients with unresectable locally advanced or metastatic pancreatic cancer. The study met its primary end point of improving overall survival rates. Compared with gemcitabine plus placebo, those patients receiving gemcitabine plus 100 mg/d of Tarceva demonstrated a statistically significant (23%) improvement in overall survival rates (hazard ratio, 0.81; P = .028). After 1 year, 24% of patients receiving Tarceva plus gemcitabine were alive compared with 19% of patients receiving gemcitabine plus placebo. A statistically significant improvement in progression-free survival (hazard ratio, 0.76; P = .006) also was demonstrated. Although no difference in tumor response was observed (8.6% in patients receiving Tarceva plus gemcitabine vs 7.9% in the gemcitabine plus placebo arm), the disease control rate (complete response + partial response + stable disease) was significantly improved (59% in patients receiving Tarceva plus gemcitabine vs 49% in the gemcitabine plus placebo arm, P = .036). The global study was conducted by the National Cancer Institute of Canada in collaboration with OSI Pharmaceuticals.
Gabe Leung, President of Oncology at OSI Pharmaceuticals, stated that Tarceva is the first therapy approved by the FDA in the last 9 years that demonstrates an improvement in overall survival of pancreatic cancer.
The drugmakers boast a well-established safety profile for Tarceva. In the phase III study in pancreatic cancer, the most common adverse events reported were fatigue, rash, nausea, anorexia, and diarrhea. Rash was reported in 69% of patients who received Tarceva plus gemcitabine and in 30% of patients who received gemcitabine plus placebo. Diarrhea was reported in 48% of patients who received Tarceva plus gemcitabine and in 36% of patients who received gemcitabine plus placebo. Two percent of the patients discontinued use of Tarceva because of rash and 2% because of diarrhea. In addition, severe and potential fatal adverse events included interstitial lung disease–like complications, myocardial infarction or ischemia, cerebrovascular accident, and microangiopathic hemolytic anemia with thrombocytopenia.
Tarceva is a once-daily oral tablet already approved for use in the treatment of non–small cell lung cancer for those patients whose disease has progressed after 1 or more courses of chemotherapy. The drug is a small molecule designed to target the human epidermal growth factor receptor 1 (EGFR/HER1) pathway, which is one of the factors critical to cell growth in a number of different cancer types. EGFR/HER1 is a component of the HER signaling pathway, which plays a role in the formation and growth of numerous cancers. The medication is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell, which may block tumor cell growth. Tarceva is the only EGFR therapy to show in a phase III trial improved survival for patients with advanced non–small cell lung cancer. Additional early-stage trials of the drug are being conducted in other solid tumors.
Pancreatic cancer has the highest 1-year mortality rate of any cancer. The average life expectancy for a patient diagnosed with metastatic pancreatic cancer is 3 to 6 months, according to The Pancreatic Cancer Action Network (PanCAN), a national patient advocacy organization for the pancreatic cancer community.
According to the World Health Organization, more than 216,000 people worldwide are diagnosed each year with pancreatic cancer. The American Cancer Society predicts that in 2005 about 32,180 people in the United States will be diagnosed with pancreatic cancer and about 31,800 will die of the disease. Although pancreatic cancer accounts for 2% of new cancer cases in the United States, it is the fourth leading cause of all cancer deaths. Most pancreatic tumors originate in the exocrine duct cells or in the cells that produce digestive enzymes. Adenocarcinomas account for nearly 95% of pancreatic cancers.
For full prescribing information on Tarceva, call 1-877-TARCEVA or visit tarceva.com.
November 1, 2005
ST. LOUIS (MD Consult) - The US Food and Drug Administration announced on October 28, 2005, that it has approved a new formulation of Kaletra (lopinavir/ritonavir). The drug is now available as a film-coated tablet (200 mg/50 mg) that provides advantages over the currently marketed capsule formulation for HIV-1–infected patients.
Specifically, the tablet formulation:
Additions and revisions were made to the Kaletra package insert to reflect the new approval. The Clinical Pharmacology section contains the following additions:
| Pharmacokinetics
Plasma concentrations of lopinavir and ritonavir after administration of two 200/50-mg Kaletra tablets are similar to three 133.3/33.3-mg Kaletra capsules under fed conditions with less pharmacokinetic variability. Effects of Food on Oral Absorption Kaletra Tablets No clinically significant changes in Cmax [peak concentration] and AUC [area under the curve] were observed following administration of Kaletra tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of Kaletra tablets with a moderate-fat meal (500-682 Kcal, 23% to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of Kaletra tablets with a high-fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9%, but not Cmax. Therefore, Kaletra tablets may be taken with or without food. |
In addition, under the Drug-drug Interactions heading of the Clinical Pharmacology section, Tables 2 and 3 were updated to clarify which formulations of Kaletra (capsule, oral solution, or tablets) were used in the drug-drug interaction studies. Results of the drug-drug interaction study between efavirenz and Kaletra tablets were included.
The following text was added or revised in the Precaution: Information for Patients section:
| Kaletra tablets can be taken at the same time as didanosine without food. Patients taking didanosine should take didanosine 1 hour before or 2 hours after Kaletra oral solution.
Kaletra tablets may be taken with or without food. Kaletra oral solution should be taken with food to enhance absorption. |
Also in the Precaution section, Table 10 ("Established and Other Potentially Significant Drug Interactions") was revised to include the following:
|
The Dosage and Administration sections of the Kaletra package insert was revised to include the following information regarding the new tablet formulation:
The recommended oral dose of Kaletra is as follows (please refer also to Indications and Usage and Adverse Reactions): Adults Therapy-Naive Patients
Therapy-Experienced Patients
Once-daily administration of Kaletra is not recommended in therapy-experienced patients. Concomitant Therapy: Efavirenz, Nevirapine, Fosamprenavir, or Nelfinavir
Increasing the dose of Kaletra tablets to 600/150 mg (3 tablets) twice daily coadministered with efavirenz significantly increased the lopinavir plasma concentrations approximately 35% and ritonavir concentrations approximately 56% to 92% compared to Kaletra tablets 400/100 mg twice daily without efavirenz (see Clinical Pharmacology: Drug-drug Interactions, Table 2 and/or Precautions, Table 10). Kaletra tablets and oral solution should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir, or nelfinavir. |
Finally, the How Supplied section was revised to include storage information for the Kaletra tablets as follows:
| Recommended storage: Store Kaletra film-coated tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Dispense in original container. For patient use: exposure of this product to high humidity outside the original container for longer than 2 weeks is not recommended. |
Kaletra is a product of Abbott Laboratories. The capsule formulation will be phased out over time by the company. The original formulation was approved on September 15, 2000.
October 17, 2005
ST. LOUIS (MD Consult) - On September 15, 2005, biotechnology company Amgen announced that the US Food and Drug Administration (FDA) has approved an update to the Neulasta (pegfilgrastim) prescribing information to include data from a landmark phase 3 study. This trial demonstrated that the white blood cell booster helps protect patients with most types of cancer undergoing moderately myelosuppressive chemotherapy from infection, as manifested by febrile neutropenia, one of the most serious adverse effects of chemotherapy.
Previously, first- and subsequent-cycle administration of Neulasta to stimulate production of infection-fighting white blood cells was indicated for patients receiving myelosuppressive chemotherapy associated with a more than 30% to 40% risk of febrile neutropenia. Administration of Neulasta beginning in the first cycle of chemotherapy is now approved for patients receiving myelosuppressive chemotherapy associated with at least a 17% risk of febrile neutropenia. Myelosuppressive chemotherapy is toxic to the bone marrow where white blood cells, red blood cells, and platelets are produced.
The expanded label was based on a randomized, placebo-controlled study of 928 patients with metastatic or nonmetastatic breast cancer that was published in Journal of Clinical Oncology earlier this year. Compared with placebo, first- and subsequent-cycle administration of Neulasta resulted in a 94% reduction in the incidence of febrile neutropenia (1% vs 17% with placebo), a 93% reduction in the incidence of hospitalization (1% vs 14%), and an 80% reduction in the incidence of intravenous anti-infective use (2% vs 10%) in patients receiving moderately myelosuppressive chemotherapy.
"Approximately two thirds of neutropenic complications happen in the first cycle of chemotherapy," said study lead investigator Charles Vogel, MD, Cancer Research Network, Plantation, Fla. "This study demonstrates that administering Neulasta beginning in the first cycle of chemotherapy reduces the chance of patients developing an infection."
Neutropenia is an abnormally low level of neutrophils, important infection-fighting white blood cells, in the bloodstream. Neutropenia can put some patients at risk for severe infections and interruptions in cancer treatment. In fact, complications associated with a low white blood cell count are a common cause of dose reductions or delays in chemotherapy.
Febrile neutropenia is the most common presentation of infection in patients receiving chemotherapy. Infection in this setting can be serious and even life threatening because chemotherapy can compromise the patient's ability to fight infection.
Although white blood cell boosters have been available for more than a decade, only 17% of patients receiving myelosuppressive chemotherapy currently receive proactive first-cycle protection from neutropenic complications, which include infection, hospitalization, and anti-infective use. Approximately half of the 1.3 million patients receiving chemotherapy are at risk for developing neutropenia.
Neulasta was approved by the FDA in 2002 for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.
Rare cases of splenic rupture and sickle cell crises have been reported in postmarketing experience. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing antiallergic treatment.
In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta-treated patients compared with placebo-treated patients (31% vs 26%). The most common adverse events reported in either active or placebo-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain. Although not reported in patients receiving Neulasta, rare events of adult respiratory distress syndrome have been reported in patients receiving the parent compound, filgrastim.
Full prescribing information for Neulasta is available at NEULASTA.com or via fax by calling 1-800-772-6436. Consumers can call 1-866-611-3784 for more information.
October 17, 2005
ST. LOUIS (MD Consult) - Centocor, Inc, announced on September 16, 2005, that Remicade (infliximab) has been approved by the US Food and Drug Administration for the treatment of ulcerative colitis. This approval makes the drug the first and only biologic agent approved to treat ulcerative colitis, a chronic inflammatory bowel disease (IBD).
Remicade is now indicated for reducing signs and symptoms, achieving clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. Before this approval, no therapy had ever been indicated for mucosal healing and eliminating the use of corticosteroids.
"Not only did many patients in clinical trials experience a significant reduction in the occurrence of symptom flare-ups with Remicade, some achieved clinical remission and mucosal healing as well," said William J. Sandborn, MD, professor of medicine, Mayo Clinic College of Medicine and head of the IBD Interest Group and director of the IBD Clinical Research Unit at Mayo Medical Center. "This is welcome news for these patients whose only option otherwise may have been surgery to remove their colons."
Remicade's efficacy in the treatment of IBD is well established. First approved in the United States for the treatment of Crohn's disease in 1998, Remicade remains the only anti–tumor necrosis factor alpha (TNF-alpha) therapy indicated for the treatment of Crohn's disease. With this new approval for the treatment of ulcerative colitis, Remicade is now the only biologic agent indicated for the treatment of both types of IBDs, Crohn's disease and ulcerative colitis.
In addition to ulcerative colitis and Crohn's disease, Remicade is indicated for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.
Ulcerative colitis is an incurable, debilitating chronic disease affecting more than 500,000 Americans. But although ulcerative colitis affects more persons in the United States than multiple sclerosis or cystic fibrosis, general awareness of this disease is lower. Characterized by inflammation and ulceration of the inner lining of the colon, ulcerative colitis symptoms can often include unwanted weight loss, severe and sometimes uncontrollable bloody diarrhea, fatigue, and frequent abdominal pain. For some patients, symptoms may lead to surgical removal of the colon or to secondary complications such as colorectal cancer.
"Results from a recent patient survey revealed that ulcerative colitis affects many aspects of people's lives, from their relationships with families and employers to the ability to participate in social activities," said Rodger DeRose, president and CEO of the Crohn's & Colitis Foundation of America.
The new approval of Remicade is based on positive results seen in 2 randomized, placebo-controlled pivotal phase 3 clinical trials, ACT 1 and ACT 2, which were conducted to evaluate the safety and efficacy of Remicade in people with active, moderate to severe ulcerative colitis. Each trial enrolled 364 patients with active ulcerative colitis who were unresponsive to at least 1 standard therapy, including corticosteroids, immunosuppressants, or 5-aminosalicylic acids. Patients in ACT 1 and ACT 2 had evidence of moderate or severe ulcerative colitis (total Mayo score of 6 to 12 and an endoscopy score > 2). In both trials, patients were randomly assigned to receive placebo or Remicade (5 or 10 mg/kg). ACT 1 patients received the study agent at weeks 0, 2, and 6 and then every 8 weeks through week 46 and had their last evaluations at week 54. Patients in the ACT 2 study received the study agent at weeks 0, 2, and 6 and then every 8 weeks through week 22 and had their last evaluations at week 30.
In ACT 1, significantly higher proportions of patients receiving 5 mg/kg (69%) and 10 mg/kg (62%) of Remicade achieved clinical response at week 8 versus placebo-treated patients (37%; P < .001 for both). In addition, at week 30, 52% of patients in the group receiving 5 mg/kg of Remicade and 51% of patients in the group receiving 10 mg/kg were in clinical response versus 30% of placebo-treated patients (P < .001 and P < .01, respectively). At week 8, 39% and 32% of patients treated with Remicade 5 and 10 mg/kg, respectively, were in clinical remission compared with 15% of placebo-treated patients (P < .001 and P < .01, respectively). These differences in remission rates persisted at week 30 (34% for 5 mg/kg and 37% for 10 mg/kg versus 16% for placebo; P < .001 for both). Mucosal healing was achieved at week 8 in 62% and 59% of patients receiving Remicade 5 and 10 mg/kg, respectively, versus 34% of placebo-treated patients (P < .001). This difference in mucosal healing was maintained at week 30 (50% for 5 mg/kg and 49% for 10 mg/kg versus 25% for placebo; P < .001 for both). The proportion of patients who were able to discontinue treatment with corticosteroids while in clinical remission at week 30 was greater in both Remicade groups compared with the placebo group (24% for 5 mg/kg, 19% for 10 mg/kg, 10% for placebo; P = .030 and P = .125, respectively).
In ACT 2, significantly higher proportions of patients receiving 5 mg/kg (65%) and 10 mg/kg (69%) of Remicade were in clinical response at week 8 versus 29% who received placebo (P < .001 for both). At week 30, 47% of patients receiving Remicade 5 mg/kg and 60% receiving 10 mg/kg were in clinical response versus 26% of patients receiving placebo (P < .001 for both). Clinical remission was achieved at week 8 in 34% and 28% of Remicade 5 and 10 mg/kg patients, respectively, compared with 6% of placebo-treated patients (P < .001 for both). Differences in remission rates persisted at week 30 (26%, 5 mg/kg; 36%, 10 mg/kg; 11%, placebo; P < .01 and P < .001). Mucosal healing was achieved at week 8 in 60% and 62% of patients receiving Remicade 5 mg/kg and 10 mg/kg, respectively, compared with 31% of placebo-treated patients (P < .001 for both). Mucosal healing at week 30 was achieved in 46% and 57% of patients receiving Remicade 5 and 10 mg/kg, respectively, compared with 30% of placebo-treated patients (P < .01 and P < .001). The proportion of patients who were able to discontinue taking corticosteroids while in clinical remission at week 30 was significantly greater in both Remicade groups compared with the placebo group (18%, 5 mg/kg; 27%, 10 mg/kg; 3%, placebo; P = .010 and P < .001, respectively).
In the United States, Remicade, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Remicade is the only biologic agent indicated for the treatment of patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. Remicade is also indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn's disease. In December 2004, Remicade was approved for the treatment of active ankylosing spondylitis in the United States. On May 13, 2005, Remicade was approved for the treatment of psoriatic arthritis.
Unlike self-administered therapies that require patients to inject themselves frequently, Remicade is the only anti-TNF biologic agent administered directly by caregivers in the clinic or office setting. In cases of rheumatoid arthritis and Crohn's disease, Remicade is administered as a 2-hour infusion given every 8 weeks, following a standard induction regimen that requires treatment at weeks 0, 2, and 6. As a result, patients taking Remicade may require as few as 6 treatments each year. When used in the treatment of ankylosing spondylitis, Remicade is given as a 2-hour infusion (5 mg/kg) administered every 6 weeks, following a standard induction regimen that requires treatment at weeks 0, 2, and 6. The safety and efficacy of Remicade have been well established in clinical trials over the past 12 years.
Many persons with heart failure should not take Remicade; before treatment, patients should discuss any heart conditions they have with their doctors. Patients should notify their physicians immediately if new or worsening symptoms of heart failure (eg, shortness of breath or swelling of the ankles or feet) are experienced.
There have been reports of serious infections, including tuberculosis, sepsis, and pneumonia among persons taking Remicade. Some of these infections have been fatal. Patients should notify their doctors of recent or past exposure to persons with tuberculosis, and a skin test and evaluation for tuberculosis will be administered. If a patient has latent tuberculosis, his or her doctor should begin tuberculosis treatment before beginning the administration of Remicade. Remicade can lower a person's ability to fight infections, so if a patient is prone to or has a history of infections or develops any signs of an infection such as fever, fatigue, cough, or influenza while taking Remicade, he or she should notify a physician immediately. Also, patients should tell their doctors if they have lived in a region where histoplasmosis or coccidioidomycosis is common.
There have been rare cases of serious liver injury in persons taking Remicade, some of which have been fatal. Symptoms such as jaundice, dark brown urine, right-sided abdominal pain, fever, or severe fatigue should be reported to a physician.
Blood disorders have been reported among persons taking this medication, and some of these have been fatal. Possible signs of blood disorders include persistent fever, bruising, bleeding, or paleness, and these should be reported to a physician if experienced while taking Remicade. Nervous system disorders have also been reported; patients should tell their doctors if they have or have had a disease that affects the nervous system or if they experience any numbness, weakness, tingling, or visual disturbances while taking Remicade.
Reports of lymphoma in patients taking Remicade and other TNF blockers are rare but occur more often than in the general population. Patients should notify their doctors if they have or have had cancer. Persons who have been treated for rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, or psoriatic arthritis for a long time, particularly those with highly active disease, may be more prone to develop lymphoma. Cancers other than lymphoma have also been reported. Patients should be informed that their risk of developing lymphoma or other cancers may increase if they take Remicade or other TNF blockers.
Serious infusion reactions have been reported in association with Remicade, including hives, difficulty breathing, and low blood pressure. Reactions have occurred during or after infusions. In clinical studies, some persons experienced the following common side effects: respiratory infections (that may include sinus infections and sore throat), coughing, stomach pain, or mild reactions to infusion such as rash or itchy skin.
More details about Remicade, including full prescribing information, is available at remicade.com.
October 6, 2005
ST. LOUIS (MD Consult) - Pfizer Inc announced on October 5, 2005, that it has received approval from the US Food and Drug Administration to market its aromatase inhibitor Aromasin (exemestane tablets) to postmenopausal women with early breast cancer. The drug is now indicated for use as adjuvant treatment of breast cancer after the completion of 2 to 3 years of tamoxifen therapy, leading to a total of 5 consecutive years of adjuvant hormonal therapy. Aromasin was previously approved in the United States late in 1999 for the treatment of advanced breast cancer in postmenopausal women whose tumors have stopped responding to tamoxifen.
The approval was based on the results of the Intergroup Exemestane Study. In this study, patients who switched to Aromasin after 2 to 3 years of treatment with tamoxifen, for a combined total of 5 years of therapy, had 31% more protection from cancer recurrence than those who contined to take tamoxifen for 5 years.
This landmark study, published in The New England Journal of Medicine, established the superiority of switching to Aromasin rather than remaining on tamoxifen. After its publication, the American Society of Clinical Oncologists and the National Comprehensive Cancer Network updated their guidelines to support the use of a new switch-regimen using Aromasin adjuvant treatment.
The Intergroup Exemestane Study trial involved over 4,700 postmenopausal women with estrogen-receptor–positive breast cancer who were followed up for an average of 35 months. Patients receiving Aromasin experienced a significant reduction in the risk for recurrence of the disease, compared with those continuing to take tamoxifen. This reduction includes fewer local and distant tumors as well as new cancers in the other breast.
The most common adverse effects associated with Aromasin, which were mild to moderate, include hot flashes (21.2%), fatigue (16.1%), and arthalgia/bone pain (14.6%). Aromasin should not be administered to premenopausal women or women who are pregnant. Dose modifications should be considered for patients taking concomitant CYP3A4 inducers.
Breast cancer is one of the most common cancers occurring in women and the second leading cause of death from cancer in women, after lung cancer.
More information on this medication is available at aromasin.com. For full prescribing information, visit pfizer.com/pfizer/download/uspi_aromasin.pdf.
October 5, 2005
ST. LOUIS (MD Consult) - On October 4, 2005, Abbott announced that the US Food and Drug Administration (FDA) has approved Humira (adalimumab) for two new indications: (1) for first-line treatment of recent-onset moderate to severe rheumatoid arthritis (RA), and (2) for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis.
Rheumatoid Arthritis
The approval for the expanded RA indication is based on clinical and radiographic data from the 2-year PREMIER study of 799 methotrexate (MTX)-naive patients with active recent-onset moderate to severe RA (defined as disease of less than 3 years' duration). On average, patients had less than 9 months of disease duration from the time of diagnosis. The trial compared 3 arms—Humira monotherapy, MTX monotherapy, and the 2 drugs combined. The study showed Humira in combination with MTX was superior to MTX alone on several efficacy end points, including the 2 primary end points (inhibition of joint damage and improvement in signs and symptoms at 1 year) and a secondary end point (achievement of clinical remission measure of Disease Activity Score [DAS] 28 < 2.6 at 1 year). The DAS measures disease activity responses in RA by assessing tender and swollen joint count, general health status, and an inflammatory marker.
The PREMIER study showed patients taking Humira in combination with MTX experienced significantly less joint damage than those taking MTX alone, as measured by the change in modified Total Sharp Score (mTSS). The mTSS assesses bone erosion and joint space narrowing on radiographs. A smaller change in mTSS reflects less progression of joint damage. Also, approximately twice as many patients taking the Humira-MTX regimen experienced no further joint destruction compared with those taking MTX alone (61% vs 34%) after 2 years. No joint destruction was defined as ≤0.5 units change from baseline in mTSS. After 1 year, patients taking MTX alone had 4 times the disease progression as those taking the Humira-MTX regimen, with mean changes in mTSS of 5.7 and 1.3, respectively, and after 2 years the patients taking MTX alone had 5 times more disease progression than those taking the Humira-MTX regimen, with mean changes in mTSS of 10.4 and 1.9, respectively.
PREMIER is the first RA trial to include, as a primary end point, the measurement of ACR50 (a 50% or greater improvement in signs and symptoms of RA, as defined by the American College of Rheumatology [ACR]). ACR scores measure the percentage of improvement in tender and swollen joint count and several other clinical measures. In this trial, Humira in combination with MTX significantly improved the signs and symptoms of RA. After 1 year, 62% of patients taking the Humira-MTX regimen achieved ACR50 compared with 46% of those taking MTX alone and 41% taking Humira alone. After 2 years, 59% of patients taking the Humira-MTX regimen achieved ACR50 compared with 43% taking MTX alone and 37% taking Humira alone.
Forty-three percent of patients taking the Humira-MTX regimen achieved a measure of clinical remission as defined by DAS28 < 2.6 at 1 year versus 21% of patients taking MTX only, and nearly 1 in 2 patients receiving the combination therapy achieved clinical remission at 2 years compared with 1 in 4 patients taking MTX alone (49% vs 25%). Additionally, almost half of patients receiving the Humira-MTX regimen achieved major clinical response, defined as achieving and maintaining an ACR70 response for 6 or more continuous months, compared with MTX alone (49% vs 28%). Also, 27% of patients on the Humira-MTX regimen achieved ACR90 at 2 years, a 90% or greater improvement in signs and symptoms, compared with 13% of those taking MTX alone.
In the PREMIER trial, all treatment arms had a comparable overall rate of adverse events. Among patients taking Humira, the most common adverse events were nasopharyngitis, headache, nausea, diarrhea, joint pain, and pharyngitis.
More than 5 million persons worldwide have RA, a chronic autoimmune disease that causes pain, swelling, and stiffness in the joints of the hands, feet, and wrists and often leads to the destruction of joints. Unlike osteoarthritis, the most common form of arthritis, RA is an autoimmune disease in which joints are inflamed, potentially resulting in destruction of the joints' interior and the surrounding bone.
Psoriatic Arthritis
The FDA approval of Humira for patients with psoriatic arthritis is based on results of the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), which is the largest biologic trial in psoriatic arthritis. ADEPT studied 313 adult patients with moderately to severely active psoriatic arthritis who had an inadequate response to nonsteroidal anti-inflammatory drug therapy. Patients taking Humira experienced significantly greater improvement in both joint and skin disease symptoms than placebo-treated patients at 24 weeks. Improvements in both skin lesions and joint symptoms were seen as early as 2 weeks after initiation of treatment and continued to improve over time.
Patients' arthritic symptoms also responded to Humira, with nearly 60% of patients achieving ACR20 at week 12, 1 of the study's primary end points, and with a sustained response through week 24. ACR70, a more stringent response criterion, was achieved by nearly 25% of patients treated with Humira versus 1% of patients treated with placebo at week 24.
Clinical trial data from ADEPT showed the ability of Humira to improve both the skin and joint symptoms associated with psoriatic arthritis. Among the 69 patients in the trial who had skin lesions involving more than 3% body surface area and were treated with Humira, 3 of 4 (75%) achieved a Psoriasis Area and Severity Index (PASI) score of 50, approximately 3 of 5 (59%) achieved a PASI score of 75, and approximately 2 of 5 (42%) achieved a PASI score of 90 at 24 weeks, which reflects at least 50%, 75%, or 90% improvement, respectively, in skin symptoms assessed by the PASI.
The recommended dose of Humira for psoriatic arthritis is 40 mg taken every other week by subcutaneous injection; this is also the usual dose used for Humira in the treatment of moderate to severe RA.
The rates of adverse events and serious adverse events in the ADEPT trial were comparable with other Humira RA clinical trials. Among patients taking Humira, the most common adverse events (affecting at least 5% of patients) were upper respiratory infection, nasopharyngitis, injection site reaction, headache, and hypertension. The safety profile of Humira in the ADEPT clinical trial was similar to that observed in the Humira RA clinical trials.
Abbott simultaneously submitted applications with the FDA and the European Medicines Agency seeking approval to market Humira to treat psoriatic arthritis and early moderate to severe RA in December 2004.
Psoriatic arthritis is a chronic disease that combines the symptoms of arthritis, including joint pain and inflammation, with those of psoriatic skin disease, such as dry, scaly skin. Psoriatic arthritis is a serious autoimmune disease, and few available treatment options address the combination of symptoms affecting both the skin and joints. Common symptoms of psoriatic arthritis include varying degrees of skin involvement along with stiffness, pain, swelling, and tenderness of the joints that can lead to a reduced range of motion and potential severe joint destruction.
Left untreated, psoriatic arthritis can be a progressively disabling disease. The arthritic manifestations often include debilitating disease of the hands and feet, as seen in RA, as well as painful inflammation of the tendon insertions and arthritis of the spine. Psoriatic arthritis is most often found in patients who have psoriasis, a chronic skin disease that affects nearly 3% of the world's population. It is estimated that up to 30% of persons with psoriasis also develop psoriatic arthritis.
Like RA, psoriatic arthritis is an autoimmune disorder in which a human protein, tumor necrosis factor-alpha (TNF-α), has been suggested to play a role in disease development. Humira, which is a fully human monoclonal antibody that resembles antibodies normally found in the body, works by specifically blocking TNF-α.
Important Safety Information
Cases of tuberculosis have been observed in patients taking Humira. Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including Humira. Many of these infections occurred in patients also taking other immunosuppressive agents that, in addition to their underlying disease, could predispose them to infections. Treatment with Humira should not be initiated in patients with active infections. The combination of Humira and anakinra is not recommended.
TNF-blocking agents, including Humira, have been associated with rare cases with demyelinating disease and severe allergic reactions. Infrequent reports of serious blood disorders have been reported with TNF-blocking agents. More cases of malignancies have been observed among patients receiving TNF blockers, including Humira, compared with control patients in clinical trials. These malignancies, other than lymphoma and nonmelanoma skin cancer, were similar in type and number to what would be expected in the general population. There was an approximately 4-fold higher rate of lymphoma in combined controlled and uncontrolled open-label portions of Humira clinical trials. The potential role of TNF-blocking therapy in the development of malignancies is not known.
The most frequent adverse events seen in the placebo-controlled clinical trials in RA (Humira vs placebo) were injection site reactions (20% vs 14%), upper respiratory infection (17% vs 13%), injection site pain (12% vs 12%), headache (12% vs 8%), rash (12% vs 6%), and sinusitis (11% vs 9%). Discontinuations due to adverse events occurred in 7% of patients taking Humira and 4% of those taking placebo. As with any treatment program, the benefits and risks of Humira should be carefully considered before initiating therapy.
The safety profile for patients with psoriatic arthritis treated with Humira in the clinical trials has been similar to the safety profile seen in patients with RA.
Humira is the first fully human monoclonal antibody to be approved by the FDA for reducing the signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults with moderately to severely active RA. In 2002, HUMIRA was approved to treat patients with moderately to severely active RA, who have had insufficient response to one or more disease-modifying anti-rheumatic drugs (DMARDs). With the new FDA approval, Humira can be used alone or in combination with methotrexate or other DMARDs.
More information about Abbott Immunology and Humira, including full prescribing information, is available at rxabbott.com.
October 5, 2005
ST. LOUIS (MD Consult) - On September 28, 2005, the US Food and Drug Administration (FDA) approved a new indication for Emtriva (emtricitabine). The medication, in combination with other antiretroviral agents, is now approved for the treatment of human immunodeficiency virus-1 infection in patients older than 3 months.
In addition, the FDA also approved Emtriva oral solution 10 mg/mL. The approval of this new formulation allows for dosing recommendations in pediatric patients.
The following changes to the label were made to reflect this new information:
To review the new label, please visit fda.gov/cder/foi/label/2005/021896lbl.pdf
September 28, 2005
ST. LOUIS (MD Consult) - On September 27, 2005, Pfizer Inc announced that the US Food and Drug Administration (FDA) has approved its cholesterol-lowering medicine Lipitor (atorvastatin calcium) to reduce the risk of stroke and heart attack in persons with type 2 diabetes without evidence of heart disease but with other risk factors. Lipitor also received approval to reduce the risk of stroke in persons without evidence of heart disease but with multiple risk factors other than diabetes. Common risk factors for heart disease include high cholesterol, high blood pressure, family history, age older than 55 years, smoking, diabetes, and obesity.
The FDA's decision was based on the findings of the Collaborative Atorvastatin Diabetes Study (CARDS), a landmark trial of more than 2,800 patients with type 2 diabetes, near normal cholesterol levels, and at least 1 other risk factor, such as high blood pressure or smoking. The study showed that patients taking Lipitor experienced nearly 50% fewer strokes than those taking placebo. The CARDS trial was stopped nearly 2 years earlier than planned by the study's Steering Committee because of the strong benefits among patients who took Lipitor.
The additional approval of Lipitor to reduce the risk of stroke in patients with multiple risk factors reflects findings from The Anglo-Scandinavian Cardiac Outcomes Trial: Lipid-Lowering Arm (ASCOT-LLA), another landmark trial that was also halted nearly 2 years earlier than planned. The trial found that Lipitor reduced the relative risk of stroke by 26% compared with placebo. The study involved more than 10,300 persons with normal or borderline cholesterol levels and no prior history of heart disease, but with controlled high blood pressure and at least 3 other risk factors for heart disease, such as family history, age older than 55 years, smoking, diabetes, and obesity.
Lipitor is used in patients with type 2 diabetes and one other risk factor such as high blood pressure, smoking, or other complications of diabetes, including eye disease and protein in urine, to reduce the risk of stroke and heart attack. The medication is not indicated for persons with liver problems, nor for women who are nursing, pregnant, or may become pregnant.
Patients taking Lipitor should notify their doctors if they feel any unusual muscle pain or weakness. This could be a sign of serious muscle side effects. Patients should tell their doctors about all of the medications they take; this may help avoid serious drug interactions. The most commonly encountered side effects are gas, constipation, stomach pain, and heartburn, and these tend to be mild and often of limited duration.
The American Heart Association (AHA) estimates that 700,000 Americans—or 1 person every 45 seconds—will experience a stroke in 2005. Stroke is more prevalent in adults age 65 and older, and the incidence of stroke continues to rise as age increases. According to the AHA, stroke is a leading cause of major disability in the United States. Direct (medical) and indirect (disability) costs related to stroke are anticipated to reach $57 billion in 2005.
The 2004 update to guidelines issued by the National Cholesterol Education Program confirms the added benefit of prescribing cholesterol-lowering medication, along with diet modification and exercise, to patients at risk for cardiovascular disease.
More than 18 million Americans have diabetes, which is a leading risk factor for cardiovascular disease. The majority of persons with diabetes (roughly 65%) will suffer a heart attack or stroke, a rate that is up to 4 times higher than in adults without diabetes. According to the American Diabetes Association–recommended treatment guidelines, adults with type 2 diabetes should be considered for statin therapy regardless of their low-density lipoprotein levels.
For additional information about Lipitor, visit lipitor.com or call 1-888-LIPITOR.
September 7, 2005
ST. LOUIS (MD Consult) - On September 6, 2005, Paris-based pharmaceutical company Sanofi-aventis announced that the US Food and Drug Administration has approved Ambien CR (zolpidem tartrate extended-release tablets) C(IV), a new formulation of the prescription sleep aid Ambien (zolpidem tartrate) CIV, for the treatment of insomnia. Ambien CR is a non-narcotic non-benzodiazepine and is formulated to offer a similar safety profile to Ambien with a new indication for sleep maintenance, in addition to sleep induction.
According to its manufacturer, Ambien CR is the first extended-release prescription sleep medication to help persons with insomnia fall asleep fast and maintain sleep with no significant decrease in next-day performance. Ambien CR, a bi-layered tablet, is delivered in 2 stages. The first layer dissolves quickly to induce sleep, and the second layer is released more gradually into the body to help provide more continuous sleep.
"Insomnia is a significant public health problem, affecting millions of Americans. Insomnia impacts daily activities and is associated with increased health care costs," said James K. Walsh, PhD, Executive Director and Senior Scientist, Sleep Medicine and Research Center at St Luke's Hospital in St Louis, Mo. "Helping patients stay asleep is recognized as being as important as helping them fall asleep."
According to a recent National Sleep Foundation poll, more than one half (54%) of Americans said they experience at least 1 symptom of insomnia at least a few nights a week. Additionally, 1 in 5 adults experienced difficulty falling asleep and 1 in 3 reported waking often during the night at least a few nights a week.
For important safety and prescribing information, please view the FDA-approved product label at fda.gov/cder/foi/label/2005/021774lbl.pdf.
Ambien CR will be available in a 12.5-mg dose recommended for adults and a 6.25-mg dose recommended for elderly persons.
Sanofi-aventis Group subsidiaries in the United States include Sanofi-Synthelabo Inc, Aventis Pharmacuticals Inc, and Sanofi Pasteur Inc.
August 29, 2005
ST. LOUIS (MD Consult) - On August 19, 2005, pharmaceutical company Allergan, Inc, announced it has received approval from the US Food and Drug Administration (FDA) to market Alphagan P (brimonidine tartrate ophthalmic solution) 0.1%, indicated for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
The new product is an optimized formulation of Alphagan 0.2% and was developed to further minimize drug exposure while maintaining the drug's favorable efficacy profile.
In a clinical trial, Alphagan P ophthalmic solution 0.1% was proved to have IOP-lowering efficacy equivalent to Alphagan 0.2%, effectively lowering IOP in patients with open-angle glaucoma or ocular hypertension by approximately 2 to 6 mm Hg. Alphagan P 0.1% is contraindicated in patients receiving monoamine oxidase inhibitor therapy. The most frequently reported adverse events included allergic conjunctivitis, conjunctival hyperemia, and eye pruritus.
Full prescribing information for Alphagan P 0.1% can be found at Allergan.com.
Allergan, Inc, is headquartered in Irvine, Calif.
August 25, 2005
ST. LOUIS (MD Consult) - Solvay Pharmaceuticals, Inc, and CV Therapeutics, Inc, announced on August 23, 2005, that the US Food and Drug Administration has approved Aceon (perindopril erbumine) Tablets for patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction (MI). Aceon, an angiotensin-converting enzyme (ACE) inhibitor, is currently indicated for the treatment of essential hypertension.
ACE inhibitors act to reduce hypertension by interfering with the conversion of angiotensin I to artery-constricting angiotensin II. Blocking the production of angiotensin II results in arterial vasodilation and an accompanying reduction in blood pressure. ACE inhibitors are currently recommended as first-line therapy for the treatment of hypertension in certain patient populations because of their safety and efficacy. Most recently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure has recommended ACE inhibitors as one of the initial therapy choices for compelling comorbidities such as heart failure, postmyocardial infarction, high coronary disease risk, diabetes, chronic kidney disease, and recurrent stroke prevention.
Certain ACE inhibitors, including Aceon, have been shown to have an enhanced affinity for the tissues and are known as tissue-ACEs.
The new indication is based on the EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease (EUROPA). EUROPA was a multicenter, randomized, double-blind, placebo-controlled trial involving 12,218 patients with stable coronary disease and without heart failure, which assessed the ability of perindopril to reduce cardiovascular death, nonfatal MI, or cardiac arrest. Patients underwent a mean follow-up of 4.2 years.
In this study, in a broad population of patients with stable coronary artery disease, there was a 20% reduction in the combined end point of cardiovascular mortality, nonfatal MI, and cardiac arrest compared with placebo. This significant (P = .0003) reduction in relative risk was seen in patients receiving a treatment regimen of 8 mg of perindopril, including patients treated with conventional cardiovascular preventive therapy, such as aspirin, other anticoagulants, beta-blockers, and other antihypertensive therapy and lipid-lowering therapy, such as statins. Patients not randomly assigned to receive perindopril received placebo in addition to their conventional therapy.
In the EUROPA study, the 20% reduction in the risk of cardiovascular events with Aceon 8 mg was observed in a broad range of older and younger stable coronary artery disease patients with or without hypertension or previous MI, and including patients treated with a background of conventional therapies for the management of coronary artery disease.
Aceon offers continuous 24-hour blood pressure control with once-daily dosing. The medication may be used alone or with other classes of antihypertensive agents.
Aceon is contraindicated in patients known to be hypersensitive to this product or to any other ACE inhibitor and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. When used in pregnant patients during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Aceon should be discontinued as soon as possible.
In the EUROPA study, the overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent among patients taking perindopril than those taking placebo were cough, drug intolerance, and hypotension.
Aceon prescribing information is available at solvaypharmaceuticals-us.com/products.
In the United States, perindopril is co-promoted under the brand name Aceon by CV Therapeutics and Solvay Pharmaceuticals. CV Therapeutics is headquartered in Palo Alto, Calif, and Solvay Pharmaceuticals is based in Marietta, Ga, and is a subsidiary of Solvay Group, which is headquartered in Brussels, Belgium.
August 19, 2005
ST. LOUIS (MD Consult) - Merck & Co, Inc, announced on August 18, 2005, that the US Food and Drug Administration (FDA) has approved Singulair (montelukast sodium) for the relief of symptoms of perennial allergic rhinitis (PAR), also known as indoor allergies, in adults and children 6 months of age and older. A once-a-day tablet, Singulair has been proved to help relieve a broad range of indoor and outdoor allergy symptoms for up to 24 hours.
Allergic rhinitis, an inflammation of the mucous membranes of the nose due to allergens, is one of the most common allergic conditions in the United States, affecting approximately 50 million Americans. Allergic rhinitis is classified as either seasonal or perennial, depending on the type of trigger and the duration of symptoms. SAR symptoms occur in the spring, summer, and early fall and are triggered by outdoor allergens such as airborne tree, grass, and weed pollens, whereas PAR is usually persistent and chronic with symptoms occurring year-round and is commonly associated with indoor allergens such as dust mites, animal dander, and mold spores. Symptoms of allergic rhinitis may include runny nose, nasal itching, sneezing, watery eyes, and nasal congestion.
Approved for the treatment of the symptoms of seasonal allergic rhinitis (SAR) in 2003, Singulair is different from most oral allergy medications, which block histamine, in that it blocks leukotrienes. Leukotrienes are an important contributor to allergy symptoms, and Singulair is the only medication indicated for the treatment of allergic rhinitis that specifically targets this particular underlying contributor to allergy symptoms. The medication is approved to treat SAR in adults and children 2 years and older and for PAR in adults and children 6 months and older. For treatment of symptoms of allergic rhinitis, Singulair is available in tablet form for adults (10 mg), as a cherry-chewable tablet (4 or 5 mg) for children aged 2 to 14 years, and in oral granules (4 mg) for children aged 6 months to 5 years.
In separate clinical trials of PAR and SAR, Singulair (10 mg) has provided significantly greater symptom relief compared with placebo. The efficacy of Singulair for the treatment of PAR was evaluated in 2 randomized, double-blind, placebo-controlled studies in patients aged 15 to 82 years with PAR. In one of these studies, the drug demonstrated effectiveness in improving daytime nasal symptoms score, the primary end point, measured as the average of individual scores for nasal congestion, runny nose, and sneezing.
The efficacy of Singulair for the treatment of symptoms of SAR was previously established in placebo- and active-controlled clinical studies of patients aged 15 to 82 years. In these studies, the drug demonstrated effectiveness in improving daytime nasal symptoms score, the primary end point, measured as the average of individual scores for nasal congestion, runny nose, nasal itching, and sneezing.
In clinical studies for both SAR and PAR, Singulair was generally well tolerated with a safety profile similar to that of placebo for both children and adults. The incidence of sleepiness was similar to placebo in all studies for adults and adolescents 15 years of age and older with SAR and PAR. In these studies, the most frequently reported adverse effects included headache, ear infection, sore throat, and upper respiratory infection. These events varied by age and were reported at a frequency greater than or equal to 2%, and at an incidence greater than placebo in either the SAR or PAR studies.
Singulair is also indicated for the prevention and chronic treatment of asthma in adults and pediatric patients 12 months and older. The use of Singulair for asthma may not eliminate the need for inhaled or oral corticosteroids. Patients should be advised to take Singulair daily as prescribed even when they have no symptoms, as well as during periods of worsening asthma, and to contact their health care providers if their asthma is not well controlled. This medication should not be used for the fast relief of acute asthma attacks nor used alone to treat and manage asthma made worse by exercise. Patients with known aspirin sensitivity should continue avoidance of aspirin or nonsteroidal anti-inflammatory agents while taking Singulair.
In clinical studies for asthma, adverse effects in adults and children taking Singulair were usually mild and generally did not cause patients to discontinue therapy. The most commonly reported adverse effects varied by age and included headache, ear infection, sore throat, and upper respiratory infection.
For more information on Singulair and its manufacturer, visit merck.com.
August 17, 2005
ST. LOUIS (MD Consult) - On August 12, 2005, the US Food and Drug Administration (FDA) approved Actonel with Calcium (risedronate sodium tablets with calcium carbonate tablets), the first prescription osteoporosis therapy to include calcium.
Actonel with Calcium is a prescription therapy indicated for the prevention and treatment of postmenopausal osteoporosis. Both Actonel and Calcium decrease the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. Each package contains a 28-day course of therapy. Each week contains 7 tablets (one 35-mg once-a-week Actonel tablet and 6 tablets that each provide 500 mg of calcium). This new treatment option comes in light of the recent Surgeon General's Report on Bone Health and Osteoporosis, which emphasizes the need for osteoporosis regimens to be simplified and organized.
Calcium is a basic building block of bone and is essential for maintaining bone health. Despite this, 2 new surveys suggest that many women may not take enough calcium or may take it incorrectly with a bisphosphonate therapy like Actonel. According to a study conducted by Information Resources, Inc. (IRI), 73% of women who filled a bisphosphonate prescription purchased less than the equivalent of 1 calcium tablet per day. A second survey conducted by Harris Interactive revealed that 1 in 4 US women aged 50 years and over (26%) take calcium within 30 minutes of their bisphosphonate, which decreases the effectiveness of the bisphosphonate. Both surveys were conducted on behalf of The Alliance for Better Bone Health, which was formed in 1997 by Procter & Gamble Pharmaceuticals and Aventis Pharmaceuticals to promote bone health and disease awareness.
Harris Interactive, a Rochester, NY–based global research company, conducted the online and telephone survey between February 9 and 18, 2005, among 1,004 US women aged 50 years and over, of which 372 were bisphosphonate users. Data were weighted to be representative of the total US adult female population aged 50 years and over on the basis of age, race/ethnicity, education, region, income, and propensity to be online. Although the online sample is not a probability sample, with probability samples of this size, Harris Interactive estimates with 95% certainty that the overall results have a sampling error of ±3 percentage points. Sampling error for the various sub-sample results, including bisphosphonate users (372); bisphosphonate users who also take calcium supplements (338); and calcium supplement users (755), is higher and varies.
The study conducted by IRI analyzed calcium purchasing practices of current bisphosphonate users over a 1-year period. Four hundred ninety-eight households of women who filled a prescription for a bisphosphonate 1 year before and at least once during the current 52-week period were included in this study. Households were part of IRI's RxPulse Patient Panel, a subset of IRI's Consumer Network Panel, a nationally representative set of 70,000 households that scan all of their bar-coded purchases at home. Households within the RxPulse Patient Panel used scanning devices to record prescription information, including name of drug, strength and dose frequency, for each person in their households. Data for supplement purchases included brand, calcium content (mg), and total tablet count.
The panel provided a single source of data for bisphosphonate usage as well as total number of calcium supplement tablets (including Tums) purchased. Panel data are weighted to match US demographics, and aggregate claimed purchases are verified through a comparison to store level scanner data. For this study, the supplement category was specifically examined and confirmed to fit within standard limits.
"Osteoporosis is a serious, widespread and growing public health threat," said Judith Cranford, Director, National Osteoporosis Foundation. Osteoporosis affects millions of postmenopausal women, making their bones weak and more likely to fracture over time. In fact, in the United States today, 8 million women are estimated to already have osteoporosis, and almost 27 million more are estimated to have low bone mass, placing them at increased risk for fracture. Each year the incidence of osteoporosis-related fractures is greater than the incidence of heart attacks, strokes, and breast cancer combined. However, there are prescription medications available that effectively reduce both vertebral and nonvertebral fracture risk
When the body does not get enough calcium, it breaks down bone to help meet its calcium needs. According to the Surgeon General's Report on Bone Health and Osteoporosis, the average adult intake of calcium is approximately 700 mg daily, which is below the US recommended daily allowance of 1,200 mg for women over the age of 50 years. Many women who are taking a bisphosphonate may be able to make up this difference by taking a 500-mg calcium tablet, which is the amount of calcium found in Actonel with Calcium.
Calcium, whether from diet or supplements, is absorbed best by the body when it is taken in doses of 500 mg or less of elemental calcium at one time. Calcium should not be taken at the same time as a bisphosphonate; bisphosphonate effectiveness decreases if calcium is taken within 30 minutes of its own administration. Women should talk with their doctors about the bone health regimen that's right for them.
Actonel with Calcium is contraindicated in patients with known hypersensitivity to any component of this product or an inability to stand or sit upright for at least 30 minutes. Actonel tablets and calcium are contraindicated, respectively, in patients with hypocalcemia and hypercalcemia. These and other disturbances of bone and mineral metabolism should be effectively treated before starting Actonel with Calcium therapy. Actonel with Calcium is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). In patients with conditions causing or predisposing to hypercalcemia and in patients with a history of kidney stones, the administration of calcium should be assessed before prescribing and then should be monitored appropriately.
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer. Patients should pay particular attention to the dosing instructions because failure to take the drug according to instructions may compromise clinical benefits and may increase the risk of adverse events. Calcium may cause gastrointestinal adverse effects such as constipation, flatulence, nausea, abdominal pain, and bloating.
Among patients treated with bisphosphonates, there have been infrequent reports of severe and occasionally incapacitating bone, joint, or muscle pain. Rare occurrences of osteonecrosis, primarily of the jaw (ONJ), have been reported in patients receiving bisphosphonates. Most ONJ cases have occurred in patients with cancer who are undergoing dental procedures. In the majority of cases reported, patients had received intravenous bisphosphonate therapy.
In clinical trials, Actonel was generally well tolerated. The overall incidence of adverse events with Actonel 5 mg daily was comparable to placebo. The most commonly reported adverse events, regardless of causality, were infection (primarily upper respiratory; placebo 29.7% vs Actonel 5 mg 29.9%), back pain (23.6% vs 26.1%), and arthralgia (21.1% vs 23.7%).
In a 1-year clinical trial comparing Actonel 35 mg given once a week and Actonel 5 mg daily, the overall incidence of adverse events with the two dosing regimens was similar. The most commonly reported adverse events, regardless of causality, were infection (Actonel 35 mg 20.6% vs Actonel 5 mg 19.0%), arthralgia (14.2% vs 11.5%), and constipation (12.2% vs 12.5%).
For more information about Actonel with Calcium, visit actonel.com. The Actonel label, approved by the FDA on August 12, 2005, is available at fda.gov/cder/foi/label/2005/021823lbl.pdf.
August 16, 2005
ST. LOUIS (MD Consult) - Merck & Co, Inc, announced on August 15, 2005, that the US Food and Drug Administration has approved Vaqta (hepatitis A vaccine, inactivated) for use in children 12 months of age and older. Vaqta is the first hepatitis A vaccine indicated for use in children as young as 12 months of age. Previously, Vaqta was approved for use in persons 2 years of age and older.
"Surveillance data have shown that young children often transmit hepatitis A in the United States, but since they do not typically show symptoms, they unknowingly pass the infection on to older siblings and parents who can become very ill from hepatitis A," said Fernando Guerra, MD, MPH, director of Health, San Antonio Metropolitan Health District. The expanded indication for Vaqta provides an opportunity to guard against hepatitis A infection in children earlier in life.
Hepatitis A is a contagious disease caused by a virus that can result in an infection of the liver. Symptoms include jaundice, fever, abdominal pain, dark urine, and nausea. Signs and symptoms usually last less than 2 months, although 10% to 15% of symptomatic persons have prolonged or relapsing disease for up to 6 months. The virus is transmitted most frequently by the fecal-oral route through person-to-person contact and/or ingestion of contaminated food or water. The source of a case of hepatitis A is unknown in nearly half of all instances. There is no specific treatment available for the disease.
According to a Centers for Disease Control and Prevention report issued in September 2004, there were 8,795 reported cases of hepatitis A in 2002, down from an average of 28,000 cases per year from 1987 through 1997, before hepatitis A vaccines became widely used. Approximately 25% of hepatitis A cases reported in 2002 required hospitalization, and approximately 1 in 200 cases resulted in death.
The younger age indication for Vaqta is supported by the results of an open-label study of children with no evidence of hepatitis A infection. The study was designed to investigate the immunogenicity and safety of Vaqta in this age group when it was administered with and without other routinely used vaccines given at the same age.
In this study of 617 children 12 to 23 months of age, 343 children were evaluated for indicators of an immune response to Vaqta after the second dose of a 2-dose series. Of these children (n = 343), 100% developed protective immune responses. The study also showed that Vaqta may be given concomitantly with M-M-R II (measles, mumps, and rubella virus vaccine live), another Merck vaccine. The availability of data on concomitant use with other routinely recommended childhood vaccines is limited.
In combined clinical trials involving healthy children aged 12 to 23 months (n = 706) who received 1 or more doses (˜25 U) of Vaqta alone or in combination with other routinely recommended pediatric vaccines, the most commonly reported complaints (>2% of injections) after 1 or both of the doses of Vaqta included rash, cough, fever, diarrhea, vomiting, irritability, rhinorrhea, otitis media, upper respiratory infection, and localized injection-site reactions (eg, pain/tenderness/soreness).
Clinical trials involving healthy children 12 to 23 months of age and children and adolescents 2 to 18 years of age were also undertaken. In these studies, the most commonly reported complaints (>2% of injections) in one or both of these groups included rash, cough, warmth, fever, headache, diarrhea, vomiting, rhinorrhea, irritability, otitis media, upper respiratory infection, and localized injection-site reactions (eg, pain/tenderness/soreness, erythema, swelling).
In combined clinical trials involving healthy adults 19 years of age and older, the most commonly reported complaints (>2% of injections) were localized injection-site reactions (eg, tenderness, pain, warmth, swelling, and erythema), headache, asthenia/fatigue, fever, pharyngitis, upper respiratory infection, diarrhea, and nausea. As with any vaccine, there is the possibility that use of Vaqta in very large populations might reveal adverse experiences not observed in clinical trials.
Primary immunization with Vaqta should be given at least 2 weeks before expected exposure to hepatitis A virus. Persons 12 months through 18 years of age should receive a single 0.5-mL (˜25 U) dose of vaccine at an elected date and a booster dose of 0.5 mL (˜25 U) 6 to 18 months later. Adults older than 19 years of age should receive a single 1.0-mL (˜50 U) dose of vaccine at an elected date and a booster dose of 1.0 mL (˜50 U) 6 to 18 months later.
Vaqta is contraindicated in persons who are hypersensitive to any component of the vaccine. Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a prior dose of hepatitis A vaccine or to a vaccine component. As with any vaccine, vaccination with Vaqta may not result in a protective response in all people.
For details about the indications, contraindications, warnings, precautions, adverse reactions, and dosage and administration for Vaqta, please read the prescribing information available at merck.com/product/usa/pi_circulars/v/vaqta/vaqta_pi.pdf.
For more information about Merck, visit merck.com.
August 5, 2005
ST. LOUIS (MD Consult) - On August 1, 2005, Pfizer Inc announced that the US Food and Drug Administration has approved the company's selective cycloxygenase-2 inhibitor Celebrex (celecoxib) for the relief of the signs and symptoms associated with ankylosing spondylitis, a form of arthritis that affects the spine.
Ankylosing spondylitis, which affects over 400,000 Americans, is the sixth approved indication for Celebrex in the United States. Unlike other forms of arthritis that typically affect older persons, ankylosing spondylitis usually strikes between the ages of 17 and 35 years. Approximately as common as rheumatoid arthritis, ankylosing spondylitis also can cause inflammation, pain, and stiffness in other areas of the body such as the shoulders, knees, hips, ribs, and feet.
"With this new indication, Celebrex offers physicians a new treatment option for this difficult-to-treat patient population," said Dr Joseph Feczko, Pfizer's chief medical officer. "The inflammation associated with ankylosing spondylitis can cause such severe pain that people who suffer from this condition—often young men—cannot perform even simple, everyday activities like walking and may have trouble attending school or work."
For the management of the signs and symptoms of ankylosing spondylitis, the recommended dose of Celebrex is 200 mg daily in single or divided twice-per-day doses. If no effect is seen after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely, and consideration should be given to alternate treatment options.
Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All nonsteroidal anti-inflammatory drugs (NSAIDs) may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Celebrex is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft surgery.
NSAIDs, including Celebrex, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
As with all NSAIDs, Celebrex can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. NSAIDs should be used with caution in patients with hypertension.
Celebrex is a sulfonamide and can cause serious skin adverse events, which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy.
The most common adverse effects in arthritis trials were dyspepsia, diarrhea, and abdominal pain and were generally mild to moderate. The types of adverse events reported in the ankylosing spondylitis studies were similar to those reported in the arthritis studies.
For complete prescribing information, please see www.celebrex.com.
July 29, 2005
ST. LOUIS (MD Consult) - Shire Pharmaceuticals Group PLC announced on July 22, 2005, that the US Food and Drug Administration (FDA) has approved Adderall XR (mixed salts of a single-entity amphetamine product) as a once-daily treatment for adolescents aged 13 to 17 years with attention-deficit/hyperactivity disorder (ADHD). Since October 2001, Adderall XR has been approved in the United States for treatment in children aged 6 to 12 years and since August 2004 in adults 18 years and older.
In support of this new approval, Dr Timothy Wilens of Massachusetts General Hospital stated, "The symptoms of ADHD often continue past childhood into adolescence and adulthood, where they can have a significant impact on an individual's family, academic performance, and overall quality of life. Stimulant therapies are effective and generally well tolerated, and have been used medically in patients for more than 60 years."
The FDA based its approval on data provided by Shire that included the results of a pharmacokinetic study and a placebo-controlled, fixed-dose clinical trial of a range of doses of once-daily Adderall XR in adolescents with ADHD.
In a randomized, double-blind, placebo-controlled clinical trial, Adderall XR was proved to be significantly more effective than placebo in the treatment of ADHD symptoms in adolescents. Adderall XR was generally safe and well tolerated, with adverse events similar to those seen in other populations. The most common adverse events were loss of appetite, insomnia, abdominal pain, and weight loss. The results of this study show that Adderall XR produces a positive clinical response in adolescents diagnosed with ADHD. The study showed Adderall XR at doses between 10 and 40 mg daily were statistically significantly superior to placebo (P < .0001) on the ADHD-RS-IV (investigator-rated with the parent and adolescent). Furthermore, 63% of investigators considered their subjects' ADHD symptoms to be much improved or very much improved with Adderall XR, compared with 27% for placebo (P < .0001).
Adderall XR may not be right for everyone. Adderall XR was generally well tolerated in clinical studies. The most common adverse events in pediatric trials included loss of appetite, insomnia, abdominal pain, and emotional lability; the most common adverse effects in the adolescent trial included loss of appetite, insomnia, abdominal pain, and weight loss; and the most common in the adult trial included dry mouth, loss of appetite, insomnia, headache, and weight loss.
The effectiveness of Adderall XR for long-term use has not been systematically evaluated in controlled trials. As with other psychostimulants indicated for ADHD, there is a potential for exacerbating motor and phonic tics and Tourette's syndrome. An adverse effect associated with use of drugs in the amphetamine class is psychosis. Caution also should be exercised in prescribing Adderall XR to patients with a history of psychosis.
Abuse of amphetamines can lead to dependence. Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities. Adderall XR is contraindicated in patients with symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism and glaucoma, known hypersensitivity to this class of compounds, agitated states, history of drug abuse, or current or recent use of monoamine oxidase inhibitors. Adderall XR should be prescribed with close physician supervision.
ADHD affects approximately 3% to 7% of all school-aged children, or approximately 2 million US children, and is considered the most commonly diagnosed psychiatric disorder in children and adolescents. ADHD is a neurologic brain disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in other persons at comparable age and maturity levels. ADHD can have a profound effect on a child's quality of life and can be serious enough to affect not only academics, but can lead to problems maintaining friendships, focusing on after-school activities, and relating well with family members. Untreated ADHD has long-term adverse effects on academic performance, vocational success, and social-emotional development. Evidence also suggests that many with untreated ADHD may be at risk for other problems, such as drug abuse, antisocial behavior, and poor self-esteem. As they age, up to 65% of adolescents with ADHD may still exhibit symptoms into adulthood.
To be properly diagnosed with ADHD, a child must demonstrate at least 6 of 9 symptoms determined to be representative of inattention; at least 6 of 9 symptoms of hyperactivity/impulsivity; the onset of such symptoms before age 7 years; that some impairment from the symptoms is present in 2 or more settings (eg, at school and at home); and that the symptoms continue for at least 6 months.
Although there is no cure for ADHD, there are accepted treatments that specifically target its symptoms. The most common standard treatments include educational approaches, psychological or behavioral modification, and medication.
For further information on Adderall XR, visit the product's Web site at AdderallXR.com.
July 18, 2005
ST. LOUIS (MD Consult) - On July 15, 2005, Schering-Plough Corporation announced that the US Food and Drug Administration has approved reformulated Clarinex (desloratadine 2.5 mg and 5 mg) Reditabs tablets for the treatment of allergy symptoms caused by both perennial indoor and seasonal outdoor allergens and chronic idiopathic urticaria (CIU) in adults and children aged 6 years and older. The tablet disintegrates orally and is taken once daily for 24-hour relief.
This new formulation will be available in both 2.5- and 5-mg doses. The tablet dissolves rapidly, allowing persons with allergies to take their medication when it is convenient for them, even when they do not have access to water. Patients who have active lifestyles or dislike swallowing pills may prefer this treatment option.
Seasonal allergies affect an estimated 36 million people in the United States. Symptoms, which include sneezing, runny nose, congestion, itchy throat, and itchy and watery eyes, can have a significant impact on everyday activities at work and school and during leisure time. According to Schering-Plough, there is also a growing body of evidence that points to an association between allergies and more serious conditions, such as asthma.
CIU refers to ongoing outbreaks of hives that last longer than 6 weeks and have no known cause. These outbreaks can develop anywhere on the body and are usually associated with itching. The itchy, red spots appear quickly, usually disappear within 24 hours, and may reappear elsewhere on the body.
Clarinex is the only prescription nonsedating antihistamine approved for patients as young as 6 months old and is available in different forms to accommodate patient preference and symptoms. Other available formulations of Clarinex include Clarinex (0.5 mg/1 mL) Syrup for children as young as 6 months old, and Clarinex (5 mg) Tablets and Clarinex-D 24-Hour (desloratadine 5 mg/pseudoephedrine 240 mg) Extended Release Tablets for patients 12 years of age and older. Clarinex-D 24-Hour combines an antihistamine with a decongestant for patients suffering from nasal congestion associated with seasonal allergic rhinitis.
Clarinex is also the only prescription nonsedating 24-hour antihistamine approved for the treatment of indoor and outdoor allergies and CIU. The efficacy and safety of Clarinex in outdoor allergies has been established in 4 double-blind, randomized, placebo-controlled studies involving more than 2,300 patients with seasonal allergies. Clarinex was also studied in indoor allergies in 2 double-blind, randomized, placebo-controlled studies involving more than 1,300 patients with perennial allergies. A single 5-mg dose of Clarinex taken once daily provides 24-hour nonsedating relief from nasal and non-nasal symptoms of indoor and outdoor allergies. The approval for Clarinex in CIU was based on 2 double-blind, randomized, placebo-controlled studies involving more than 400 patients.
In clinical trials, Clarinex provided significantly greater symptom relief than placebo. Also, Clarinex provided powerful morning symptom relief with significant improvement in morning symptom scores over placebo. Tablet side effects in patients 12 years of age and older with seasonal and year-round allergies were similar to placebo and included sore throat, dry mouth, and fatigue. Tablet side effects in patients 12 years of age and older with ongoing itching and rash from hives of unknown cause were headache, nausea, and fatigue. Syrup side effects in children aged 6 to 11 years were similar to placebo. For children 6 months to 5 years of age, syrup adverse effects varied by age and included fever, diarrhea, upper respiratory infection, irritability, and coughing.
Due to its pseudoephedrine component, Clarinex-D 24-Hour Extended Release Tablets should not be taken by patients with narrow-angle glaucoma, difficulty urinating, severe high blood pressure, or severe heart disease, nor by patients who have taken a monoamine oxidase inhibitor within the past 14 days. Patients with high blood pressure; diabetes; heart disease; increased intraocular pressure; thyroid, liver, or kidney problems; or enlarged prostate should check with their health care provider before taking Clarinex-D 24-Hour Extended Release Tablets. Care should be used if Clarinex-D 24-Hour Extended Release Tablets is taken with other antihistamines and decongestants because combined effects on the cardiovascular system may be harmful. The most commonly reported adverse events for Clarinex-D 24-Hour Extended Release Tablets were dry mouth, headache, insomnia, fatigue, sore throat, and drowsiness.
Full prescribing information for Clarinex is available at spfiles.com/piclarinex.pdf. The company expects the reformulated Clarinex Reditabs to be in pharmacies by September 2005.
Schering-Plough is based in Kenilworth, NJ. For more information about the company, visit schering-plough.com.
July 5, 2005
ST. LOUIS (MD Consult) - On June 30, 2005, Johnson & Johnson announced that the US Food and Drug Administration (FDA) has approved a new indication for Topamax (topiramate) Tablets and Topamax Sprinkle Capsules as initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures.
Johnson & Johnson Pharmaceutical Research and Development, LLC, demonstrated the drug's effectiveness as a monotherapy in a controlled trial involving patients with epilepsy who had no more than 2 seizures in the 3 months before enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.
Epilepsy is one of the most common neurologic disorders, occurring in an estimated 2.7 million Americans. Each year in the United States, approximately 200,000 people are diagnosed with epilepsy for the first time. Epilepsy is characterized by seizures, which are abnormal electrical discharges in the brain that temporarily disrupt normal brain function. Seizures are classified as "generalized," originating in both sides of the brain simultaneously, or "partial-onset," starting in one area of the brain.
"Anti-epilepsy medications, or neuromodulators, are selected based on seizure type; however, the specific seizure type may not always be obvious at the time of diagnosis," said Tracy Glauser, MD, director of the Comprehensive Epilepsy Center at the Cincinnati Children's Hospital. By providing coverage for both partial-onset and primarily generalized tonic-clonic seizures, Dr Glauser continued, Topamax may serve as a treatment option when distinguishing between seizure types is problematic.
In a double-blind clinical trial, 470 patients with partial-onset or primary generalized tonic-clonic seizures were randomly assigned to receive 50 or 400 mg/d of Topamax. The primary efficacy assessment was a group comparison of time to first seizure during the double-blind phase of the study. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the 400-mg/d group over the 50-mg/d group. The recommended dose for monotherapy in patients 10 years of age and older is 400 mg/d in 2 divided doses. Approximately 58% of patients assigned to receive 400 mg/d achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/d.
As monotherapy, the most common adverse effects of Topamax (in the 400-mg/d group and at a rate higher than the 50-mg/d group) in adults were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory. The most common adverse effects experienced by children were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems.
In addition, Topamax has been associated with serious adverse events such as hyperchloremic, nonanion gap metabolic acidosis; measurement of baseline and periodic serum bicarbonate levels is recommended. Some patients taking Topamax may experience acute myopia and secondary angle closure glaucoma; therefore, persons should seek medical attention if they experience blurred vision or ocular pain. Oligohidrosis and hyperthermia may also occur, most often in hot weather and in children. Also reported have been cognitive/psychiatric adverse effects, including somnolence and fatigue, cognitive dysfunction, and psychiatric/behavioral disturbances; hyperammonemia with or without encephalopathy (associated with the concomitant use of valproic acid); and kidney stones. Patients should maintain an adequate fluid intake to minimize the risk of renal stone formation.
In women taking oral contraceptives in combination with Topamax, a significant decrease in estrogen exposure has been shown in conjunction with Topamax doses greater than or equal to 200 mg/d. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered.
For more details, including full US prescribing information, visit TOPAMAX-epilepsy.com or ortho-mcneilneurologics.com.
June 27, 2005
ST. LOUIS (MD Consult) - On June 24, 2005, Belgian pharmaceutical company UCB announced that the US Food and Drug Administration (FDA) has approved the company's anti-epilepsy drug Keppra (levetiracetam) as add-on therapy in the treatment of partial-onset seizures in children 4 years of age and older with epilepsy. The FDA approved this new pediatric indication for Keppra under priority review, a designation for products that address unmet medical needs and represent a significant improvement to therapies already available.
"More than 25% of children with epilepsy experience treatment-resistant seizures or intolerable side effects from medication," said Tracy Glauser, MD, director of the Comprehensive Epilepsy Program, Cincinnati Children's Hospital, and principal investigator of the well-controlled study reviewed for the pediatric indication. Dr. Glauser added, "Keppra was effective and well-tolerated by the children in the study, many of whom had failed on multiple anti-epileptic drugs (AEDs) prior to trying Keppra."
This approval of Keppra for children was based on findings from 1 multicenter, randomized, double-blind, placebo-controlled pivotal study conducted at 60 sites in North America, involving 198 children aged 4 to 16 years with partial-onset seizures with or without secondary generalization uncontrolled by standard AEDs. Study participants were taking 1 or 2 other AEDs at entry. The study consisted of an 8-week baseline period and a 4-week titration period, followed by a 10-week evaluation period.
In terms of efficacy, those taking Keppra had a significantly larger reduction (26.8%) in weekly seizure frequency over placebo, on average. Additionally, another measure of efficacy for patients taking Keppra—responder rates (ie, the portion of patients achieving a 50% or greater reduction in seizures)—were 44.6% versus 19.6% for placebo (both with a P = .0002 compared with placebo).
In pediatric patients 4 to 16 years of age, the most common adverse events associated with Keppra in combination with other AEDs were somnolence, accidental injury, hostility, nervousness, and asthenia. Keppra is associated with somnolence, fatigue, and behavioral abnormalities as well as hematologic abnormalities.
In the United States, Keppra is approved for adjunctive therapy in the treatment of partial-onset seizures in adults and children 4 years of age and older with epilepsy. Keppra is available in 250-, 500-, and 750-mg tablets and a grape-flavored (100 mg/mL) oral solution for patients who prefer a solution or have difficulty swallowing tablets. Keppra dosing must be individualized according to renal function status.
In adults, Keppra use is associated with the occurrence of central nervous system adverse events, including somnolence and fatigue, coordination difficulties, and behavioral abnormalities as well as hematologic abnormalities. In well-controlled adult clinical studies, the most frequently reported adverse events associated with the use of Keppra in combination with other AEDs that were not seen at an equivalent frequency among placebo-treated patients included somnolence, asthenia, infection, and dizziness.
Keppra was approved in 1999 as adjunctive therapy for adults with partial-onset seizures. For full prescribing information, visit www.keppra.com.
June 22, 2005
ST. LOUIS (MD Consult) - On June 15, 2005, The Medicines Company announced that the US Food and Drug Administration (FDA) has approved new prescribing information for the anticoagulant Angiomax (bivalirudin). The expanded label now includes treatment of patients undergoing percutaneous coronary intervention (PCI) in addition to those undergoing percutaneous transluminal coronary angioplasty.
PCI, also referred to as angioplasty, is conducted on approximately 850,000 Americans annually to clear restricted blood flow in arteries around the heart. A. Michael Lincoff, MD, Professor of Medicine at The Cleveland Clinic, was principal investigator of the REPLACE-2 trial, which evaluated Angiomax with provisional glycoprotein IIb/IIIa inhibitors (GPI) use in PCI. Dr. Lincoff commented, "The large-scale REPLACE-2 trial demonstrated that Angiomax with provisional GPI reduces the risk of death, heart attack, and repeat procedures following coronary intervention. Relative to the use of heparin and GPI, Angiomax with provisional GPI showed significantly less risk of bleeding, lower cost, and greater ease of use."
The new label, which is effective immediately, also includes a new Angiomax dosing recommendation, which is the same used in REPLACE-2. The new dose has a smaller bolus (0.75 mg/kg) and a smaller infusion (1.75 mg/kg/h) for the duration of the procedure, instead of a 4-hour infusion. Medical publications report that the REPLACE-2 dose enables streamlined patient care and significantly reduced costs.
Clive Meanwell, The Medicines Company's Chairman and CEO, stated, "In its approval letter, [the] FDA said the totality of evidence indicates that Angiomax with provisional use of GPI is safe and effective for anticoagulation during PCI, including placement of intracoronary stents. The Agency also noted in the letter, however, that, in their view, 'statistical non-inferiority was not demonstrated for the triple (ischemic) endpoint' at 30 days in the REPLACE-2 trial. As published in The Journal of the American Medical Association [August 11, 2004, and February 29, 2003] the REPLACE-2 investigators concluded non-inferiority was established for the 30-day ischemic endpoint. The 1-year mortality data also supported non-inferiority conclusions for Angiomax with provisional GPI and this, together with the consistency of effect, is, we believe, persuasive."
The Medicines Company has an additional supplemental new drug application filed with the FDA for the use of Angiomax in patients with heparin-induced thrombocytopenia and thrombosis syndrome undergoing PCI. The company expects FDA action on this application in the second half of 2005.
Angiomax is a reversible antithrombotic agent with a short half-life (25 minutes). In clinical trials, the medication has demonstrated excellent ischemic protection while simultaneously reducing bleeding complications compared with heparin as the foundation anticoagulant in the contemporary catheterization lab setting. Angiomax with provisional use of GPI is indicated for use as an anticoagulant in patients undergoing PCI. Angiomax is intended for use with aspirin.
The most common adverse events reported in clinical trials with Angiomax were back pain, pain, nausea, headache, and hypotension. The incidence of these adverse events was comparable in both treatment groups in these trials. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of Angiomax administration.
This medication is contraindicated in patients with active major bleeding or hypersensitivity to Angiomax or its components. Full prescribing information for the drug, which is marketed under the trade name Angiox in Europe, is available at angiomax.com.
June 20, 2005
ST. LOUIS (MD Consult) - On June 16, 2005, Romark Laboratories announced that the US Food and Drug Administration (FDA) has approved Alinia (nitazoxanide) tablets and oral suspension for treating diarrhea caused by Cryptosporidium parvum infection in adults and children 12 years and older. The product is already approved to treat the same infection in younger children.
For US adults and teens, this marks the first-ever treatment for infections caused by the waterborne protozoan that is recognized as widespread in the United States. Cryptosporidia are reported to be found in 65% to 97% of surface water in the United States and are recognized as the leading cause of waterborne disease outbreaks. Infection is typically spread by person-to-person contact or through contaminated water or food.
Cryptosporidium infection typically causes watery diarrhea with abdominal pain that lasts for 1 to 4 weeks or more. Children, elderly persons, and persons with weak immune systems are particularly susceptible to severe or protracted disease. Traditional antibiotics used to treat gastrointestinal infections are not effective in treating Cryptosporidium infection.
In a recent study of patients with diarrhea caused by Cryptosporidium, nitazoxanide significantly reduced the duration of diarrhea and other gastrointestinal symptoms compared with placebo. Ninety-six percent of patients treated with Alinia tablets and 87% of patients treated with Alinia suspension were well within 7 days after initiating treatment compared with only 41% of patients who received a placebo. The study also showed that Alinia was safe and well-tolerated by patients. All patients in the Alinia treatment groups completed their treatment. Mild adverse events (ie, abdominal pain, headache, and nausea) reported by patients receiving Alinia were similar to those reported by patients receiving placebo.
Earlier studies showed that Alinia suspension is effective in reducing the duration of diarrhea and other gastrointestinal symptoms caused by Cryptosporidium in pediatric outpatients aged 1 through 11 years and in pediatric inpatients aged 12 to 35 months who were immunocompromised due to severe malnutrition.
The approval granted by the FDA is the third approval for Alinia within the past 3 years. Alinia is now indicated for treatment of diarrhea caused by Giardia or Cryptosporidium in patients 1 year of age and older. It is available as a tablet or a strawberry-flavored liquid to be taken orally twice daily for 3 days. Romark is continuing to conduct research to determine Alinia's effectiveness in treating other important gastrointestinal diseases including Clostridium difficile-associated diarrhea and Crohn's disease.
Alinia tablets, 500 mg, are indicated for treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in patients 12 years of age and older. Alinia suspension, 100 mg/5 mL, is indicated for treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in patients 1 year of age and older. Alinia tablets are administered as 1 tablet twice daily for 3 days. Alinia suspension is administered as 5 mL twice daily for 3 days for patients 1 through 3 years of age, 10 mL twice daily for 3 days for patients 4 through 11 years of age, and 25 mL twice daily for 3 days for patients 12 years of age and older. Alinia has not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients.
The most common adverse events reported by patients receiving Alinia have been abdominal pain, diarrhea, headache, and nausea. In controlled trials, the frequency of these events has been similar to those experienced by patients receiving a placebo. For more information on Alinia, visit alinia.com.
Romark Laboratories is a privately owned, research-based pharmaceutical company based in Tampa, Fla. For more information, visit romark.com.
June 10, 2005
ST. LOUIS (MD Consult) - On June 15, 2005, Swiss pharmaceutical company Roche announced that the US Food and Drug Administration (FDA) has approved Xeloda (capecitabine) oral chemotherapy for the postsurgical treatment of patients with Dukes' C colon cancer.
Adjuvant chemotherapy is the standard treatment approach for Dukes' C colon cancer (ie, cancer that has spread to the lymph nodes), for which chemotherapy is given after the tumor has been surgically removed. This approval will give patients who have undergone complete resection of their primary tumor the option of an oral chemotherapy when fluoropyrimidine therapy alone is preferred.
The adjuvant indication was based on data from the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial. This pivotal trial showed that Xeloda met its primary end point of noninferiority to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival. At this time, neither Xeloda nor combination chemotherapy has been shown to prolong overall survival; combination chemotherapy has demonstrated an improvement in disease-free survival compared with 5-FU/LV.
Although intravenous 5-FU/LV (also known as the Mayo Clinic Regimen) has been the foundation of such treatment for 40 years, researchers have long recognized the need for more convenient treatment regimens. The Mayo Clinic intravenous regimen for colon cancer can require up to 30 clinic visits over the 24-week treatment course, compared with a minimum of 8 visits for patients receiving Xeloda.
The 3-year disease-free survival rates were 66% for patients treated with Xeloda and 62.9% treated with 5-FU/LV. The overall incidence of grade 3-4 toxicities were similar between Xeloda and 5-FU/LV. Patients treated with Xeloda experienced fewer severe (grade 3-4) toxicities for certain events, including less stomatitis and neutropenic fever/sepsis compared with those receiving intravenous 5-FU/LV. Hand-and-foot syndrome (a common toxicity seen with fluoropyrimidines) was higher in the Xeloda arm in this study (grade 3-4).
Xeloda is an oral drug that is activated into a chemotherapy agent by a naturally occurring enzyme called thymidine phosphorylase (TP). Once in contact with TP, which is expressed at higher levels by colorectal cancers, Xeloda is transformed inside the tumor into 5-FU, an anti-cancer drug.
Roche is investigating the use of Xeloda in combination with other chemotherapies and targeted therapies. The drug is covered by Medicare.
Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the second worldwide. The American Cancer Society (ACS) estimates that in 2005, more than 145,000 Americans will be diagnosed with colorectal cancer and more than 56,000 will die from the disease-a number that could be cut in half if Americans followed ACS recommendations to begin screening at the age of 50 years. Benchmarks provided in the National Cancer Data Base show approximately 24,000 new patients will be diagnosed with Dukes' C colon cancer, the specific type and stage of the disease studied in X-ACT. Chemotherapy after surgery is one of the most common treatment strategies in patients diagnosed during the later stage of the disease.
A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters, bleeding, and death have been reported. Clinically significant increases in prothrombin time (PT) and international normalized ratio (INR) have been observed within days to months after starting Xeloda and infrequently within 1 month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended.
Age greater than 60 years and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
Xeloda is contraindicated in patients who have a known hypersensitivity to 5-FU and in patients with known dihydropyrimidine dehydrogenase deficiency. Xeloda is also contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required. Xeloda can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored. Patients aged 80 years and older receiving Xeloda monotherapy may experience a greater incidence of grade 3 or 4 adverse events.
Xeloda may cause fetal harm when given to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with this medication. It is recommended that nursing be discontinued when using Xeloda. Men should use birth control when taking the drug.
Common adverse events in the adjuvant setting were diarrhea (Xeloda, 47%; 5-FU/LV, 65%); nausea (34% vs 47%), stomatitis (22% vs 60%), vomiting (15% vs 21%), fatigue (16% vs 16%), and hand-foot syndrome (60% vs 9%). As with any cancer therapy, there is a risk of adverse effects, and these are usually manageable and reversible with dose modification or interruption.
For more information, visit www.xeloda.com or call Roche at 800-526-6367.
June 14, 2005
ST. LOUIS (MD Consult) - On June 13, 2005, Pfizer Inc announced that it has received U.S. Food and Drug Administration (FDA) approval to market Lyrica (pregabalin) for adjunctive treatment of partial-onset seizures in adults with epilepsy. Partial-onset seizures represent over half of all seizures in patients with epilepsy, a chronic neurologic condition affecting nearly 3 million Americans. Although epilepsy can be caused by genetic predisposition or a head injury, in most cases the cause is unknown. Despite the availability of current treatments, many patients still experience uncontrolled seizures.
The efficacy of Lyrica was established in 3 double-blind, controlled trials involving 1,052 patients. At the start of treatment with Lyrica, patients experienced approximately 10 seizures a month despite taking 1 to 3 other antiepileptic medications. Patients receiving adjunctive treatment with Lyrica experienced a reduction in the frequency of partial seizures by up to 51%. Lyrica can be given to patients either 2 or 3 times a day.
The most common adverse effects across all Lyrica clinical trials were dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight gain, and difficulty with concentration and attention. The discontinuation rate due to adverse effects was low.
Lyrica will be designated a controlled substance, recommended for classification in the category with lowest potential for abuse or misuse relative to controlled substances in other categories. The medication will be available in pharmacies in the fall of 2005.
In December 2004, the FDA approved Lyrica for the management of diabetic peripheral neuropathy and postherpetic neuralgia. Developed by Pfizer, Lyrica is an alpha-2-delta ligand with a newly defined mechanism of action that is believed to work by calming hyperexcited neurons.
June 13, 2005
ST. LOUIS (MD Consult) - Sanofi pasteur, the vaccines division of the sanofi-aventis Group, announced on June 13, 2005, that the US Food and Drug Administration (FDA) has licensed Adacel (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed) vaccine for protection against tetanus, diphtheria, and pertussis from adolescence through adulthood. Adacel vaccine is the first booster to address pertussis (whooping cough) protection across a wide range of ages (11-64 years) and the first such booster licensed for adults in the United States.
The number of reported cases of pertussis continues to rise across the United States at a rate of great concern to the public health and medical communities. Pertussis immunity from early childhood vaccinations wears off, leaving adults and adolescents susceptible to the disease, which they can then transmit to others. According to the US Centers for Disease Control and Prevention (CDC), at particular risk are newborns who have not yet been fully vaccinated against pertussis, are more vulnerable to severe pertussis, and face the possibility of serious complications and even death. Over the last decade, 80% of pertussis deaths have occurred in infants younger than 6 months of age.
Adults are often the source of pertussis for infants and young children. A 2004 study conducted by the CDC reported that in cases where the source of the disease was identifiable, adults were responsible for over half of pertussis cases in infants, with parents the source for 47% and grandparents for 8% of cases.
The CDC's Advisory Committee on Immunization Practices will meet in upcoming months to update recommendations for the prevention and control of pertussis, including vaccination of adults and adolescents. The announcement of the licensure of Adacel vaccine follows a unanimous recommendation on March 15, 2005, by the Vaccines and Related Biological Products Advisory Committee of the FDA to recommend the vaccine's licensure.
Preliminary data from the CDC indicate that there were nearly 19,000 case reports of pertussis in 2004, a 63% increase over 2003 and the highest number of case reports in 4 decades. In particular, adolescents and adults have experienced a 5-fold increase over the past 14 years. Among adults aged 20 years and older, the number of reported cases of pertussis nearly doubled to 5,365 cases in 2004 from 2,854 cases in 2003.
Pertussis also has a financial effect on the patient's family. One study found that the average medical costs for an infant with pertussis was more than $2,800, and parents lost an average 6 days of work to care for an ill child. This loss of productivity cost families an average of $767. Another study, published in 2004, found that the majority of adults missed an average of 9.8 days of work due to their disease, whereas adolescents missed an average 5.5 days of school.
The FDA reviewed the results of 4 principle clinical studies that included more than 7,200 persons. The studies concluded that the safety profile of Adacel vaccine was very similar to that of Td vaccine when administered to adults and adolescents. In these studies, Adacel vaccine stimulated robust antibody responses nearly identical to those from Td vaccine for protection against tetanus and diphtheria, and exceeding those following 3 doses of the analogous diphtheria-tetanus-acellular pertussis given to infants for protection from pertussis.
In addition, studies were conducted that demonstrated that Adacel vaccine can be administered concomitantly with 2 other common adolescent and adult vaccines-hepatitis B and trivalent inactivated influenza.
In clinical studies, the adverse events associated with Adacel vaccine were very similar to those from the current Td vaccine and consisted primarily of transient pain, swelling or redness at the injection site, and low-grade fever of short duration. The most common systemic adverse events include headache, body ache, and tiredness. Adacel vaccine is contraindicated in persons with known systemic hypersensitivity to any component of Adacel vaccine or a life-threatening reaction after previous administration of the vaccine or a vaccine containing the same substances. Because intramuscular injection can cause injection site hematoma, Adacel vaccine should not be given to persons with any bleeding disorder, such as hemophilia or thrombocytopenia, or to persons receiving anticoagulant therapy unless the potential benefits clearly outweigh the risk of administration. If the decision is made to administer Adacel vaccine in such persons, it should be given with caution, with steps taken to avoid the risk of hematoma formation after injection.
The development of a pertussis booster vaccine for use from adolescence through adulthood was not possible before the advent of acellular vaccines in the mid 1990s. Before then, only whole cell pertussis vaccine was available, which carried an increased risk of adverse events in persons older than 7 years. A children's diphtheria, tetanus, and acellular pertussis vaccine is currently recommended by the CDC for administration in a 5-dose series for patients between the ages of 2 months and 6 years.
For more information on sanofi pasteur, visit sanofipasteur.com.
June 10, 2005
ST. LOUIS (MD Consult) - On May 26, 2005, AstraZeneca announced that the US Food and Drug Administration (FDA) has approved its antibiotic Merrem IV (meropenem for injection) to treat adults and children with complicated skin and skin structure infections (cSSSI). Merrem is currently indicated and approved for use in the United States as a single-agent therapy for intra-abdominal infections and bacterial meningitis.
David Melnick, MD, Senior Medical Director for Infection and Oncology at AstraZeneca Pharmaceuticals LP, stated that cSSSI "can be caused by many different bacteria, including gram-positive, gram-negative, and anaerobic pathogens. Its broad spectrum of activity against a variety of disease-causing microorganisms makes Merrem a valuable agent for treating cSSSI in both adults and children."
The approval is based on results from one of the largest studies conducted to date of hospitalized patients with cSSSI. The international, phase III, randomized, double-blind, multicenter clinical trial of 1,037 patients with cSSSI compared the efficacy, safety, and tolerability of Merrem, given at 500 mg IV every 8 hours, and imipenem-cilastatin given at 500 mg IV every 8 hours. The primary efficacy end point was clinical outcome at follow-up in the clinically evaluable (CE) and modified intent-to-treat (MITT; patients who met eligibility criteria and received ≥1 dose of study drug) populations.
The success rates in the CE patients at follow-up were 86% in the Merrem arm and 83% in imipenem-cilastatin arm (95% confidence interval [CI], –2.8, 9.3) and 73% (Merrem) and 75% (imipenem-cilastatin) in the MITT population (95% CI, –8.4, 4.7). The frequency of adverse events and drug-related adverse events were similar between treatment groups. The most common adverse events reported in both treatment groups were headache, nausea, constipation, diarrhea, anemia, pain, and pruritus.
Of note were the clinical responses by the subgroups. Among CE patients 65 years of age and over, 81% of patients treated with Merrem had a satisfactory clinical response at follow-up, compared with 72% of patients treated with imipenem-cilastatin. Similarly, in the CE population, among those with diabetes mellitus, 86% of patients treated with Merrem had a satisfactory clinical response at follow-up, compared with 72% of patients treated with imipenem-cilastatin. Among patients with microbiologically documented infection, Merrem demonstrated an excellent success rate in patients infected with gram-positive aerobes (88% and 83% with Merrem and imipenem-cilastatin, respectively), gram-negative aerobes (80% vs 75%), and anaerobic pathogens (84% vs 85%).
The pivotal clinical trial was supported by a pharmacokinetic trial demonstrating that Merrem administered at 500 mg IV every 8 hours achieves levels in interstitial skin fluid sufficient to treat the common pathogens associated with complicated skin infections.
Approximately 1.5 million patients annually receive broad-spectrum antibiotics in hospitals for cSSSI. cSSSI involves the skin and may involve deeper soft tissues, often requiring surgical intervention and antibiotic therapy. These infections include complicated cellulitis, complex abscesses, perirectal abscesses, and other skin infections requiring intravenous antimicrobials and hospitalization.
Merrem is a broad-spectrum carbapenem injectable antibiotic that is active against various strains of susceptible organisms and can be administered by intravenous infusion or intravenous bolus injection. Merrem is generally well tolerated and has a low incidence of adverse events. Systemic adverse events reported with Merrem are typical of those seen with other intravenous antibiotics. Serious and occasionally fatal hypersensitivity reactions have been reported in patients receiving therapy beta-lactams.
For more information about AstraZeneca, visit astrazeneca-us.com.
June 10, 2005
ST. LOUIS (MD Consult) - Baxter Healthcare Corporation announced on May 2, 2005, that the US Food and Drug Administration (FDA) has approved Gammagard Liquid (immune globulin intravenous [human]; IGIV) 10% Solution for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. The safety of Gammagard Liquid 10% has been demonstrated in a wide spectrum of patients with primary immunodeficiency disorders.
Gammagard Liquid 10% consists of highly purified and concentrated immunoglobulin (Ig) G antibodies. It is processed from human plasma and contains a broad spectrum of IgG antibodies against bacterial and viral agents. This ready-to-use, sterile liquid preparation eliminates the need for reconstitution. In addition, its high concentration, compared with 5% concentrations, allows for a reduction in the length of infusion.
The FDA approval was based on a phase III, multicenter study of 61 patients between the ages of 6 and 72 years who were treated with 300 to 600 mg/kg every 21 to 28 days for 12 months. In this study, no validated acute serious bacterial infections occurred in any of the treated subjects.
Baxter plans to launch Gammagard Liquid 10% in 5 vial sizes (1, 2.5, 5, 10, and 20 g). Gammagard Liquid 10% can be stored for up to 9 months at room temperature or for up to 36 months if kept under refrigeration. The medication is free of added sugar, sodium, and preservatives.
Baxter will continue to supply its current product Gammagard S/D to those patients who require a low-IgA therapy.
Primary immunodeficiency is a group of genetic disorders in which the immune system fails to produce adequate amounts of antibodies, thereby predisposing persons to increased risk of infection. According to the Immune Deficiency Foundation, approximately 50,000 persons in the United States have 1 of the primary immunodeficiency disorders. For many persons with primary immunodeficiency, the cause is a lack of antibodies. IGIV therapy can help restore IgG levels to near normal, helping the immune system function properly and prevent infections or fight them when they occur.
Gammagard Liquid 10% is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to immune globulin (human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Such patients should only receive IVIG with utmost caution and in a setting where supportive care is available for treating life-threatening reactions.
A black box warning on Gammagard labeling states that IGIV products have been associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Although these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Gammagard Liquid 10% does not contain sucrose.
Products made from human plasma, such as Gammagard Liquid 10%, may carry a risk of transmitting infectious agents, such as viruses, that can cause disease. To minimize this risk, 3 validated, independent, and effective virus inactivation/removal steps have been integrated into processing and formulation of Gammagard.
The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered.
Full prescribing information is available at baxter.com.
June 2, 2005
ST. LOUIS (MD Consult) - On June 1, 2005, Amgen Inc and Wyeth Pharmaceuticals announced that the US Food and Drug Administration (FDA) approved an expanded indication for Enbrel (etanercept) to improve physical function in patients with psoriatic arthritis. Enbrel is the first and only treatment to receive this expanded indication. In addition, the FDA approved an update to the Enbrel label to include new radiographic data demonstrating that Enbrel continued to inhibit the progression of joint destruction for 2 years among most psoriatic arthritis patients who received ongoing therapy.
Enbrel received its approval to treat signs and symptoms of psoriatic arthritis in 2002. With this expanded approval, Enbrel is now indicated for reducing signs and symptoms, inhibiting the progression of joint destruction of active arthritis associated with psoriatic arthritis, and improving physical function in patients with psoriatic arthritis. Enbrel is also approved to treat moderate-to-severe rheumatoid arthritis and juvenile rheumatoid arthritis, ankylosing spondylitis, and moderate-to-severe plaque psoriasis.
The expanded approval was based on significant improvements in physical function as assessed by the disability index of the Health Assessment Questionnaire (HAQ), a test used to evaluate a patient's ability to perform daily activities such as dressing, walking, and grooming, and the Medical Outcomes Study Short-Form Health Survey (SF-36), a measurement tool that also assesses the physical impact of a disease.
Almost 40% of patients with psoriatic arthritis taking Enbrel in this study achieved an HAQ score of 0, indicating no functional disability at 24 weeks. In addition, the SF-36 revealed that many patients treated with Enbrel experienced a greater improvement from baseline, compared with placebo, in their ability to participate in physical activities such as walking, carrying groceries, or climbing a flight of stairs.
Psoriatic arthritis is a chronic, often destructive disease characterized by both joint inflammation and erosion, and is associated with psoriatic skin lesions. The progressive joint pain and swelling, which is often coupled with painful, scaly, red skin lesions, can disrupt a person's ability to perform activities of daily life. Approximately 1 million persons in the United States have psoriatic arthritis.
Enbrel is the only soluble tumor necrosis factor (TNF) receptor approved to reduce signs and symptoms, induce major clinical response, improve physical function, and inhibit the progression of structural damage in patients with moderately to severely active rheumatoid arthritis. It is approved to reduce the signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients 4 years of age or older who have had an inadequate response to 1 or more disease-modifying antirheumatic drugs. It was also the first biologic agent approved to reduce the signs and symptoms in patients with active ankylosing spondylitis. Enbrel is indicated for the treatment of adult patients (18 years or older) with chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Enbrel can be used alone or in combination with methotrexate.
Enbrel acts by binding TNF, one of the dominant inflammatory cytokines or regulatory proteins that play an important role in both normal immune function and the cascade of reactions involved in the inflammatory process of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. The binding of Enbrel to TNF renders the bound TNF biologically inactive, resulting in significant reduction in inflammatory activity. In doing so, Enbrel can also lower the ability of the immune system to fight infections.
Possible adverse effects of Enbrel include serious infections, some of which have been fatal. Many infections occurred in people prone to infection, such as those with advanced or poorly controlled diabetes. Rare cases of tuberculosis have occurred, and there have been rare reports of serious blood disorders (some fatal). In addition, Enbrel can cause injection site reactions.
In medical studies of all TNF blockers, including Enbrel, a higher rate of lymphoma was seen compared with that in the general population. The risk of lymphoma may be up to several-fold higher in patients with rheumatoid arthritis and psoriasis. The role of TNF blockers in the development of lymphoma is unknown.
Enbrel is contraindicated in patients with infections or an allergy to Enbrel or its components.
Patients for whom Enbrel has been prescribed should tell their doctors if they are prone to infection or if they have ever been treated for heart failure or serious nervous system disorders such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. A physician should be contacted immediately if a patient taking Enbrel develops symptoms such as persistent fever, bruising, bleeding, or paleness. Administration of Enbrel should be stopped if a serious infection occurs.
Additional information about Enbrel, including full prescribing information, can be found at ENBREL.com or by calling toll free 888-4ENBREL (888-436-2735).
June 1, 2005
ST. LOUIS (MD Consult) - On May 27, 2005, GlaxoSmithKline announced its anti-thrombotic drug Arixtra has been approved by the US Food and Drug Administration (FDA) for use in patients undergoing abdominal surgery. The new indication is for the prevention of venous thromboembolism (VTE) in patients undergoing abdominal surgery who are at risk of thromboembolic complications.
Arixtra is the first selective inhibitor of factor Xa, a protein central to the coagulation process. Arixtra is already approved for the prevention of VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing surgery for hip fracture (including extended prophylaxis), knee replacement, and hip replacement. Additionally, Arixtra is indicated for the treatment of acute DVT when administered in conjunction with warfarin sodium and for the treatment of acute PE when administered in conjunction with warfarin sodium, when initial therapy is administered in the hospital.
"In addition to demonstrating safety profiles comparable to enoxaparin, dalteparin, and unfractioned heparin, Arixtra has not had any reported cases of heparin-induced thrombocytopenia...or drug-drug interactions," stated Kevin Lokay, vice president of GlaxoSmithKline Oncology and Acute Care.
Up to 2 million cases of VTE occur in the United States each year. About one third of patients with symptomatic VTE will develop PE. VTE can be fatal; death occurs in about 6% of DVT cases and about 12% of PE cases within 1 month of diagnosis. Without prophylaxis, up to 25% of patients undergoing abdominal surgery will develop DVT, with 0.5% to 0.8% associated risk of PE. In patients undergoing cancer surgery, the risk of VTE and fatal PE is 2 to 4 times higher.
The recent approval of Arixtra for patients undergoing abdominal surgery is based on the results of the PEntasaccharide GenerAl SUrgery Study (PEGASUS). This study demonstrated that Arixtra is at least as effective as dalteparin in reducing the risk of VTE. In the study, 4.6% of patients receiving Arixtra experienced a VTE incident versus 6.1% of patients on dalteparin. Sixty-nine percent of the patients in the study underwent cancer-related abdominal surgery, with 4.7% of patients in the Arixtra group experiencing VTE versus 7.7% of patients in the dalteparin group. In noncancer abdominal surgery patients studied, 4.2% of patients receiving Arixtra experienced VTE versus 2.3% of patients receiving dalteparin.
PEGASUS was a double-blind, non-inferiority study performed in 131 centers in 22 countries. A total of 2,927 patients were randomly assigned to receive either subcutaneous Arixtra (2.5 mg once daily starting 6 hours after surgery) or subcutaneous dalteparin (2,500 IU 2 hours before surgery; 2,500 IU on the evening following surgery; then 5,000 IU once daily). Treatment was continued for 7 ± 2 days, and patients were followed up for 30 ± 2 days. The main sites of surgery were colonic/rectal, gastric, hepatic, cholecystectomy, or other biliary.
The primary efficacy end point was the incidence of VTE (including DVT, PE, or both) evaluated up to postsurgical day 10 (4.6% for Arixtra and 6.1% for dalteparin). The primary safety outcome was major bleeding during the initial treatment period, which was comparable between the 2 groups (3.4% for Arixtra vs 2.4% for dalteparin). However, in patients treated with Arixtra according to the recommended regimen (eg, first dose initiated 6 to 8 hours after surgery), the rate of major bleeding was 2.9%.
When epidural/spinal anesthesia or spinal puncture is used, patients anticoagulated or scheduled to be anticoagulated with low–molecular-weight heparins, heparinoids, or fondaparinux sodium are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events may be higher with postoperative use of indwelling epidural catheters or concomitant use of drugs affecting hemostasis. Patients should be frequently monitored for signs and symptoms of neurologic impairment.
Arixtra is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min); patients undergoing hip fracture, hip replacement, knee replacement, or abdominal surgery with body weight <50 kg (<110 lb); patients undergoing abdominal surgery with body weight <50 kg (<110 lb); patients with active major bleeding or bacterial endocarditis; patients with thrombocytopenia associated with a positive in vitro test result for anti-platelet antibody in the presence of fondaparinux sodium; or patients with hypersensitivity to fondaparinux sodium.
Arixtra is not intended for intramuscular administration.
Arixtra cannot be used interchangeably with heparin, low–molecular-weight heparins, or heparinoids because they differ in manufacturing process, anti-Xa and anti-IIa activity, units, and dosage.
The risk of hemorrhage increases with increasing renal impairment. Arixtra should be used with caution in patients with moderate renal impairment. Renal function should be assessed periodically in patients receiving Arixtra and should be discontinued immediately in patients who develop severe renal impairment.
Arixtra, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage.
Thrombocytopenia can occur with Arixtra. If the platelet count falls below 100,000/mm3, Arixtra should be discontinued.
For more information on GlaxoSmithKline and its products, visit gsk.com.
June 1, 2005
ST. LOUIS (MD Consult) - Novartis Pharmaceuticals Corporation announced on May 27, 2005, that the US Food and Drug Administration has approved Focalin XR (dexmethylphenidate hydrochloride) extended-release capsules for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults, adolescents, and children.
ADHD is a neurobiologic disorder that interferes with a person's ability to regulate activity level and behavior and to sustain focus in developmentally appropriate ways. It is one of the most common psychiatric disorders of childhood and is estimated to affect 5% to 7% of children. Many children with ADHD will continue to experience symptoms into adulthood. The disorder is estimated to affect approximately 4% of the adult population.
In adults and children, the core symptoms of ADHD are inattention, impulsivity, and hyperactivity; however, in adults symptoms of hyperactivity often subside with maturity or may manifest differently. Adults with ADHD may experience poor functioning in educational and occupational environments, as well as emotional, social, and economic problems. For more information, visit ADHDInfo.com.
New Jersey–based Novartis stated that Focalin XR was generally well tolerated in its preapproval trials, with no significant changes in patient weight or vital signs, such as sitting pulse or sitting blood pressure, in adults or children. The most common adverse effects in adults and children include decreased appetite, headache, dyspepsia, anxiety, insomnia, feeling jittery, and anorexia.
The approval of Focalin XR for the treatment of ADHD was based on efficacy and safety data from clinical trials involving approximately 320 adults, adolescents, and children diagnosed with ADHD.
A 5-week, double-blind, placebo-controlled study involving 221 men and women (aged 18-60 years) with ADHD demonstrated Focalin XR to be safe and effective in treating ADHD symptoms in adults. Patients received Focalin XR or placebo once daily. Results indicated that Focalin XR was statistically superior to placebo, based on changes in the Diagnostic and Statistical Manual of Mental Disorders, ed 4 (DSM-IV) ADHD Rating Scale. Secondary measures included evaluations rated by patients, clinicians, and observers.
After the completion of the 5-week double-blind clinical trial, 170 patients continued into a 6-month open-label extension phase. Patients who switched from placebo to Focalin XR showed significant clinical improvement and patients continuing treatment with Focalin XR continued to show increasing benefits over 6 months, based on changes in the DSM-IV ADHD Rating Scale. Focalin XR was generally well tolerated in this group. The most frequently reported adverse events included headache, insomnia, and decreased appetite.
The efficacy and tolerability of Focalin XR for the treatment of ADHD in children was demonstrated in a pivotal clinical trial of children and adolescents aged 6 to 17 years diagnosed with ADHD. In this trial, 103 ADHD patients received Focalin XR or placebo once daily for 7 weeks. Results indicated that Focalin XR was statistically superior to placebo, based on the Conners' ADHD/DSM-IV Scales for Teachers (CADS-T). The CADS-T Rating Scale is a tool used in clinical trials to assess attention and behavior.
In an additional trial of 54 pediatric patients aged 6 to 12 years, investigators evaluated the efficacy of Focalin XR 20 mg/d at various points throughout the day. Focalin XR was found to be significantly more effective than placebo in treating ADHD symptoms after just 1 hour, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale. The SKAMP Rating Scale evaluates attention and behavior in clinical trials.
In these studies, Focalin XR was generally well tolerated. The most frequently reported adverse events included decreased appetite, headache, dyspepsia, upset stomach, and anxiety.
Focalin is formulated by isolating the active d-isomer of methylphenidate, an isomer that data suggest is responsible for the effective management of the symptoms of ADHD. Focalin XR is available in 5-, 10-, and 20-mg capsules for oral administration.
Like most drugs approved for the treatment of ADHD, Focalin XR is contraindicated in patients known to be hypersensitive to the drug or to methylphenidate, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette's syndrome. It is also contraindicated during treatment with monoamine oxidase inhibitors and within a minimum of 14 days after discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). In addition, like most drugs approved for the treatment of ADHD, Focalin XR is a schedule II drug and should be given cautiously to patients with a history of drug dependence or alcoholism.
For more information about Focalin XR, visit FocalinXR.com.
June 1, 2005
ST. LOUIS (MD Consult) - Abbott announced on May 27, 2005, that the US Food and Drug Administration (FDA) has approved Zemplar (paricalcitol) Capsules, an oral, activated vitamin D therapy for the prevention and treatment of secondary hyperparathyroidism (SHPT). Zemplar Capsules are indicated for the prevention and treatment of SHPT in patients with stages 3 (moderate) and 4 (severe) chronic kidney disease (CKD), before the need for dialysis or transplantation.
SHPT is a major complication associated with CKD that can detrimentally affect bones and other vital organs, including the heart, muscles, and nerves if left untreated. It can occur when kidneys lose their ability to activate vitamin D obtained through diet and other sources. One in 9 adults in the United States (20 million persons) have CKD, and another 20 million are at risk for developing CKD from underlying causes such as diabetes and hypertension. Diabetes and hypertension account for two thirds of new cases each year. Minority populations also bear a disproportionate burden.
Zemplar Capsules are an oral formulation of Zemplar Injection, which was introduced in 1998 and is indicated for the prevention and treatment of SHPT among patients receiving dialysis treatment. Zemplar Capsules were designed to reduce parathyroid hormone levels (PTH) with minimal impact on calcium and phosphorus levels. Reduction of PTH is a key indicator of treatment efficacy.
The National Kidney Foundation guidelines recommend testing for and treating SHPT early in the course of CKD, well before the need for dialysis. Earlier management of CKD and its complications may reduce the devastating consequences of the disease, such as bone loss and cardiovascular events.
Study results from 3 phase III trials showed that Zemplar Capsules are safe and effective in reducing PTH levels in stage 3 and 4 kidney disease patients with SHPT. Ninety-one percent of patients treated with Zemplar Capsules had significant and sustained reduction in PTH levels, compared with only 13% of patients taking placebo, after 24 weeks of therapy. Significant reduction in PTH was defined as achievement of at least 2 consecutive ≥30% reductions in PTH. Additionally, patients had a >30% mean reduction in PTH by week 9, with a sustained reduction in PTH noted throughout the remainder of the study.
Zemplar Capsule treatment had minimal impact on calcium and phosphorus levels compared with placebo. Elevations in blood calcium, phosphorus, and urinary calcium values are known treatment-related safety concerns that have been associated with treatment of SHPT in stage 3 and 4 CKD patients with activated vitamin D therapy. The incidences of hypercalcemia (defined as 2 consecutive elevated serum calcium levels) and hyperphosphatemia in patients treated with Zemplar Capsules was similar to placebo. There were no treatment-related adverse events associated with hypercalcemia or hyperphosphatemia in the Zemplar Capsules group. No increases in urinary calcium or phosphorus were detected in patients treated with Zemplar Capsules compared with placebo.
Results from the phase III pivotal trials showed no statistically significant difference in adverse events in patients treated with Zemplar Capsules compared with placebo.
The phase III trial data were further analyzed to evaluate consistency with the National Kidney Foundation in the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for calcium and phosphorus targets. Calcium, phosphorus, and calcium and phosphorus product values were maintained within the K/DOQI targets for each: calcium, 91% paricalcitol vs 95% placebo; phosphorus, 70% paricalcitol vs 75% placebo; and calcium and phosphorus combined, 94% paricalcitol vs 96% placebo. Maintaining appropriate levels of calcium and phosphorus is critical for the effective management of SHPT. Bone disease is a known complication of SHPT that occurs as the kidneys gradually lose their ability to produce activated vitamin D, which is necessary for bone health.
Phase III clinical trials for Zemplar Capsules included patients in stages 3 and 4 of CKD, who were treated and evaluated in 3 prospective, randomized, placebo-controlled, double-blinded studies at multiple centers over a 24-week period. Additionally, this trial represents the largest number of patients studied in the early-stage CKD population with SHPT.
The safety profile of Zemplar was similar to placebo. Zemplar is contraindicated in patients with vitamin D toxicity, hypercalcemia, or hypersensitivity to any product ingredient.
PTH, calcium, and phosphorus levels should be monitored every 3 months and more frequently during dosage changes. Dosage titration is required to reach optimum reduction/levels of PTH. Excessive administration of vitamin D compounds, including Zemplar Capsules, can cause oversuppresion of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.
For full prescribing information on Zemplar Capsules, visit zemplar.com.
May 24, 2005
ST. LOUIS (MD Consult) - Centocor, Inc, announced on May 17, 2005, that the US Food and Drug Administration (FDA) has approved its anti–tumor necrosis factor (TNF) alpha medication Remicade (infliximab) to reduce the signs and symptoms of active arthritis in patients with psoriatic arthritis. Psoriatic arthritis is an immune-mediated inflammatory disease that affects approximately 1 million men and women in the United States and is often characterized by the complex symptoms of joint inflammation and skin lesions.
Data from the Induction and Maintenance of Psoriatic Arthritis Clinical Trial 2 (IMPACT 2) served as the primary basis for the approval. IMPACT 2 was a phase III randomized, double-blind, placebo-controlled study of 200 patients with active psoriatic arthritis (defined as affecting at least 5 joints). The study evaluated the safety and efficacy of Remicade in patients who had an inadequate response to disease-modifying anti-rheumatic drugs or nonsteroidal anti-inflammatory drugs. Patients received Remicade (5 mg/kg) or placebo at weeks 0, 2, and 6 and every 8 weeks until week 22. In patients with greater than 3% body surface area psoriasis involvement at baseline, psoriasis activity was assessed using PASI at baseline and weeks 2, 6, 14, and 24. Responses were achieved regardless of methotrexate use or level of joint involvement at baseline.
Significant improvements in both the American College of Rheumatology (ACR) scoring criteria and the Psoriasis Area Severity Index (PASI) were observed in Remicade-treated patients as early as week 2, with further improvements through 24 weeks. At week 14, 58% of Remicade-treated patients experienced at least 20% improvement in arthritis symptoms, according to the ACR 20, versus 11% of placebo-treated patients (P < .001). At week 24, 27% of Remicade-treated patients experienced at least 70% improvement (ACR 70) versus 2% of placebo-treated patients (P < .001). Additionally, at week 24, 60% of Remicade-treated patients experienced at least 75% improvement from baseline in psoriasis, as assessed by the PASI 75, versus 1% of placebo-treated patients. At week 24, more than one third (39%) of patients receiving Remicade achieved PASI 90, a dramatic improvement in psoriasis symptoms. No patients receiving placebo achieved a PASI 90 response at week 24.
Importantly, patients in the Remicade group also experienced decreased symptoms of dactylitis and enthesopathy, 2 common disease manifestations causing pain and swelling. Dactylitis, swelling of digits in the hands or feet, and enthesopathy, inflammation of a tendon or ligament insertion to the bone, are estimated to affect more than one third of people with psoriatic arthritis. In the study, 40% of patients treated with Remicade and 41% of patients in the placebo group had dactylitis in at least 1 digit at baseline. After 24 weeks of treatment, only 15% of Remicade patients continued to experience symptoms compared with 33% of patients receiving placebo (P < .05). At baseline, enthesopathy was observed in 42% of patients in the Remicade group and 35% of patients receiving placebo. At week 24, only 22% of Remicade patients still experienced enthesopathy, compared with 36% in the placebo group (P = .004).
Patients treated with Remicade also experienced significant improvement in the physical component summary (PCS) and mental component summary (MCS) scores of the short form 36 (SF-36). The SF-36 is a 36-item questionnaire that assesses impact in 8 areas, including physical functioning, pain, vitality, social functioning, psychological functioning, general health perceptions, and role limitations due to physical and emotional problems. SF-36 scores range from 0 to 100, with lower scores indicating poorer functioning and well-being. At week 14, patients taking Remicade experienced an average increase in PCS score of 9.1 units, compared with an average 1.1-unit increase in patients receiving placebo (P < .001). Additionally, patients in the Remicade group experienced an average 3.8-unit increase in MCS score, whereas patients receiving placebo averaged a decrease of 1.2 units (P = .001).
Through 24 weeks, a similar number of patients experienced adverse events in each treatment group. No deaths, cases of tuberculosis or other opportunistic infections, or serious infusion reactions were reported, and serious infections were uncommon. Also, with the exception of 1 case of basal cell carcinoma in the placebo group, no malignancies were reported. Significant laboratory abnormalities were unusual, with an elevation in liver function tests being the most common abnormality. There were more patients with serious adverse events in the Remicade group (8.7%) than in the placebo group (6.2%).
According to 2004 National Psoriasis Foundation surveys of more than 1,000 people with psoriasis and psoriatic arthritis, approximately 85% of patients with psoriatic arthritis reported their condition to be a problem in their everyday lives. Additionally, less than 20% of patients with psoriatic arthritis reported high satisfaction with their treatments.
Gail Zimmerman, President and CEO of the National Psoriasis Foundation, noted that surveys have consistently demonstrated a negative physical and emotional effect on quality of life among patients with psoriatic arthritis. New methods of treating the condition are welcome because they may alleviate this discomfort.
Psoriatic arthritis involves joint pain and swelling that can lead to debilitation coupled with inflamed, scaly, red patches of psoriasis. Symptoms may include stiffness and tenderness of the joints and surrounding tissue, reduced range of motion, nail changes, and uveitis. Joints of the hands, wrists, knees, ankles, feet, lower back, and neck are commonly affected. Approximately 1 million Americans have psoriatic arthritis; the disease affects both men and women equally, most commonly between the ages of 30 and 50 years.
First approved in the United States in 1998 to treat Crohn's disease, Remicade, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Remicade is the only biologic agent indicated for the treatment of patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. Remicade is also indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn's disease. In December 2004, Remicade was approved in the United States for the treatment of active ankylosing spondylitis.
Unlike self-administered therapies that require patients to inject themselves frequently, Remicade is administered directly by caregivers in the clinic or office setting. When used in the treatment of rheumatoid arthritis, Crohn's disease, and psoriatic arthritis, Remicade is a 2-hour infusion administered every 8 weeks, following a standard induction regimen that requires treatment at weeks 0, 2, and 6. As a result, patients may require as few as 6 treatments each year. In the treatment of ankylosing spondylitis, Remicade is a 2-hour infusion (5 mg/kg) administered every 6 weeks, following a standard induction regimen that requires treatment at weeks 0, 2, and 6. The safety and efficacy of Remicade have been well established in clinical trials over the past 12 years.
Many people with heart failure should not take Remicade. Before treatment with this medication, patients should discuss any heart conditions with their doctors. Patients should inform their doctors right away if they develop new or worsening symptoms of heart failure such as shortness of breath or swelling of the ankles or feet.
There have been reports of serious infections, including tuberculosis, sepsis, and pneumonia, in conjunction with use of Remicade. Some of these infections have been fatal. Patients with recent or past exposure to people with tuberculosis should notify their doctors, who should then evaluate for tuberculosis and perform a skin test. If a patient has latent tuberculosis, the doctor should begin tuberculosis treatment before administration of Remicade is begun. Remicade can lower a person's ability to fight infections, so if one is prone to or has a history of infections, or if he or she develops any signs of an infection such as fever, fatigue, cough, or the flu while taking Remicade, a doctor should be notified immediately. Patients should also tell their doctors if they have lived in a region where histoplasmosis or coccidioidomycosis is common.
There have been rare cases in which people taking Remicade have developed severe liver problems, some fatal. Signs of this problem include jaundice, dark brown-colored urine, right-sided abdominal pain, fever, and severe fatigue. Patients experiencing any of these symptoms should notify their doctors immediately. Blood disorders have also been reported, and some have been fatal. Possible signs of blood disorders such as persistent fever, bruising, bleeding, or paleness while taking Remicade should be reported to a physician.
Nervous system disorders have been reported. Patients who have or have had a disease that affects the nervous system, or who experience any numbness, weakness, tingling, or visual disturbances while taking Remicade, should notify their doctors.
Reports of lymphoma in patients taking Remicade and other TNF blockers are rare but occur more often than in the general population. Patients should make their doctors aware if they have or have had cancer.
Serious infusion reactions have been reported with Remicade, including hives, difficulty breathing, and low blood pressure. Reactions have occurred during or after infusions. In clinical studies, some people experienced the following common side effects: respiratory infections (including sinus infections and sore throat), coughing, and stomach pain or mild reactions to infusion such as rash or itchy skin.
For more information about Remicade, including full prescribing information, visit remicade.com.
Centocor is a subsidiary of Johnson & Johnson.
May 20, 2005
ST. LOUIS (MD Consult) - On May 18, 2005, the US Food and Drug Administration (FDA) announced its approval of a new indication for AstraZeneca's Atacand (candesartan cilexetil) 4-, 8-, 16-, and 32-mg tablets. In February 2005 the medication was approved for the treatment of heart failure (NYHA class II-IV) in patients with left ventricular systolic dysfunction (ejection fraction ≤40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. This new approval clears use of the drug for that purpose, with or without coadministration of an angiotensin-converting enzyme (ACE) inhibitor.
Changes to the Clinical Pharmacology, Indications and Usage, and Precautions sections of the Atacand labeling reflect the new indication.
Atacand was originally approved in 1998 for the treatment of hypertension.
Prominently featured on the Atacand product Web site is a warning that use of Atacand and Atacand HCT should be discontinued as soon as possible when pregnancy is detected in a patient. AstraZeneca advises physicians to see the full prescribing information for both products, including boxed warning regarding use in pregnancy, Precautions on use in elderly, and Clinical Pharmacology–Clinical Trials for use in black patients.
Full prescribing information is available from the FDA at fda.gov/cder/foi/label/2005/020838s022lbl.pdf.
May 18, 2005
ST. LOUIS (MD Consult) - GlaxoSmithKline announced on May 16, 2005, that the US Food and Drug Administration (FDA) has granted traditional approval status to Trizivir (abacavir sulfate, lamivudine, and zidovudine) for the treatment of HIV infection. Trizivir is a fixed-dose-combination tablet containing the 3 nucleoside reverse transcriptase inhibitors Epivir (lamivudine), Retrovir (zidovudine), and Ziagen (abacavir sulfate).
The FDA grants traditional approval for a medication based on data from clinical trials of 48 weeks or more. Accelerated approval, which requires fewer weeks of data for drugs that will meet unmet medical needs, was granted to Trizivir in 2000, based on analysis of 24-week data. Trizivir, in combination with other antiretroviral agents or alone, is indicated for the treatment of HIV infection. Limited data exist on the use of Trizivir alone in patients with higher baseline viral loads (>100,000 copies/mL).
Trizivir is dosed as a single tablet given twice a day with no food or water restrictions. The use of Trizivir in therapy-naive adults may preserve the use of other classes of antiretroviral agents for the future.
Trizivir is also available in a dispensing carton called the Trizivir Convenience Pack. Each pack contains 60 Trizivir tablets on a blister strip, providing patients with a tear-off roll for twice-daily tablet dosing. This method of administration also provides patients with a dosage calendar to help them keep track of when they take their medication and to alert them when a refill is needed.
It should be noted that HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others.
Before starting administration of Trizivir, physicians should review their patients' medical history for prior exposure to any abacavir-containing product to avoid reintroduction in a patient with a history of hypersensitivity to abacavir, which has been associated with serious and sometimes fatal reactions. Hypersensitivity to abacavir is a multiorgan clinical syndrome usually characterized by 2 or more of the following signs or symptoms: fever; rash; gastrointestinal symptoms including nausea, vomiting, diarrhea, or abdominal pain; constitutional symptoms including generalized malaise, fatigue, or achiness; or respiratory symptoms such as dyspnea, cough, or pharyngitis. Symptoms of this reaction usually occur within the first 6 weeks of treatment, although these reactions can occur at any time during therapy.
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, discontinue Trizivir as soon as a hypersensitivity reaction is suspected. Discontinue Trizivir if hypersensitivity cannot be ruled out, even when other diagnoses are possible (eg, acute onset respiratory disease, gastroenteritis, or reactions to other medication). After a hypersensitivity reaction to abacavir, administration of Trizivir or any other abacavir-containing product should never be restarted because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Reintroduction of Trizivir or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours. A medication guide and warning card for abacavir-containing products must be provided by pharmacists to the patient with each new and refill prescription to provide further information to patients taking the drug.
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV and have discontinued use of lamivudine, which is 1 component of Trizivir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue use of Trizivir and are coinfected with HIV and HBV. If appropriate, initiation of anti–hepatitis B therapy may be warranted.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including abacavir, zidovudine, lamivudine, and other antiretroviral agents.
Zidovudine has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV disease. Prolonged use of zidovudine has been associated with symptomatic myopathy.
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism, and long-term consequences of these events are currently unknown.
The most common adverse events (≥5%) of at least moderate intensity associated with the use of Trizivir include nausea, headache, malaise and fatigue, nausea and vomiting, hypersensitivity reaction, diarrhea, fever or chills, depressive disorders, musculoskeletal pain, skin rashes, ear/nose/throat infections, viral respiratory infections, and anxiety.
Isolates containing abacavir resistance-associated mutations, namely, K65R, L74V, Y115F, and M184V, exhibited cross resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in vitro and in patients.
For full prescribing information on Trizivir, visit www.treathiv.com and click the "Products" link.
May 17, 2005
ST. LOUIS (MD Consult) - On May 13, 2005, Swiss drugmaker Roche announced that the US Food and Drug Administration (FDA) has approved Pegasys (peginterferon alfa-2a), the most prescribed hepatitis C medication in the United States, for the treatment of chronic hepatitis B. Pegasys is the first pegylated interferon approved for the treatment of chronic hepatitis B; the approval applies to both HBeAg-positive and HBeAg-negative variations of the virus.
Pegasys was approved in 2002 by the FDA for use alone and in combination with Copegus (ribavirin) for the treatment of adults with chronic hepatitis C. In February 2005, Pegasys became the first therapy to be approved alone and in combination with Copegus for the treatment of chronic hepatitis C in patients coinfected with hepatitis C and HIV whose HIV is clinically stable. Pegasys and Copegus are indicated in combination for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha.
Pegasys has a dual mode of action; it slows replication of the hepatitis B virus and boosts the immune system.
The 2 large-scale multinational phase III trials involved more than 1,500 patients with both the HBeAg-positive and HBeAg-negative variations of chronic hepatitis B and demonstrated that 24 weeks after a defined 48-week period of therapy, more patients achieved a sustained response with Pegasys than with lamivudine. These studies showed that the addition of lamivudine to Pegasys did not improve response rates over Pegasys alone.
Specifically, hepatitis B patients treated with Pegasys had higher rates of:
Conclusions regarding the comparative efficacy of Pegasys and lamivudine treatment based on the end of follow-up results are limited by the different mechanisms of action of the 2 compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.
Recent results from a long-term follow-up study presented at the April 2005 meeting of the European Association for the Study of the Liver (EASL) indicate that patients with HBeAg-negative chronic hepatitis B who responded to treatment with Pegasys maintained the benefit for at least a year after treatment.
The phase III study results in HBeAg-negative chronic hepatitis B were published in September 2004 in The New England Journal of Medicine. The results of the phase III study in patients with HBeAg-positive chronic hepatitis B were presented at the 2004 annual meeting of EASL. Lead investigators of both studies stated that the results of the trials warrant Pegasys becoming a first-line treatment for HBeAg-positive and HBeAg-negative chronic hepatitis B.
Salvatore Badalamenti, MD, Medical Director at Roche, pointed out that chronic hepatitis B infection is a serious disease causing more than 5,000 deaths in the United States annually. The US Centers for Disease Control and Prevention estimate that 1.25 million people in the United States are chronically infected with hepatitis B. Chronic hepatitis B can lead to cirrhosis, hepatocellular carcinoma, and death. In the United States, the most common modes of transmission of the hepatitis B virus are sexual and blood-to-blood contact, although the disease can also be transmitted from pregnant women to their infants.
The number of new infections in the United States has decreased in recent years, in part due to the introduction of the hepatitis B vaccine in 1982. Almost all (90% to 95%) adults who contract hepatitis B clear the virus from their systems within a few months and develop immunity. The remainder of the infections become chronic, which is when the virus stays in the blood, infecting liver cells and possibly damaging them.
Patients in whom efficacy was demonstrated include patients with compensated liver disease and histologic evidence of cirrhosis.
Pegasys is contraindicated in patients with hypersensitivity to Pegasys or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic chronic hepatitis C monoinfected patients before or during treatment. Pegasys is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic chronic hepatitis C patients coinfected with HIV before or during treatment.
Pegasys is contraindicated in neonates and infants because it contains benzyl alcohol, which is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal. Pegasys and Copegus therapy is additionally contraindicated in patients with a hypersensitivity to Copegus or any of its components and in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
Pegasys is dosed at 180 mcg as a subcutaneous injection taken once a week. Copegus is administered orally at doses of 800 to 1,200 mg daily. For more information, visit Roche's worldwide (roche.com) and US Web sites (roche.us).
May 9, 2005
ST. LOUIS (MD Consult) - Canadian pharmaceutical company Biovail Corporation announced May 6, 2005, that it has received approval from the US Food and Drug Administration (FDA) for Tramadol ODT (tramadol hydrochloride), an orally disintegrating tablet in a 50-mg dose. The analgesic medication is indicated for the treatment of moderate to moderately severe pain in adults.
The orally disintegrating formulation makes administration of the medication easier for patients who have difficulty swallowing tablets. A 2004 study of the American population concluded that nearly 40% of adults have experienced problems with swallowing tablets, and a significant proportion of those fail to comply properly with their prescribed and ongoing dosage. Persons with conditions such as postprocedural pain with swelling and the associated swallowing impairment, which require acute analgesic treatment, will benefit from the immediate orally dissolving tablet form.
At this time, the FDA is willing to allow Biovail to choose a trademark when an agreement is reached with a yet-to-be-named marketing partner and a final trademark is mutually agreed. Therefore, the company is not announcing a trade name at this time.
Tramadol ODT is a central-acting analgesic in an orally disintegrating formulation. Although its mode of action is not completely understood, based on tests in animals, at least 2 complementary mechanisms appear applicable: binding of parent and M1 metabolite to µ-opioid receptors, and weak inhibition of reuptake of norepinephrine and serotonin. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall profile of tramadol. Analgesia in humans begins within approximately 1 hour after administration and reaches a peak in approximately 2 to 3 hours.
According to labeling derived from its reference listed drug, Ultram, tramadol has been given in single oral doses of 50, 75, and 100 mg to patients with pain after surgical procedures and pain after oral surgery (eg, extraction of impacted molars). In single-dose models of pain after oral surgery, pain relief was demonstrated in some patients at doses of 50 and 75 mg. A dose of 100 mg of tramadol tended to provide analgesia superior to 60 mg of codeine sulfate, but it was not as effective as the combination of aspirin (650 mg) with codeine phosphate (60 mg).
Tramadol has been studied in 3 long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of 1 to 3 months' duration. Average daily doses of approximately 250 mg of tramadol in divided doses were generally comparable to 5 doses of acetaminophen (300 mg) with codeine phosphate (30 mg) daily, 5 doses of aspirin (325 mg) with codeine phosphate (30 mg) daily, or 2 to 3 doses of acetaminophen (500 mg) with oxycodone hydrochloride (5 mg) daily.
In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol dose of 200 mg (50 mg qid), attained in 50-mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration.
Tramadol ODT should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product, or opioids. Tramadol ODT is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids, or psychotropic drugs. Tramadol ODT may worsen central nervous system (CNS) and respiratory depression in these patients.
Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous postmarketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking selective serotonin reuptake inhibitors (antidepressants or anorectics), tricyclic antidepressants and other tricyclic compounds (eg, cyclobenzaprine, promethazine), or opioid drugs.
Administration of tramadol may enhance the seizure risk in patients taking monoamine oxidase inhibitors, neuroleptic agents, or other drugs that reduce the seizure threshold. The risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or patients with a recognized risk for seizure (eg, head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In case of tramadol overdose, naloxone administration may increase the risk of seizure.
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur, it is often after the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramadol ODT.
Tramadol's minimal propensity to induce adverse effects is an advantage over morphine-like agents. According to Biovail, tramadol causes less dependence and less respiratory depression relative to morphine.
Tramadol is currently available under the brand name Ultram (Ortho-McNeil) and in several generic formulations. Branded and generic formulations of tramadol are indicated for the management of moderate to moderately severe pain and may be dosed 4 to 6 times per day, not to exceed 400 mg.
For more information about Biovail, visit the company's Website at biovail.com.
May 6, 2005
ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) has approved Requip (ropinirole hydrochloride) tablets for the treatment of moderate to severe primary restless legs syndrome (RLS) in adults, GlaxoSmithKline announced on May 5, 2005. Requip is the first and only FDA-approved treatment for those patients with moderate to severe primary RLS, a chronic and disruptive neurologic condition. RLS, which encompasses a range of severity that includes mild, moderate, and severe symptoms, affects approximately 1 in 10 adults in the United States.
Identified in the early 1940s by neurologist Dr. Karl Ekbom, RLS is characterized by a compelling urge to move the legs and by uncomfortable or sometimes painful sensations in the legs often described as creeping-crawling tingling, pulling, or tightening. Symptoms of RLS generally occur at rest, such as when sitting, lying, or sleeping, and are temporarily relieved by movement. These symptoms can significantly disrupt a patient's sleep and daily activities. People with RLS often have difficulty falling and staying asleep and can feel less alert during the day.
Requip is a second-generation dopamine agonist that directly stimulates dopamine receptors in the brain. Although its exact cause is unknown, researchers believe that the underlying cause of RLS may be related to dopamine, a chemical that carries the signals between nerve cells that control body movement. When the dopamine system does not function properly, it can upset the normal communication of these signals.
The approval of Requip for moderate to severe primary RLS is supported by data from 4 double-blind, randomized, placebo-controlled clinical trials in adults diagnosed with RLS. Patients with RLS resulting from other conditions (eg, iron deficiency, pregnancy, and renal failure) were excluded from the study groups.
In the most recently completed US trial, Requip significantly improved symptoms of moderate to severe primary RLS in patients from baseline to week 12, according to 2 validated measurement tools: the International RLS (IRLS) Rating Scale and Clinical Global Impression-Global Improvement (CGI-I) scale. Patients taking Requip achieved a significantly greater mean improvement in IRLS Rating Scale total score compared with the placebo group (–13.5 points vs –9.8 points, respectively; P < .0001) and significantly more patients taking Requip showed a "much improved" or "very much improved" score on the CGI-I scale compared with the placebo group (73.3% vs 56.5%, respectively; P = .0006). In 2 other similarly designed trials that took place in centers largely outside of the United States, Requip also significantly improved IRLS Rating Scale and CGI-I scale scores from baseline to week 12. Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week relapse prevention study. In this trial, patents taking Requip demonstrated a significantly lower relapse rate compared with patients randomly assigned to receive placebo (32.6% vs 57.8%; P = .0156).
In clinical trials in the treatment of moderate to severe primary RLS, the most commonly observed adverse events for Requip (n = 496) versus placebo (n = 500) were nausea (40% vs 8%), somnolence (12% vs 6%), vomiting (11% vs 2%), dizziness (11% vs 5%), and fatigue (8% vs 4%). Occurrences of nausea in clinical trials were generally mild to moderate in intensity.
In general, many people with RLS report a significant impact on their daily activities because of the condition. In addition to feeling less alert during the day, RLS sufferers may also have difficulty with activities that require prolonged sitting such as movies, long car rides, or airline flights. Difficulty falling asleep may frequently be associated with moderate to severe primary RLS.
Women account for approximately two thirds of persons with RLS, although RLS occurs in both men and women. RLS is generally a chronic condition, and frequency of symptoms tends to increase with age. In addition, a genetic component has been suggested for patients with primary RLS. Clinical data demonstrate a positive family history of the disorder in as many as 50% of affected persons. When evaluating patients' symptoms of RLS, it is important for health care providers to rule out other underlying conditions that are associated with secondary RLS symptoms, such as iron deficiency, pregnancy, and renal failure.
Despite the prevalence of RLS, it frequently remains underdiagnosed. A wide range of other diagnoses, including back pain, depression, arthritis, nocturnal cramps, insomnia, and neuropathy have been given to patients who exhibit symptoms of RLS.
Requip may cause patients to fall asleep or feel very sleepy while doing normal activities such as driving; or to feel faint or dizzy, nauseated, or sweaty when they stand up from sitting or lying down. If patients experience these problems, they should talk to their doctors.
For more on RLS, visit restlesslegs.com. Full prescribing information is available on Requip.com.
May 4, 2005
ST. LOUIS (MD Consult) - GlaxoSmithKline announced on May 3, 2005, that its booster vaccine, Boostrix (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed [Tdap]) has received further approval from the US Food and Drug Administration (FDA). Boostrix is now indicated to be given as a single dose to individuals aged 10 to 18 years thereby adding a pertussis component to the routine tetanus/diphtheria booster currently administered to teens. Previously, there was no pertussis vaccine approved for use in the United States in children 7 years of age or older. Immunity from childhood vaccination generally begins to wear off after 5 to 10 years, leaving many adolescents susceptible to this highly contagious disease.
Gary Marshal, MD, professor of Pediatrics, University of Louisville School of Medicine, Louisville, Ky, said, "Adding pertussis to the current tetanus and diphtheria booster shot for teens is a logical strategy to prevent this disease in adolescents—without additional injections."
Reported cases of pertussis have risen nearly 20-fold since 1976. According to the US Centers for Disease Control and Prevention (CDC), there were almost 20,000 cases in 2004—the highest number of reported cases in more than 40 years.
In addition, experts believe the disease is underreported and estimate that the true incidence of the disease in the United States may be greater than 1 million cases per year. Adolescents aged 10 to 19 years are being hit particularly hard, with almost 40% of cases reported to the CDC in 2004 occurring in this age group. Alarmingly, there was a 743% increase in reported adolescent pertussis cases in the last decade. Teens, in whom classic signs and symptoms of pertussis are often absent, may go undiagnosed and be the source of infection for susceptible family members.
In making its decision, the FDA reviewed several clinical trials that included safety and immunogenicity data from 1 pivotal trial, which studied Boostrix in approximately 3,000 adolescents in the United States, aged 10 to 18 years. The phase III clinical trial showed Boostrix to be comparable to a US-licensed tetanus and diphtheria toxoids for adult use (Td) vaccine with regard to overall safety and immunogenicity. In addition, the use of Boostrix induced antipertussis antibody levels that were not inferior to those observed in infants after a primary immunization series with a diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP) vaccine (Infanrix). In the infants in that trial, efficacy against pertussis disease had been demonstrated in a previous study. As compared with Infanrix, the ratio of geometric mean antibody levels to pertussis antigens after the use of Boostrix ranged from 1.9 to 7.3.
In this observer-blinded, randomized, controlled, multicenter clinical trial, 4,114 healthy 10- to 18-year-olds were vaccinated with 1 dose of Boostrix or a US-licensed Td vaccine. Each subject had completed his or her routine childhood vaccinations against diphtheria, tetanus, and pertussis according to the US-recommended schedule. Study results included the following:
Pertussis, commonly known as "whooping cough," is a highly contagious bacterial infection of the respiratory system that causes spasms of severe coughing. Up to 90% of nonvaccinated susceptible household members may develop the disease when exposed to people infected with pertussis. It is spread through airborne droplets of an infected person's cough or sneeze. The first symptoms of pertussis are similar to the "common cold" with a mild fever, runny nose, and a cough. Symptoms generally progress to more severe coughing episodes, often with a high-pitched "whoop," followed by vomiting. Adolescents generally exhibit different symptoms of the disease, often without the classic "whoop," making it difficult to diagnose. However, for these older pertussis sufferers, severe coughing episodes can lead to vomiting, a hernia, or even a broken rib. These severe coughing episodes can last more than 100 days. While pertussis is threatening to all, this highly contagious disease can be deadly in infants who are too young to be fully immunized.
Although the disease is usually less severe in adolescents, morbidity can be considerable. In interviews with 314 adolescents with confirmed pertussis, a total of 83% of the adolescents missed a mean of 5.5 days from school, and 38% of the adolescents were still coughing at the time of the interview, which occurred an average of 106 days after cough onset.
In addition to the public health threat pertussis poses, the disease also has economic repercussions. A cost-benefit analysis for the use of a pertussis booster vaccine in adolescents projected that vaccination of people in the United States aged 10 to 19 years old during a 10-year period would prevent up to 1.8 million cases of pertussis and save as much as $1.6 billion in direct and indirect costs.
Diphtheria is a serious disease that results in the death of approximately 5% to 10% of infected persons, with higher death rates (up to 20%) in persons younger than 5 years and older than 40 years of age. Symptoms may include malaise, sore throat, and low-grade fever. As the disease progresses, a membrane can form over the airway and result in respiratory obstruction, which can lead to death. Other complications may include heart failure and paralysis. Most cases of diphtheria occur among unvaccinated or inadequately vaccinated persons.
Tetanus is a severe, often fatal disease. The bacteria that cause tetanus are widely found in soil and the manure of many animals. Almost all reported cases of tetanus are in persons who have either never been vaccinated, or who completed a primary series, but have not had a booster in the preceding 10 years. Infants of unvaccinated mothers are at risk for neonatal tetanus. Early symptoms are lockjaw, stiffness in the neck and abdomen, and difficulty swallowing. Later symptoms may include fever, elevated blood pressure, and severe muscle spasms.
Boostrix is indicated as a booster vaccination for the prevention of tetanus, diphtheria, and pertussis as a single dose in individuals 10 to 18 years of age. Boostrix can be given if at least 5 years have elapsed since the last recommended series of childhood diphtheria, tetanus, and pertussis vaccine. In clinical studies, adverse events included injection-site pain, headache, and fatigue. As with other vaccines, rare adverse events may occur.
US operations for GlaxoSmithKline are based in Research Triangle Park, NC, and Philadelphia. For more information, visit gsk.com.
May 2, 2005
ST. LOUIS (MD Consult) - On April 29, 2005, the US Food and Drug Administration approved the use of Kaletra (lopinavir, ritonavir) 800/200 mg once-daily administration for the treatment of HIV infection in therapy-naive adult patients, based on review and analysis of 2 clinical trials comparing safety and efficacy of lopinavir/ritonavir 800/200 mg once daily (qd) and lopinavir/ritonavir 400/100 mg twice daily (bid), for a duration of at least 48 weeks in antiretroviral-naive HIV-1–infected subjects.
At this time, once-daily Kaletra is not approved for treatment-experienced patients because trough concentrations of lopinavir are approximately 60% higher than that observed in the twice-daily regimen and because there are no clinical studies comparing the 2 dosing schedules in treatment-experienced persons.
The following is a summary of the labeling changes associated with the new indication.
Pharmacokinetic data for Kaletra given as 800/200 mg once daily in HIV-1–infected antiretroviral-naive adult subjects were added. Specifically, the following text was included:
| Clinical Pharmacology
The pharmacokinetics of once-daily Kaletra have been evaluated in HIV-infected subjects naive to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir 300 mg as part of a once-daily regimen. Multiple dosing of 800/200 mg Kaletra QD for 4 weeks with food (n = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 µg/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 3.2 ± 2.1 µg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 µg/mL. Lopinavir [area under the curve] over a 24-hour dosing interval averaged 154.1 ± 361.4 µg · h/mL. |
A statement that once-daily dosing of Kaletra has not been evaluated in pediatric patients was also included.
The Indications and Usage section of the labeling was changed as follows:
| Indications and Usage
Once-daily administration of Kaletra is not recommended in therapy-experienced patients. When initiating treatment with Kaletra in therapy-naive patients, it should be noted that the incidence of diarrhea was greater for Kaletra once daily compared with Kaletra twice daily in Study 418 (57% vs 35%—events of all grades and probably or possibly related to drug; 16% vs 5%—events of at least moderate severity and probably or possibly related to drug). |
Results from study M02-418 were included as follows:
| Indications and Usage
Description of Clinical Studies Study 418: Kaletra QD + tenofovir DF + emtricitabine compared with Kaletra BID + tenofovir DF + emtricitabine Study 418 is an ongoing, randomized, open-label, multicenter trial comparing treatment with Kaletra 800/200 mg QD plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg BID plus tenofovir DF and emtricitabine in 190 antiretroviral treatment-naive patients. Patients were aged a mean of 39 years (range, 19-75 years); 54% were white and 78% were male. The mean baseline CD4 cell count was 260 cells/mm3 (range, 3-1,006 cells/mm3) and the mean baseline plasma HIV RNA was 4.8 log10 copies/mL (range, 2.6-6.4 log10 copies/mL). |
In the Precautions section of the drug labeling, the table entitled "Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction" was revised to include information that Kaletra should not be administered once daily in combination with efavirenz, nevirapine, amprenavir, nelfinavir, carbamazepine, phenobarbital, or phenytoin. In addition, a statement that Kaletra once daily has not been studied in combination with indinavir or saquinavir was included.
The adverse reaction profile and laboratory abnormalities observed in the Kaletra-once-daily study were included in the Adverse Reactions section.
The Dosage and Administration section was modified to include dosing instructions for therapy-naive and therapy-experienced patients as follows:
| Adults
Therapy-Naive Patients
Therapy-Experienced Patients
Once-daily administration of Kaletra is not recommended in therapy-experienced patients. |
In addition, Kaletra's labeling has been amended to include the instruction that the drug should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir, or nelfinavir. Also mentioned is that Kaletra once-daily has not been evaluated in pediatric patients and is therefore not approved for use in that cohort.
Kaletra is manufactured by Abbott Laboratories, North Chicago, Ill. Complete US prescribing information is available at www.rxabbott.com/pdf/kaletrapi.pdf.
April 18, 2005
ST. LOUIS (MD Consult) - Millennium Pharmaceuticals, Inc, announced on March 25, 2005, that the U.S. Food and Drug Administration (FDA) approved the company's supplemental new drug application for Velcade (bortezomib). This approval expands the label to include the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Velcade is the only drug therapy that has demonstrated a significant survival advantage compared with a standard therapy in relapsed multiple myeloma. Initial accelerated approval for relapsed and refractory multiple myeloma was granted in May 2003. Velcade is now fully approved in relapsed multiple myeloma.
The approval was based on data from the randomized phase III APEX study that compared single-agent Velcade with a traditional multiple myeloma therapy, high-dose dexamethasone. The study demonstrated a significant survival advantage with Velcade (P < .05) in patients who had received 1 to 3 prior therapies. Importantly, this pronounced survival advantage was also observed in the second-line multiple myeloma patients. The safety profile of Velcade remained consistent with previous phase II findings. This indication doubles the number of US patients who could potentially benefit from Velcade to approximately 22,000.
The approval of this supplementary filing comes approximately 22 months after the initial FDA approval of Velcade for injection. Velcade, the first of a new class of medicines called proteasome inhibitors, is the first treatment in more than a decade to be approved for patients with multiple myeloma, a cancer of the blood.
The supplemental new drug application submission was based primarily on the results of the phase III APEX study, which compared Velcade with high-dose dexamethasone. The APEX trial enrolled 669 patients with relapsed multiple myeloma (patients had received 1 to 3 prior therapies) at 93 centers in North America, Europe, and Israel. This study was conducted under the direction of Paul Richardson, MD, clinical director of the Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute. The APEX trial was halted 1 year early after an independent data-monitoring committee concluded the findings of a prespecified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of Velcade.
In the overall study population, Velcade was superior to high-dose dexamethasone based on time to progression (P < .0001), overall survival (P < .05), and response rate (P < .0001). Additional findings include the following:
Among the 251 second-line multiple myeloma patients (those who had only 1 prior therapy), Velcade was superior based on time to progression (P = .0019), response rate (P = .0035), and overall survival (P < .05). Additional findings include the following:
Adverse events on the Velcade arm were predominantly grade 1 or 2, were similar to those previously observed in other trials, and were considered manageable by the investigators. The most commonly reported adverse events were asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, and anorexia and decreased appetite. The most common serious adverse events were pyrexia, diarrhea, dyspnea, pneumonia, and vomiting.
Velcade is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. Risks associated with this medication include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events, thrombocytopenia, and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with Velcade.
In 331 patients who were treated with the 1.3-mg/m2 dose of Velcade in the phase III APEX study, the most commonly reported adverse events were asthenic conditions (61%), diarrhea (57%), nausea (57%), constipation (42%), peripheral neuropathy (36%), vomiting (35%), pyrexia (35%), thrombocytopenia (35%), psychiatric disorders (35%), and anorexia and decreased appetite (34%). Fourteen percent of patients reported at least 1 episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (4%), neutropenia (2%), and hypercalcemia (2%). A total of 144 patients taking Velcade (44%) reported serious adverse events during the study; most commonly reported were pyrexia (6%), diarrhea (5%), dyspnea and pneumonia (4%), and vomiting (3%).
Additional data on Velcade, including prescribing information, is available at mlnm.com/clinicians/oncology/velcade.
Velcade is being co-developed by Millennium, based in Cambridge, Mass, and Johnson & Johnson Pharmaceutical Research & Development, LLC. For more information about Velcade clinical trials, contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).
April 15, 2005
ST. LOUIS (MD Consult) - Merck & Co, Inc, announced on April 14, 2005, that the US Food and Drug Administration (FDA) has approved a new indication for Hyzaar (losartan potassium-hydrochlorothiazide tablets), the company's fixed-dose combination antihypertensive drug. Hyzaar is now indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (LVH), but there is evidence that this benefit does not apply to black patients.
The new indication for reduction in stroke is based on the landmark Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. In March 2003, the FDA approved the same indication for Merck's antihypertensive drug Cozaar (losartan potassium tablets). Hyzaar and Cozaar are the only angiotensin II receptor blockers indicated to reduce the risk of stroke in patients with hypertension and LVH. Hyzaar is the fixed-dose combination of Cozaar and hydrochlorothiazide. The FDA approved this indication for Hyzaar based on:
In the 9,193-patient LIFE study, treatment with a regimen based on losartan (Cozaar) significantly reduced the risk of stroke (fatal and nonfatal) by 25% in patients with hypertension and LVH versus treatment with a regimen based on the beta-blocker atenolol (P = .001). There were 232 fatal and nonfatal strokes in the group treated with losartan and 309 in the atenolol group. Other findings from the LIFE study showed no significant difference between the treatment groups in the risk of heart attack or cardiovascular death.
Blood pressure reduction measured at trough was similar for both treatment groups. At the end of the study or at the last visit before a primary end point, the mean blood pressures were 144.1/81.3 mm Hg for the losartan-based group and 145.4/80.9 mm Hg for the atenolol-based group. The difference in systolic blood pressure of 1.3 mm Hg was significant (P < .001), whereas the difference of 0.4 mm Hg in diastolic blood pressure was not significant (P = .098).
According to the 2005 update of the American Heart Association's Heart Disease and Stroke Statistics, each year an estimated 700,000 Americans experience a new or recurrent stroke. Stroke is the third leading cause of death and a leading cause of severe, long-term disability in the United States. LVH is the most common cardiac abnormality associated with longstanding hypertension and is an important predictor of the risk of stroke. Not all patients with stroke have both hypertension and LVH.
"High blood pressure is the most important risk factor for stroke," said George L. Bakris, MD, director of the Hypertension/Clinical Research Center, Rush University Medical Center. "Widely used guidelines state that more than two thirds of patients with hypertension require 2 or more therapies to reach their blood pressure goal, 1 of which should usually be a thiazide-type diuretic." In addition to effective blood pressure lowering, Hyzaar may be effective for reducing the risk of stroke in appropriate patients with hypertension and LVH.
In the LIFE trial, 4,605 patients were randomly assigned to receive 50 mg of losartan once daily and 4,588 patients were assigned to receive 50 mg of atenolol once daily. If goal blood pressure (<140/90 mm Hg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (eg, increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium channel blockers, alpha-blockers, or centrally acting agents, but not angiotensin-converting enzyme inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure. Patients in the LIFE trial were followed up for an average of 4.8 years.
The results showed that, in patients treated with losartan, the risk of first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction (primary end point) was reduced by a statistically significant 13% (P = .021) compared with patients treated with atenolol. This difference was primarily the result of an effect on fatal and nonfatal stroke. At least 1 of the components of the primary composite end point occurred in 508 patients in the group taking losartan and in 588 patients in the atenolol arm.
The new label for Hyzaar also states that, in the LIFE trial, black patients with hypertension and LVH taking atenolol had a lower risk of stroke than those taking Cozaar. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of Cozaar on reducing the risk of cardiovascular events in hypertensive patients with LVH apply to black patients.
The label indicates that the usual starting dose for hypertensive patients with LVH is 50 mg of losartan once daily. Hydrochlorothiazide 12.5 mg should be added or Hyzaar 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, Cozaar 100 mg and hydrochlorothiazide 12.5 mg may be substituted, followed by Cozaar 100 mg and hydrochlorothiazide 25 mg or Hyzaar 100-25. The maximum dose is 1 tablet of Hyzaar 100-25 once daily.
In clinical trials, including the LIFE study, treatment with losartan potassium-hydrochlorothiazide was generally well tolerated. In these trials, adverse experiences have been limited to those that were reported previously with losartan potassium, hydrochlorothiazide, or both. Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared with nonelderly patients and somewhat more frequent in blacks compared with nonblacks for both the losartan-hydrochlorothiazide and the control groups.
In addition to the new indication for Hyzaar to reduce the risk of stroke in patients with hypertension and LVH, Hyzaar is also the only combination antihypertensive product that is indicated for initial use in appropriate patients with severe hypertension. Hyzaar is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients. This unique indication is based on a 6-week double-blind, randomized study of the efficacy and safety of Hyzaar as initial therapy for severe hypertension (defined as a mean sitting diastolic blood pressure =110 mm Hg confirmed on 2 separate occasions off all antihypertensive therapy).
When used in pregnant patients during their second or third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Cozaar and Hyzaar should be discontinued as soon as possible.
Cozaar and Hyzaar are contraindicated in patients who are hypersensitive to any component of these products. Because of the hydrochlorothiazide component, Hyzaar is also contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Hyzaar is not recommended for patients with severe renal impairment (creatinine clearance ≤30 mL/min), nor is it recommended for titration for patients with hepatic impairment because the appropriate 25-mg starting dose of Cozaar cannot be given. In patients who are volume-depleted (eg, those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Hyzaar. This condition should be corrected before administration of Hyzaar. All patients receiving thiazides should be observed for clinical signs of fluid or electrolyte imbalance, including hypokalemia.
In patients who are volume depleted, symptomatic hypotension may occur after initiation of therapy with Cozaar. This condition should be corrected before administration of Cozaar, or a 25-mg dose of Cozaar should be used. In patients with a history of hepatic impairment, a starting dose of Cozaar 25 mg should be used. As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
In other clinical trials with losartan for hypertension, the most common adverse events with an incidence =2% of patients treated with Cozaar (n = 1,075) and occurring more commonly than placebo (n = 334) included upper respiratory infection (8% for losartan vs 7% for placebo), dizziness (3% vs 2%), nasal congestion (2% vs 1%), and back pain (2% vs 1%).
In other clinical trials with losartan potassium-hydrochlorothiazide, the overall incidence of adverse events was comparable to placebo. The most common adverse events occurring with various doses of losartan potassium-hydrochlorothiazide (n = 858) at a rate of 1% or more above placebo (n = 173) were upper respiratory infection (6.1% vs 4.6%), dizziness (5.7% vs 2.9%), cough (2.6% vs 2.3%), back pain (2.1% vs 0.6%), palpitations (1.4% vs 0%), and rash (1.4% vs 0%).
In the clinical study supporting the initial therapy indication, the overall side effect profile for patients with severe hypertension treated with Hyzaar as initial therapy was similar to the side effect profile in patients with severe hypertension treated with Cozaar as initial therapy. During the study period, there were no reported cases of syncope in either treatment group. There were 2 cases (0.6%) and no cases of hypotension reported in the groups treated with Hyzaar and Cozaar, respectively. There were 3 cases (0.8%) and 2 cases (1.2%) of increased serum creatinine (>0.5 mg/dL) in the groups treated with Hyzaar and Cozaar, respectively, during the same time period.
For complete presribing information for Hyzaar, visit cozaar.com/cozaar/shared/documents/pi_hyzaar.pdf.
April 12, 2005
ST. LOUIS (MD Consult) - On March 29, 2005, GlaxoSmithKline announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental new drug application for Zofran (ondansetron hydrochloride) injection to prevent nausea and vomiting associated with general anesthesia in children as young as 1 month of age and nausea and vomiting associated with chemotherapy in children as young as 6 months of age.
The application was filed on September 28, 2004, and was granted priority review status by the FDA. This new indication makes Zofran the only medication approved to prevent postoperative nausea and vomiting (PONV) and chemotherapy-induced nausea and vomiting (CINV) in infants. Zofran was previously the first product to receive a pediatric indication for the prevention of PONV and CINV in children 2 years of age and older.
In a double-blind, multicenter, placebo-controlled study of 670 pediatric patients aged 1 month to 2 years undergoing routine surgery under general anesthesia, a single (0.1 mg/kg intravenous) dose of Zofran Injection, administered within 5 minutes after induction of anesthesia, was significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of patients experienced vomiting compared with 11% of subjects who received Zofran. Overall, 10% of patients given placebo received antiemetic rescue medication or prematurely withdrew from the study, compared with 5% of patients who received Zofran. The incidence of adverse events considered possibly related to study medication was similar between Zofran and placebo (2% vs 1%). The most commonly reported related adverse events, agitation and swelling, occurred in less than 1% of either group.
The safety and antiemetic effects of Zofran Injection in the prevention of chemotherapy-induced vomiting were studied in an open-label, multicenter, noncomparative trial of Zofran in 75 pediatric cancer patients 6 months to 4 years of age receiving chemotherapy that would be expected to result in at least 50% of patients experiencing an episode of vomiting if no antiemetic agent were administered. Study results showed that 56% of patients who received Zofran intravenously over 15 minutes in 3 doses of 0.15 mg/kg (first dose administered 30 minutes before the start of chemotherapy, the second and third doses administered at 4 and 8 hours after the first dose, respectively) experienced a complete response, defined as no vomiting, no use of rescue medication, and no early withdrawal from the study. No serious adverse events were reported in the study. Only one adverse event in the study, a rash, was thought to be possibly related to treatment with Zofran.
For more details, including full prescription information, visit gsk.com or zofran.com.
April 12, 2005
ST. LOUIS (MD Consult) - On March 25, 2005, Roche and GlaxoSmithKline announced that the U.S. Food and Drug Administration (FDA) has approved once-monthly oral Boniva (ibandronate sodium) 150-mg tablets, the first once-a-month treatment of postmenopausal osteoporosis. Boniva, an effective bisphosphonate, is the first oral treatment administered as a single tablet given once a month for any chronic disease. Current regimens involve weekly or daily treatments.
Once-monthly Boniva is a small, film-coated tablet. Patients should take Boniva with plain water on an empty stomach upon rising in the morning. They should remain upright and avoid food, drink, and other medications for at least 60 minutes.
According to GlaxoSmithKline, once-monthly Boniva is expected to be available in U.S. pharmacies in April 2005. The alternate formulation of Boniva (2.5 mg daily) is currently available and is also indicated for the treatment and prevention of postmenopausal osteoporosis.
Daily Boniva (2.5 mg) was approved based on studies showing that, over 3 years, the drug significantly reduced the risk of new vertebral fractures in women with postmenopausal osteoporosis and increased bone mineral density (BMD) in postmenopausal women without osteoporosis.
Once-monthly oral Boniva (150 mg) was approved based on results from the Monthly Oral iBandronate In LadiEs (MOBILE) study, a randomized, double-blind, multinational, noninferiority trial in 1,602 women with postmenopausal osteoporosis. MOBILE showed the following:
Boniva is contraindicated in patients unable to stand or sit upright for at least 60 minutes, those with uncorrected hypocalcemia, or those with known hypersensitivity to any component of Boniva. Boniva, like other bisphosphonates administered orally, may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer. Boniva is not recommended for patients with severe renal impairment. Adequate intake of calcium and vitamin D is important in all patients.
Patients taken Boniva have reported, though rarely, severe bone, joint, or muscle pain after taking bisphosphonate therapy for osteoporosis. Additionally, osteonecrosis of the jaw has rarely been reported in patients treated with bisphosphonates; most cases have been in patients with cancer undergoing dental procedures.
The most commonly reported adverse events with once-monthly Boniva regardless of causality were abdominal pain (Boniva 150 mg, 7.8% vs Boniva 2.5 mg, 5.3%), hypertension (6.3% vs 7.3%), dyspepsia (5.6% vs 7.1%), arthralgia (5.6% vs 3.5%), nausea (5.1% vs 4.8%), and diarrhea (5.1% vs 4.1%). For complete prescribing information for Boniva, visit rocheusa.com/products/boniva/.
The approval of this new formulation follows a 2004 report from the U.S. Department of Health and Human Services (DHHS) in which osteoporosis was named as a major public health threat on par with smoking and obesity. Forty-four million Americans older than 50 years of age are affected by or at risk for osteoporosis, a disease that can result in severe pain, deformity, disability, hospitalization, and even death. According to the National Osteoporosis Foundation, the prevalence of osteoporosis is growing as the number of postmenopausal women in the population increases. Together, osteoporosis and osteopenia are expected to affect 52 million women and men aged 50 years and older by 2010, and 61 million by 2020. In the DHHS report, the Surgeon General recommended simplifying and organizing treatment regimens.
GlaxoSmithKline invites patients who take Boniva to sign up for MyBONIVA, a patient support program designed to enhance compliance and persistence with the once-monthly regimen. More information on this program is available by calling 1-800-4BONIVA.
April 11, 2005
ST. LOUIS (MD Consult) - Merck & Co, Inc, announced on April 8, 2005, that the U.S. Food and Drug Administration (FDA) has approved Fosamax Plus D (alendronate sodium/cholecalciferol), a single once-weekly tablet containing 70 mg Fosamax (alendronate sodium) and 2,800 IU vitamin D3, representing a 7-day supply of 400 IU/d of vitamin D. Fosamax, a bisphosphonate, is indicated to reduce the risk of both hip and spine fractures in postmenopausal women with osteoporosis.
As the company pointed out, maintaining adequate levels of vitamin D is necessary for the development of strong bones because it helps increase the intestinal absorption of calcium. Vitamin D insufficiency is associated with reduced calcium absorption, bone loss, and increased risk of fracture. Patients at increased risk for vitamin D insufficiency (eg, those who are nursing-home bound, chronically ill, over the age of 70 years) and those with gastrointestinal malabsorption syndromes should receive vitamin D supplementation in addition to that provided in Fosamax Plus D.
The sustained efficacy of Fosamax for the treatment of osteoporosis in postmenopausal women was demonstrated in a trial that found, in over 10 years of therapy, 10 mg of Fosamax administered once daily maintained or continued to build bone.
Fosamax Plus D is indicated for the treatment of osteoporosis in postmenopausal women. The medication increases bone mass and reduces the incidence of fracture, including those of the hip and spine. Fosamax Plus D is also indicated to increase bone mass in men with osteoporosis.
The standard dosing regimen for Fosamax Plus D includes swallowing the tablet with 6 to 8 ounces of plain water the first thing on rising for the day and at least 30 minutes before ingesting any food, beverage, or other medication. After swallowing Fosamax Plus D, patients should not lie down for at least 30 minutes and not until after consuming their first food of the day. Patients should not chew or suck on a tablet of Fosamax Plus D.
Fosamax Plus D, like other bisphosphonate-containing products, should be used with caution in people with certain stomach or digestive problems. Fosamax Plus D should not be used if a patient has certain disorders of the esophagus that delay emptying or if the patient is unable to stand or sit upright for at least 30 minutes. In addition, this medication should not be used in patients with severe kidney disease or low levels of calcium in their blood, in persons who are allergic to Fosamax Plus D, or in women who are pregnant or nursing. Fosamax Plus D alone should not be used to treat vitamin D deficiency.
"Many physicians and patients frequently are unaware of the importance of vitamin D in bone health. Given its effect on calcium absorption, vitamin D insufficiency is an important medical concern for patients with osteoporosis, as it can lead to bone loss and an increased risk of fracture," said Robert Heaney, MD, Professor of Medicine at Creighton University, Omaha, Neb.
Vitamin D is obtained from two sources: sunlight and diet. The skin manufactures the majority of the body's vitamin D after direct exposure to sunlight, but as adults age the ability to make vitamin D through the skin diminishes. Avoiding sun exposure or using sunscreen can also limit a person's production of vitamin D. Vitamin D can come from the diet, too, but there are limited dietary sources that contain the nutrient. Good dietary sources include fatty fish (eg, salmon), vitamin D–fortified milk, and orange juice. However, for many people, dietary sources alone are not enough. For example, one must drink four 8-ounce glasses of milk to receive 400 IU of vitamin D.
According to an analysis published in 2004 and based on the Third National Health and Nutrition Examination Survey, a majority of Americans are not consuming enough vitamin D. The study estimated that over 70% of women aged 51 to 70 years and almost 90% of women older than 70 years are not getting an adequate intake of vitamin D from food and supplements. This analysis was based on the adequate intake, as defined by the National Institutes of Health's Institute of Medicine, of 400 IU/d for women aged 51 to 70 years and 600 IU/d for women older than 70 years. Other organizations, such as the National Osteoporosis Foundation, recommend vitamin D intake of up to 800 IU/d. As a weekly treatment for osteoporosis in postmenopausal women, Fosamax Plus D offers 2,800 IU vitamin D.
Some patients taking Fosamax Plus D may develop severe digestive reactions including irritation, inflammation, or ulceration of the esophagus. The risk of severe esophageal experiences appears to be greater in patients who fail to follow dosing instructions. Patients who experience new or worsening heartburn, difficulty or pain when swallowing, or chest pain should stop taking the drug and contact a physician immediately. Patients who develop severe bone, joint, or muscle pain at any time should contact a physician. The most commonly reported adverse effects with Fosamax in clinical studies have been abdominal pain (3.7%), musculoskeletal pain (2.9%), indigestion (2.7%), regurgitation (1.9%), and nausea (1.9%).
Osteoporosis, the most prevalent bone disease in the United States, can lead to bone loss and an increased risk of fractures. Over 10 million Americans older than 50 years of age have osteoporosis, and another 34 million have low bone mass. Osteoporosis is especially common in women after menopause, but it also occurs in older men. Most often, it is due to an increase in the rate of resorption of bone tissue that is not matched by the rate of bone formation. The risk of having an osteoporosis-related fracture increases with age. According to the U.S. Surgeon General, osteoporosis is a national health threat, and by 2020, 1 in 2 Americans over the age of 50 years will be at risk for fractures from osteoporosis or low bone mass. In fact, 1 of every 2 women older than 50 years will have an osteoporosis-related fracture in their remaining lifetime, with the risk of fracture increasing with age.
Full prescribing information for Fosamax Plus D is available by calling 1-800-344-7833 or by visiting merck.com/product/usa/pi_circulars/f/fosamax/fosamax_plus_d_pi.pdf.
April 4, 2005
ST. LOUIS (MD Consult) - On April 1, 2005, AstraZeneca announced that a new administration formulation for its prescription proton pump inhibitor Nexium (esomeprazole magnesium) has been approved by the U.S. Food and Drug Administration. Nexium I.V. is now approved as an intravenous infusion or injection for the short-term treatment (up to 10 days) of gastroesophageal reflux disease (GERD) in patients with a history of erosive esophagitis who are unable to take capsules.
Nexium I.V. for injection is administered once daily as either a 10- to 30-minute intravenous infusion or by intravenous injection (no less than 3 minutes). Treatment is given for up to 10 days and does not require an in-line filter.
The approval of Nexium I.V. was based, in part, on the findings of 4 multicenter, open-label, 2-period crossover studies. These studies compared the pharmacodynamic efficacy of the intravenous formulation with Nexium delayed-release capsules at corresponding doses of 20 and 40 mg in GERD patients with or without a history of erosive esophagitis. They demonstrated that, after 10 days of once-daily administration, Nexium I.V. 20 and 40 mg are similar in their ability to suppress acid to the corresponding oral dosage form of Nexium.
There were no relevant changes in acid suppression when switching between intravenous and oral dosage forms.
Nexium (delayed-release capsules) is indicated for treating frequent, persistent heartburn and other symptoms associated with acid reflux disease. The drug was recently approved for reducing the risk of gastric ulcers in at-risk patients receiving continuous nonsteroidal anti-inflammatory drug therapy. Nexium is also approved for healing erosive esophagitis. Studies show that conditions in up to 94% of patients were resolved with Nexium. Most erosions heal in 4 to 8 weeks.
For more information, visit nexium-us.com.
March 30, 2005
ST. LOUIS (MD Consult) - On March 24, 2005, the U.S. Food and Drug Administration announced that Wyeth Pharmaceuticals have reformulated Trecator-SC (ethionamide tablets, USP) Sugar-Coated Tablets to film-coated tablets. The new name of the product is Trecator Tablets. The immediate bottle label has been revised.
The new formulation was designed for improved stability. However, because the new film-coated tablet is more rapidly absorbed, resulting in higher peak concentrations (Cmax) of ethionamide, it may potentially lead to patient intolerance when introduced at the same initial dose as the old sugar-coated tablet.
In a study of 40 healthy adult volunteers, the mean ethionamide area-under-the-curve for the film-coated tablet was not significantly different from that of the sugar-coated tablet; however, the mean Cmax for the film-coated tablet was significantly higher (approximately 46%) than that of the sugar-coated tablet. The median time to reach Cmax was also significantly shorter for the film-coated tablet compared with that of the sugar-coated tablet. Therefore, patients should be monitored and have their dosages retitrated when switching from the sugar-coated tablet to the film-coated tablet.
Trecator is primarily indicated in combination with other antituberculous drugs for the treatment of active tuberculosis in patients with Mycobacterium tuberculosis that is resistant to isoniazid or rifampin or when there is intolerance on the part of the patient to other drugs.
The usual adult dose is 15 to 20 mg/kg/d administered once daily or, if the patient exhibits poor gastrointestinal tolerance, in divided doses, with a maximum daily dose of 1 g. Therapy should be initiated at a dose of 250 mg daily, with gradual titration to optimal doses as tolerated by the patient. A regimen of 260 mg daily for 1 or 2 days followed by 250 mg twice daily for 1 or 2 days with a subsequent increase to 1 g in 3 or 4 divided doses has been reported with the sugar-coated formulation. This regimen has not been studied with the film-coated formulation.
The use of Trecator alone in the treatment of tuberculosis results in rapid development of resistance. Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug. The most common adverse effects of ethionamide are gastrointestinal disturbances, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 g as a single dose. Gastrointestinal effects can be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent.
Other adverse events include the following:
Full prescribing information for Trecator is available at www.wyeth.com/content/ShowLabeling.asp?id=473.
March 30, 2005
ST. LOUIS (MD Consult) - On March 29, 2005, Pfizer Inc announced that it has received U.S. Food and Drug Administration (FDA) approval for Depo-subQ Provera 104 (medroxyprogesterone acetate injectable suspension) for the management of pain associated with endometriosis, a gynecologic condition that affects 1 in 10 women of reproductive age. The medicine is the first new treatment option for endometriosis pain in 15 years.
Depo-subQ Provera 104 is a long-acting injectable contraception and a new formulation of medroxyprogesterone acetate, which is the same active ingredient as Depo-Provera Contraceptive Injection (medroxyprogesterone acetate injectable suspension).
Endometriosis occurs when excess endometrial tissue of the uterus migrates and implants in other areas of the body, most commonly on the ovaries, fallopian tubes, and other organs in the pelvic region. The major symptom of endometriosis is pelvic pain, particularly during the menstrual cycle. Endometriosis is 1 of the top 3 causes of infertility—30% to 40% of women with the disease are infertile—although the exact link is unknown.
Clinical data showed that Depo-subQ Provera 104 is equally as effective for treating pain caused by endometriosis as leuprolide acetate (LA), marketed by TAP Pharmaceutical Products Inc as Lupron Depot (leuprolide acetate for depot suspension), with significantly less decline in bone mineral density and lower incidence and severity of menopausal symptoms, such as hot flashes. Current treatment options include pain medication, surgery, or hormone therapy, including oral contraceptives or gonadotropin-releasing hormone agonists.
In an 18-month study involving 274 patients, Depo-subQ Provera 104 administered every 3 months was statistically equivalent to Lupron given every 3 months across all endometriosis-associated pain categories including pelvic pain, pelvic tenderness, painful periods, painful intercourse, and hardening/thickening of tissue. Lupron-treated patients showed significant decreases from baseline in both femur and lumbar spine bone mineral density at month 18, whereas patients taking Depo-subQ Provera 104 did not.
Administered by subcutaneous injection 4 times a year (every 12-14 weeks), Depo-subQ Provera 104 is effective in halting menstruation, which results in thinner, more compact endometrial tissue. This in turn halts the growth of endometrial implants, relieving endometriosis-associated pain. Depo-subQ Provera 104 is expected to be widely available in May 2005.
Depo-subQ Provera 104 received FDA approval for use as a contraceptive agent in December 2004. Injected every 3 months, Depo-subQ Provera 104 provides better efficacy than the original Depo-Provera Contraceptive Injection, but with 30% less hormone.
Women who use Depo-subQ Provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown whether use of Depo-subQ Provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture in later life. Depo-subQ Provera 104 should be used as a long-term birth control method (eg, longer than 2 years) only if other birth control methods are inadequate.
In the clinical trials, the most common side effect was irregular menstrual bleeding, typically followed by amenorrhea (loss of monthly menstrual period). The average weight gain after 1 year of use was 3.5 pounds.
Depo-subQ Provera 104 does not protect against sexually transmitted diseases, including HIV/AIDS.
Depo-subQ Provera 104 is contraindicated in patients with undiagnosed vaginal bleeding, known or suspected pregnancy, known or suspected breast malignancy, current or past thromboembolic or cerebral vascular disorders, or significant liver disease. Depo-subQ Provera 104 may be considered among the possible risk factors for the development of osteoporosis. The risk of osteoporosis should be assessed for women with multiple risk factors.
Depo-subQ Provera 104 does not require dosing adjustments based on body type, body mass index, or weight.
March 18, 2005
ST. LOUIS (MD Consult) - On March 16, 2005, the U.S. Food and Drug Administration announced it has approved a new indication for Temodar (temozolomide). The drug now has approval to be used concurrently with radiotherapy and as maintenance therapy after radiotherapy for adult patients newly diagnosed with glioblastoma multiforme (GBM), the most common form of malignant brain cancer.
GBM is usually fatal. The annual incidence of GBM is 4 to 5 cases per 100,000 persons with 8,000 to 10,000 new cases diagnosed per year in North America.
The new approval of Temodar for GBM was based on efficacy and safety data from a large randomized controlled study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in patients with newly diagnosed GBM. Patients were randomly assigned to receive treatment with radiation alone or treatment with radiotherapy plus temozolomide. In the multicenter trial of 573 patients, the median survival was improved by 2½ months in the temozolomide group, a significant benefit. The median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone.
Temodar was previously granted accelerated approval in 1999 for the treatment of adult patients with another form of brain tumor (anaplastic astrocytoma) in relapse after chemotherapy with nitrosourea and procarbazine.
Accelerated approval is a regulatory mechanism that allows approval of certain new drug products that treat serious or life-threatening illnesses and that may provide a meaningful therapeutic benefit to patients over existing treatments. Products approved through this route have been studied using an end point that is thought be reasonably likely to predict clinical benefit. After such accelerated approvals, the company must continue the clinical trials to determine whether the end point used as the basis for the accelerated approval indeed did predict a clinical benefit for the patient. If so, the product with an accelerated approval then will receive a traditional approval.
Based on the clinically important outcome in the GBM study (GBM and anaplastic astrocytoma are closely related tumors), the anaplastic astrocytoma indication is now approved under traditional procedures, and the accelerated approval requirements no longer apply.
Adverse effects for Temodar reported include nausea, vomiting, headaches, fatigue, and anorexia. Preventive treatment for pneumocystis carinii pneumonia is required when Temodar is administered with radiotherapy.
Temodar is manufactured by the Schering-Plough Corporation, Kenilworth, NJ. Full prescribing information is available at fda.gov/cder/foi/label/2005/021029s008lbl.pdf.
March 15, 2005
ST. LOUIS (MD Consult) - On March 11, 2005, Sepracor Inc announced that the U.S. Food and Drug Administration (FDA) has approved its new drug application for Xopenex HFA (levalbuterol tartrate) Inhalation Aerosol, a hydrofluoroalkane (HFA) metered-dose inhaler (MDI) for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease. Reversible obstructive airway disease includes respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).
Massachusetts-based Sepracor expects to launch Xopenex HFA near the end of 2005. Mark H.N. Corrigan, MD, Executive Vice President of Research and Development at Sepracor, stated that the new formulation will make Xopenex available to people with asthma who prefer to use an MDI. The new product will allow patients who are currently receiving Xopenex Inhalation Solution administered by nebulization to continue to use Xopenex when handheld administration is appropriate, he added.
The MDI development program included approximately 1,870 pediatric and adult subjects and 54 studies (preclinical and clinical). In 2003, Sepracor completed its phase III studies of Xopenex HFA. In each of the three, large-scale, pivotal phase III trials that Sepracor conducted, the Xopenex HFA MDI was well tolerated and met the targeted efficacy end points in both adults and children with asthma. In the primary airway function measure, forced expiratory volume in 1 second, the Xopenex HFA MDI produced statistically and clinically significant improvements relative to placebo.
Sepracor's Xopenex MDI uses state-of-the-art HFA technology and does not contain a chlorofluorocarbon (CFC) propellant. MDIs are portable, handheld devices consisting of a pressurized canister containing medication and a mouthpiece through which the medicine is inhaled. Each canister provides 200 inhalations. Xopenex HFA combines Sepracor's short-acting beta-agonist, Xopenex, and 3M's ability to manufacture MDIs, the device most commonly used by patients for the treatment of asthma and COPD.
Sepracor currently markets Xopenex Inhalation Solution, a short-acting bronchodilator indicated for the treatment or prevention of bronchospasm in patients 6 years of age and older with reversible obstructive airway disease. Xopenex Inhalation Solution is available for use in a nebulizer at 0.31-mg and 0.63-mg dosage strengths for treatment of children 6 to 11 years old, and in 0.63-mg and 1.25-mg doses for patients 12 years and older.
Approximately 90% of the short-acting beta-agonist inhalers sold in 2004 contained CFC propellants, according to IMS Health information. Under provisions in the Montreal Protocol on Substances that Deplete the Ozone Layer, an international agreement that requires the phasing out of substances that deplete the ozone layer, MDIs containing CFC propellants would be subject to eventual removal from the marketplace. In June 2004, the FDA issued a proposed rule for the removal of the essential use exemption for albuterol, which currently permits the use of CFC-containing albuterol inhalers despite environmental concerns. Removal of this essential use exemption would prevent albuterol products containing CFC propellants, including MDIs, from being marketed in the United States.
Asthma is a chronic lung disorder characterized by reversible airway obstruction and the pathologic finding of airway inflammation. According to the 2002 National Health Interview Survey conducted by the U.S. Centers for Disease Control and Prevention, nearly 31 million Americans have been diagnosed with asthma. It is the most common childhood illness and affects nearly 9 million children in the United States younger than 18 years of age. Short-acting beta-agonists are the most prescribed asthma therapy among primary care physicians and pediatricians in the United States, according to IMS Health information.
Xopenex HFA is contraindicated in patients with a history of hypersensitivity to levalbuterol, racemic albuterol, or any other component of Xopenex HFA. Xopenex HFA and other beta-agonists can produce paradoxical bronchospasm, which may be life threatening. If additional adrenergic drugs, including other short-acting sympathomimetic aerosol bronchodilators or epinephrine, are to be administered with Xopenex HFA by any route, they should be used with caution to avoid deleterious cardiovascular effects. Due to the cardiovascular adverse effects associated with beta-agonists, caution is generally recommended for patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders. Also, see the complete prescribing information regarding potential drug interactions with beta-blockers, diuretics, digoxin, or MAOI and tricyclic antidepressants.
FDA-approved labeling text for Xopenex HFA is available at www.sepracor.com.
March 9, 2005
ST. LOUIS (MD Consult) - Schering-Plough Corporation announced on March 4, 2005, that the U.S. Food and Drug Administration (FDA) has approved Clarinex-D 24 Hour (desloratadine 5 mg and pseudoephedrine sulfate USP 240 mg) Extended Release tablets for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in patients 12 years of age and older.
Available in April 2005, Clarinex-D 24 Hour will be the only once-daily prescription antihistamine and decongestant combination treatment on the market to provide 24-hour relief of nasal and non-nasal allergy symptoms. Clarinex-D 24 Hour Extended Release tablets should be administered when the antihistaminic properties of desloratadine and the nasal decongestant properties of pseudoephedrine are desired.
Seasonal allergies affect an estimated 36 million people in the United States. Symptoms include sneezing, runny nose, congestion, itchy throat, and itchy and watery eyes. In addition, there is a growing body of evidence that points to an association between allergies and more serious conditions, such as asthma.
According to a Schering-Plough press release, a survey of 1,000 adults with allergies found that 83% reported they experience symptoms in the morning, and more people indicated they suffer from nasal congestion, compared with other allergy symptoms, when they first wake up.
The drug's manufacturer, based in Kenilworth, NJ, stated that Clarinex-D 24 Hour controls the release of the pseudoephedrine component, ensuring once-daily 24-hour efficacy and allowing patients to wake up with their symptoms under control.
The FDA approved Clarinex-D 24 Hour based on results from two 2-week, randomized, parallel-group clinical trials involving 2,852 patients 12 to 78 years of age with seasonal allergic rhinitis, 708 of whom received Clarinex-D 24 Hour. In both trials, when symptoms of allergic rhinitis excluding nasal congestion were examined, the antihistaminic efficacy of Clarinex-D 24 Hour was significantly greater than pseudoephedrine or Clarinex 5 mg alone during the treatment period. And the decongestant efficacy of Clarinex-D 24 Hour, when measured by nasal congestion, was significantly greater than desloratadine during the treatment period.
The administration of Clarinex-D 24 Hour Extended Release tablets is contraindicated in patients with narrow-angle glaucoma, urinary retention, severe hypertension, or severe coronary artery disease and in patients receiving monoamine oxidase inhibitor therapy or within 14 days of stopping such treatment.
This medication should generally be avoided by patients with hepatic insufficiency. It should also be used with caution in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy. Pseudoephedrine hydrochloride may produce arrhythmias and cardiovascular collapse with accompanying hypotension or central nervous system stimulation with convulsions. Care should be taken in the concomitant administration of other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient.
The most commonly reported adverse events for Clarinex-D 24 Hour Extended Release tablets compared with desloratadine alone are dry mouth (8% vs 2%), headache (6% vs 5%), insomnia (5% vs 1%), fatigue (3% vs 3%), pharyngitis (3% vs 2%), and somnolence (3% vs 2%).
Clarinex is currently available in regular tablet, syrup, and new decongestant combination tablet formulations. Clarinex tablets are approved to treat the symptoms of seasonal and year-round allergies and hives of unknown cause in patients 12 years of age and older. Clarinex syrup is indicated to relieve allergy symptoms caused by seasonal allergens such as ragweed, grass, and tree pollens in patients 2 years of age and older and year-round allergens such as dust mites, animal dander, and mold spores in patients 6 months of age and older. Clarinex syrup is also approved to treat the ongoing itching and rash due to hives from unknown causes in patients 6 months of age and older.
Full prescribing information is available at www.spfiles.com/piclarinex.pdf.
March 3, 2005
ST. LOUIS (MD Consult) - On February 25, 2005, the U.S. Food and Drug Administration (FDA) approved efficacy supplements for Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), making them the first approved therapies for treatment of hepatitis C in patients who are also infected with HIV. Hepatitis C has become the most frequent cause of liver disease in patients with HIV and in some regions may be a leading cause of death.
The approvals expand the therapeutic indications to include peginteferon alone, or in combination with ribavirin, for the treatment of adult chronic hepatitis C in patients coinfected with HIV who have clinically stable HIV disease (patients either receiving stable HIV antiretroviral therapy, or those who have not met the criteria to begin therapy).
Coinfection has emerged as a major public health concern with data suggesting that, globally, about 30% of HIV-infected patients are coinfected with hepatitis C virus (HCV). Hepatitis C and HIV are the two most prevalent bloodborne infections in the United States, according to Roche, the Switzerland-based manufacturer of both Pegasys and Copegus.
The FDA and recent European Commission approval of Pegasys combination therapy for the treatment of HCV-HIV coinfected patients are based on results from the AIDS Pegasys Ribavirin International CO-infection Trial (APRICOT), the largest study to have evaluated chronic hepatitis C treatment in patients coinfected with HIV and HCV. The study included 868 patients from 19 countries. Patients coinfected with HIV-HCV were randomly assigned to receive either Pegasys 180 mcg once weekly plus Copegus 800 mg daily, Pegasys 180 mcg monotherapy once weekly (plus placebo), or conventional interferon alfa-2a (Roferon A) 3MIU three times a week in combination with Copegus 800 mg daily, all for 48 weeks.
The key results of APRICOT were:
The FDA notes that patients receiving Pegasys/Copegus and nucleoside reverse transcriptase inhibitors should be closely monitored for treatment-associated toxicities.
The FDA notes that patients receiving Pegasys/Copegus and nucleoside reverse transcriptase inhibitors should be closely monitored for treatment-associated toxicities.
The agency also notes that alpha interferons, including Pegasys (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping Pegasys therapy.
Complete prescribing information for both Pegasys and Copegus is available at www.rocheusa.com/products/pegasys/.
February 24, 2005
ST. LOUIS (MD Consult) - AstraZeneca announced on February 23, 2005, that the U.S. Food and Drug Administration (FDA) has approved its angiotensin-receptor blocker Atacand (candesartan cilexetil) for the treatment of heart failure (New York Heart Association [NYHA] class II-IV and ejection fraction ≤40%) to reduce the risk of death from cardiovascular causes and reduce hospitalizations from heart failure. Atacand is the first angiotensin-receptor blocker in the United States approved for reduction of both cardiovascular mortality and hospitalizations for heart failure.
Heart failure, also called chronic heart failure, is a condition in which the heart is unable to pump blood adequately to the rest of the body. It is a serious, progressive, debilitating condition and frequently leads to a fatal outcome. Many patients who experience heart failure have impaired left ventricular systolic function and this is the population that has been studied in most previous heart failure trials. In these patients, the heart's ability to function as a pump is compromised, as evidenced by a reduced ejection fraction. The normal heart ejects more than 50% of the blood in the left ventricle with each beat. Common causes of heart failure include coronary artery disease, heart attacks, hypertension, and heart disease of unknown origin. The American Heart Association estimates that nearly 5 million Americans are currently living with heart failure, and more than half a million new cases are diagnosed each year.
The FDA approval was primarily based on results from Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity Alternative Trial (CHARM-Alternative), an international, double-blind, placebo-controlled, parallel study that examined the effect of Atacand (n = 1,013) compared with placebo (n = 1,015) in 2,028 heart failure patients who were intolerant to angiotensin-converting enzyme inhibitors but were receiving other standard heart failure therapy. In most cases, the starting dose of Atacand was 4 mg once daily, which was doubled every 2 weeks up to the sixth week. Patients received the highest dose tolerated up to the target dose of 32 mg once daily. Patients were evaluated at 2, 4, and 6 weeks; at 6 months; and every 4 months after until the end of the trial (34 months on average). The primary end point was time to either cardiovascular mortality or hospitalization for heart failure. The trial demonstrated that, in these patients with chronic heart failure, the use of Atacand resulted in a 23% (P < .001) relative risk reduction in cardiovascular death or heart failure hospitalization (406 events in the placebo arm vs 334 events in the patients receiving Atacand), with both components contributing to this effect.
This finding was supported by a second study of 2,548 subjects (CHARM-Added) with NYHA class II-IV heart failure and ejection fraction ≤40%, in which subjects were already taking angiotensin-converting enzyme inhibitors. Together, in these studies, patients taking Atacand had a 15% lower risk of cardiovascular mortality (P = .005). In these studies, symptoms of heart failure as assessed by NYHA functional class were also improved (P < .001).
The recommended initial dose of Atacand for the treatment of heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient. Candesartan cilexetil was first approved by the FDA in 1998 for the treatment of hypertension.
For more information, visit www.astrazeneca.com.
February 4, 2005
ST. LOUIS (MD Consult) - On February 3, 2005, French pharmaceutical company Sanofi-aventis announced that it has received approval from the U.S. Food and Drug Administration for a new formulation of Eloxatin (oxaliplatin) for injection. The new injectable formulation is a clear, preservative-free, colorless solution that does not require reconstitution. It therefore offers additional benefit to physicians and nurses because its administration involves fewer steps.
In the United States, Eloxatin in combination with infusional 5-fluorouracil/leucovorin (5-FU/LV), received approval on January 9, 2004, for the first-line treatment of advanced carcinoma of the colon or rectum. This same Eloxatin-based combination had initially (August 2002) received FDA approval for second-line treatment.
On November 4, 2004, this Eloxatin-based regimen was approved for the adjuvant treatment of stage III colon cancer after complete resection of the primary tumor.
Every year about 1 million new cases of colorectal cancer are diagnosed worldwide. About 194,000 new cases are detected in Europe and 150,000 in the United States. According to the America Cancer Society, colorectal cancer is the second leading cause of cancer-related death in the United States, accounting for 10% to 15% of all cancer deaths. Over a lifetime, about 1 in 18 people contract colorectal cancer, and more than 56,000 people die from it in the United States each year. In Europe, 94,000 people die from colorectal cancer each year.
An extensive worldwide clinical development program is ongoing to explore the potential benefits of injectable Eloxatin in other types of cancer.
Eloxatin, used in combination with infusional 5-FU/LV, is indicated for adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years.
Labeling information for injectable Eloxatin includes a warning that the drug should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
Anaphylactic-like reactions to Eloxatin have been reported and may occur within minutes of Eloxatin administration. Epinephrine, corticosteroids, and antihistamines have been used to alleviate symptoms, and discontinuation of Eloxatin therapy may be required.
The incidence of grade 3 or 4 events was 70% and 31% on the Eloxatin combination arm and infusional 5-FU/LV arm, respectively. Granulocytopenia, paresthesia, diarrhea, vomiting, and nausea were the most common grade 3 or 4 adverse events. Paresthesia was seen in 92% of patients receiving the Eloxatin combination; 21% had residual paresthesia at 18-month follow-up. Three percent and 0.5% had grade 2 and 3 paresthesias, respectively, at 18-month follow-up. Grade 3 or 4 hypersensitivity was noted in 3% and may require discontinuation of therapy. Hepatotoxicity, evidenced by increase in transaminases (57% vs 34%) and alkaline phosphatases (42% vs 20%), was observed more commonly in the Eloxatin arm of the study. The incidence of increased bilirubin was similar on both arms. Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension are present and cannot be explained by liver metastases or other known causes.
Fatigue, neuropathy, nausea, vomiting, diarrhea, stomatitis, neutropenia, and thrombocytopenia were the more common adverse events. Neither febrile neutropenia nor requirement for platelet transfusion was increased compared with treatment with irinotecan plus bolus 5-FU/LV. Eloxatin for injection has been associated with pulmonary fibrosis (<1% of study patients), which can be fatal. There have been reports from clinical trials and from postmarketing surveillance of prolonged prothrombin time and international normalized ratio occasionally associated with hemorrhage in patients who received Eloxatin plus 5-FU/LV while taking anticoagulants. Patients requiring oral anticoagulants may require closer monitoring. Hypersensitivity has been observed (<2% grade 3/4) in clinical studies and trials. It was usually managed with standard epinephrine, corticosteroid, and antihistamine therapy and may require discontinuation of Eloxatin therapy.
Full prescribing information is available at fda.gov/cder/foi/label/2004/021492s004lbl.pdf.
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) has granted approval to Mylan Technologies, Inc, for the first generic version of Alza Corporation's Duragesic Patch (Fentanyl Transdermal System) used to treat patients suffering from severe chronic pain that cannot be managed with alternative analgesics. When applied to the skin, this patch technology delivers fentanyl, an opioid pain medication that is slowly absorbed into the body through the skin providing pain relief for up to 72 hours.
The agency's approval is expected to provide patients with access to a less expensive alternative of this pain management system. At the same time that the FDA approved Mylan's generic product, it acted on several citizens' petitions requesting that the FDA deny or delay approval of the product.
The original Fentanyl Transdermal System was approved in August 1990. It is currently approved for the management of chronic pain in patients who require continuous opioid analgesia for pain that cannot be managed by acetaminophen-opioid combinations or nonsteroidal analgesics, or as needed dosing with short-acting opioids.
Fentanyl is currently a schedule II controlled substance, which is the highest level of control for drugs with a recognized medical use. As a controlled substance in schedule II of the Controlled Substances Act (CSA), fentanyl also comes under the jurisdiction of the U.S. Drug Enforcement Administration (DEA), which administers the CSA. Schedule II drugs are subject to manufacturing quotas set by the DEA with input on medical need from the FDA, distribution tracking, import and export controls, registration of prescribers and dispensers, and written prescriptions without refills.
January 13, 2005
ST. LOUIS (MD Consult) - On January 10, 2005, Serono Inc announced the U.S. Food and Drug Administration (FDA) has approved its medication Saizen (somatropin [rDNA origin] for injection) for use in the treatment of patients with adult growth hormone deficiency (AGHD).
With the US approval, patients who were growth hormone deficient during childhood and have growth hormone deficiency as adults can continue to use Saizen. In addition, patients who have adult-onset growth hormone deficiency, either alone or associated with multiple hormone deficiencies, can take this medication.
Saizen can be administered using a needle-free device, a recently launched autoinjector pen device, or traditional needle and syringe.
Growth hormone deficiency can be a significant problem for adults even though they no longer get taller. AGHD is recognized as a specific clinical syndrome with numerous physiologic consequences, having effects on the following:
There are also studies indicating that patients with AGHD have an increased risk of mortality from cardiovascular disease, possibly attributable to their growth hormone deficiency.
AGHD can result from a pituitary or peri-pituitary tumor or as a direct result of the surgery/radiation used to manage these conditions. Less commonly, growth hormone deficiency in adults arises from a deficiency acquired in childhood.
Saizen is a human growth hormone produced by recombinant DNA technology. The recommended dose for adults at the start of therapy is 0.005 mg/kg daily. The dosage can be increased to not more than 0.01 mg/kg daily after 4 weeks, depending on the patient's tolerance to treatment.
Saizen is indicated for the long-term treatment of growth failure due to inadequate secretion of endogenous growth hormone in children. It is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency that meets the criteria of adult onset or childhood onset.
In patients with AGHD, the most common adverse events with associated growth hormone therapy are joint and muscle pain, edema, carpal tunnel syndrome, and tingling.
Growth hormone should be used with caution in patients with insulin resistance, glucose intolerance, diabetes, hypothyroidism, and intracranial hypertension and in women who are pregnant or nursing. Growth hormone should not be used in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment, in the presence of active neoplasia, in patients with proliferative or preproliferative diabetic retinopathy, nor in patients who have been hospitalized with acute critical illnesses.
More information about Saizen and Serono's growth hormone delivery devices, including full prescribing information for Saizen, can be found at seronousa.com.
January 7, 2005
ST. LOUIS (MD Consult) - Bristol-Myers Squibb Company and Otsuka Pharmaceutical Co, Ltd, announced on January 4, 2005, that the companies have received approval from the U.S. Food and Drug Administration (FDA) for an oral solution formulation of Abilify (aripiprazole). Abilify Oral Solution will provide an additional treatment option for adult patients who are unable to swallow or have difficulty swallowing tablets.
Abilify is indicated for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. According to Bristol-Myers Squibb, Abilify is the first and only dopamine partial agonist.
The medication was approved by the FDA in 2002 for the treatment of schizophrenia. The efficacy and tolerability of Abilify in the treatment of schizophrenia was established by short-term and longer-term placebo-controlled trials. In September 2004, Abilify was approved for the treatment of acute bipolar mania, including manic and mixed episodes associated with bipolar disorder.
As with all antipsychotic medications, a rare condition called neuroleptic malignant syndrome has been reported in association with Abilify. Prescribing should be consistent with the need to minimize the risk of tardive dyskinesia.
Hyperglycemia, including some serious cases ranging from ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Abilify was not included in epidemiologic studies suggesting this risk; therefore, the risk of hyperglycemia with Abilify is not known. However, there have been few reports of hyperglycemia in patients treated with Abilify. Patients should be appropriately tested before and monitored during treatment.
Abilify may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions that would predispose them to hypotension.
As with other antipsychotic drugs, Abilify should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Seizures occurred in 0.3% of bipolar patients treated with Abilify in placebo-controlled trials. In addition, Abilify may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain Abilify does not affect them adversely.
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant anticholinergic medications, or be subject to dehydration.
Because antipsychotic drugs have been associated with esophageal dysmotility, Abilify should be used cautiously in patients at risk for aspiration pneumonia. And due to the possibility that a suicide attempt is inherent in psychotic illnesses and bipolar disorder, close supervision of high-risk patients should accompany drug therapy.
While taking Abilify, patients should not drink alcohol or breast-feed infants. Patients taking Abilify should alert their physicians if they become pregnant or intend to become pregnant. In addition, physicians should be notified of all other medications the patients are taking.
Commonly observed adverse events reported with Abilify in 3-week bipolar mania trials at a ≥5% incidence for Abilify and at a rate at least twice the rate of placebo include, respectively, akathisia (15% vs 4%), constipation (13% vs 6%), and accidental injury (6% vs 3%).
Treatment-emergent adverse events reported with Abilify in short-term trials at an incidence ≥10% and greater than placebo, respectively, include headache (31% vs 26%), agitation (25% vs 24%), anxiety (20% vs 17%), insomnia (20% vs 15%), nausea (16% vs 12%), dyspepsia (15% vs 13%), somnolence (12% vs 8%), akathisia (12% vs 5%), lightheadedness (11% vs 8%), vomiting (11% vs 6%), and constipation (11% vs 7%).
The adverse events reported in a 26-week, double-blind schizophrenia trial comparing Abilify and placebo were generally consistent with those reported in the short-term, placebo-controlled schizophrenia trials, except for a higher incidence of tremor: 9% for Abilify versus 1% for placebo. In this study, the majority of the cases of tremor were of mild intensity (9/13 mild and 4/13 moderate), occurred early in therapy (9/13 ≤49 days), and were of limited duration (9/13 ≤10 days). Tremor infrequently led to discontinuation (<1%) of Abilify. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor for Abilify was 4%.
The oral solution formulation will be available in pharmacies in February 2005. For full product information, visit ABILIFY.com.
January 4, 2005
ST. LOUIS (MD Consult) - On January 3, 2005, GlaxoSmithKline announced that the U.S. Food and Drug Administration has approved expanded use of Bexxar (tositumomab and iodine 131 tositumomab). The medication is now indicated for the treatment of patients with CD20 antigen expressing relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with rituximab-refractory non-Hodgkin's lymphoma.
Bexxar's original indication specified that patients have disease that was refractory to rituximab and had relapsed after chemotherapy. Determination of the effectiveness of the Bexxar therapeutic regimen was based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and rituximab. The effects of the Bexxar therapeutic regimen on survival are not known. Bexxar is not indicated for the initial treatment of patients with CD20-positive non-Hodgkin's lymphoma. The drug is intended as a single course of treatment. The safety of multiple courses, or a combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.
The expanded indication will make Bexxar an earlier option for patients with relapsed low-grade or follicular non-Hodgkin's lymphoma.
The approval was based on a multicenter, single-arm, open-label study of 60 chemotherapy refractory patients. The median age of study participants was 60 years (range, 38-82), the median time from diagnosis to protocol entry was 53 months (range, 9-334), and the median number of prior chemotherapy regimens was 4 (range, 2-13). Fifty-three patients had not responded to prior therapy, and 7 patients had responded with a duration of response of less than 6 months. As determined by an independent panel that reviewed patient records and radiologic studies, the overall response rate for Bexxar in this study was 47% (95% confidence interval [CI], 34% to 60%), with a median duration of resonse of 12 months (range, 2-47; CI, 7-47), and the complete response rate was 20% (95% CI, 11% to 32%), with the median duration of response of 47 months (range, 9-47; 95% CI, 47 to Not Reached) after a median follow-up of 30 months.
Bexxar pairs the targeting ability of a monoclonal antibody (tositumomab) and the therapeutic potential of radiation (iodine 131). Combined, these agents form a radiolabeled monoclonal antibody regimen that is able to bind to the target antigen CD20 found on B cells, including normal cells and those that become cancerous in non-Hodgkin's lymphoma, thereby delivering the dose of radiation. Bexxar, which is given in 4 visits over 1 to 2 weeks, is specifically dosed based on a person's drug clearance rate, allowing the delivery of a predetermined amount of radiation to each patient.
Patients who are pregnant or allergic to any components of the Bexxar regimen should not take the medication. Serious hypersensitivity reactions, including some with fatal outcome, have been observed with Bexxar. Treatment with the drug resulted in severe decreases in blood counts (platelets, white blood cells, and red blood cells) in the majority of patients, which could be life-threatening, for an extended period of time (approximately 1 month). In up to 7 of 100 patients, these decreases persisted for more than 90 days.
Infections occurred in almost half the patients, bleeding in 1 in 8 patients, and treatment with supportive care in about 1 in 4 patients. Other less severe reactions during or after the infusion have included fever, chills, sweating, nausea, low blood pressure, shortness of breath, and difficulty breathing. Patients may also experience weakness, fever, nausea, increased cough, infection, pain, chills, rash, or headache. There is a risk of hypothyroidism after administration of Bexxar. Administration resulted in the development of antibodies to the mouse antibody (ie, HAMA).
Certain cancer therapies, including Bexxar, have been associated with the development of a second type of blood cancer and solid tumors. Health care providers must be specifically trained to administer Bexxar.
For more details, including complete prescribing information, visit bexxar.com.
December 29, 2004
ST. LOUIS (MD Consult) - Pfizer Inc announced on December 28, 2004, that the U.S. Food and Drug Administration has approved the use of its extended-spectrum antifungal agent Vfend (voriconazole; intravenous for injection, tablets, and oral suspension) for the treatment of candidemia in nonneutropenic patients and the following Candida infections: disseminated (deep tissue) infections in skin and infections in abdomen, kidney, bladder wall, and wounds. Bloodstream infections caused by Candida are the fourth most common type of hospital-acquired bloodstream infections in the United States and have the highest mortality rate.
According to the U.S. Centers for Disease Control and Prevention, candidemia occurs in 8 of every 100,000 persons per year. Those at risk for disseminated Candida infections include patients with compromised immune systems such as stem-cell and organ-transplant recipients, surgical patients, and critically ill patients in the intensive care unit.
The basis for the approval of Vfend to treat candidemia in nonneutropenic patients was a randomized, open-label, comparative, multicenter study involving 422 patients worldwide. Patients were randomly assigned two-to-one to receive either Vfend (n = 283) or amphotericin B followed by fluconazole (n = 139). A data review committee comprising fungal disease experts assessed clinical response at the end of therapy and 2, 6, and 12 weeks after the end of therapy. Success in the primary end point was defined as the patient experiencing a cure or improvement at the 12-week assessment. In the study, Vfend was shown to be as effective as a regimen of amphotericin B followed by fluconazole. Treatment with Vfend was able to clear Candida from the blood as quickly as amphotericin B with lower incidence of treatment-related adverse events. The most common adverse events in the study were sepsis, fever, hypokalemia, hypotension, and respiratory disorder.
Vfend was discovered by Pfizer researchers and was developed to address the unmet medical need for more effective and better-tolerated options for patients with serious fungal infections. Said Dr. Ann Kolokathis, Vice President US Medical at Pfizer, "Vfend is effective against clinically relevant Candida species including hard-to-treat pathogens, such as C glabrata and C krusei, which cause these life-threatening infections."
Since its introduction, Vfend has proved to be an important treatment option for patients with serious and potentially life-threatening fungal infections. Vfend received U.S. approval in 2002 for the first-line treatment of invasive aspergillosis and as salvage therapy for fungal infections caused by the pathogens Scedosporium apiospermum and Fusarium species. In 2003, Vfend received an additional U.S. indication for use in treating esophageal candidiasis. Vfend comes in intravenous and oral formulations, allowing patients to take the same medication throughout the course of treatment, both on an inpatient and outpatient basis.
The most frequently reported adverse events in all Vfend clinical trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, and headache. The treatment-related adverse events that most often led to discontinuation were elevated liver function tests, rash, and visual disturbances.
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