Revlimid approved by FDA to treat MDS-related anemia December 29, 2005
New kidney cancer drug approved in US December 22, 2005
New leukemia and lymphoma treatment approved in accelerated FDA channels November 1, 2005
Extended-release formulation of tramadol approved September 12, 2005
FDA ok's growth treatment drug from Tercica September 1, 2005
Nasal spray approved to treat postmenopausal osteoporosis August 18, 2005
Non-scheduled prescription sleep aid approved in US July 26, 2005
Heart failure treatment approved by FDA for black patients June 27, 2005
New insulin analog from Novo Nordisk approved in US June 20, 2005
New single-dose antibiotic approved by FDA June 14, 2005
FDA approves new treatment for type II diabetes June 6, 2005
FDA approves extended-release treatment for UTI May 23, 2005
FDA approves product to treat adverse reactions to smallpox vaccine May 5, 2005
ISTA wins approval for new ocular inflammation treatment April 18, 2005
New once-daily asthma treatment approved by FDA April 1, 2005
Antifungal prophylaxis wins FDA approval March 18, 2005
Urea disorder treatment approved in U.S. February 22, 2005
New filler for facial wrinkles approved by FDA January 31, 2005
First in new class of drugs approved to treat metastatic breast cancer January 11, 2005
FDA approves Pfizer's new treatment for neuropathic pain January 4, 2005
FDA approves non-narcotic analgesic for severe chronic pain December 29, 2004
Bristol-Myers Squibb wins approval for new rheumatoid arthritis drug December 28, 2005
Oral iron chelator gives patients new option, Novartis announces November 4, 2005
New treatment for menopausal symptoms approved by US FDA September 30, 2005
Merck combines vaccines for measles, mumps, rubella, and varicella September 7, 2005
New vaccine approved in time for 2005-2006 flu season September 1, 2005
Alcon wins approval for treatment of inflammation due to cataract surgery August 30, 2005
New acne treatment wins nod from FDA July 28, 2005
FDA approves new treatment of brain vascular disorder July 25, 2005
New anti-HIV drug approved for use in combination therapy June 24, 2005
FDA ok's antibiotic for complicated skin and intra-abdominal infections June 17, 2005
Pfizer wins ok for pulmonary arterial hypertension treatment June 7, 2005
Mucopolysaccharidosis treatment approved by FDA June 2, 2005
New formulation of fenofibrate approved in US May 10, 2005
Amylin and Lilly win FDA approval for type 2 diabetes treatment May 2, 2005
Bausch & Lomb's uveitis treatment approved by US FDA April 12, 2005
Hepatitis B treatment wins U.S. approval March 31, 2005
New adjuvant diabetes treatment approved by FDA March 18, 2005
FDA approves new psoriasis treatment February 18, 2005
FDA approves new vaccination against meningococcal disease January 18, 2005
Pulmonary arterial hypertension treatment approved in U.S. January 7, 2005
New drug approved to treat common form of pediatric leukemia December 30, 2004
Novartis wins FDA approval for overactive bladder treatment December 28, 2004
December 29, 2005
ST. LOUIS (MD Consult) - On December 28, 2005, Celgene Corporation announced that the US Food and Drug Administration has granted approval of the new product Revlimid (lenalidomide). The drug is indicated for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. However, a risk for birth defects exists with use of Revlimid, and a restricted distribution program for the drug will be in effect.
Revlimid will be available in capsules containing doses of 5 or 10 mg. Most initial shipments will be distributed in early 2006.
"The clinical data from a Phase II trial of 148 patients demonstrated that Revlimid can reduce or even eliminate the need for transfusions in many patients with deletion 5q MDS," said Dr Alan List, the study's lead investigator and Professor of Oncology and Medicine and Chief of the Division of Hematologic Malignancies Hematologic Malignancies at H. Lee Moffitt Cancer Center, Tampa, Fla.
The safety profile for Revlimid has shown that neutropenia, thrombocytopenia, or both were the most common adverse events and that patients may require a dose adjustment. Other observed and common adverse events include diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, and pharyngitis..
Celegene released the following safety notice regarding its new drug:
| WARNING: Potential for human birth defects
Lenalidomide is an analogue of thalidomide. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is taken during pregnancy, it may cause birth defects or death to an unborn baby. Females should be advised to avoid pregnancy while taking lenalidomide. Because of this potential toxicity and to aviod fetal exposure to Revlimid (lenalidomide), it is only available under a special restricted distribution program. This program is called "RevAssist." Under this program, only prescribers and pharmacists registered with the program are allowed to prescribe and dispense the product. In addition, patients must agree to comply with the requirements of the RevAssist program to receive [the] drug. WARNING: Hematological toxicity (neutropenia and thrombocytopenia) Lenalidomide is associated with significant neutropenia and thrombocytopenia. Patients should have their [complete blood cell count] checked weekly for the first 8 weeks of Revlimid (lenalidomide) treatment and at least monthly thereafter to monitor for cytopenias. Most deletion 5q MDS patients studied required a dose adjustment for neutropenia and thrombocytopenia. WARNING: Deep vein thrombosis and pulmonary embolism Revlimid (lenalidomide) has demonstrated significant risk of deep vein thrombosis and pulmonary embolism in some patients with certain medical conditions. |
Revlimid is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components. Revlimid is substantially excreted by the kidney, so the risk of toxic reactions may be greater in patients with impaired renal function.
MDS are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or "blast" stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States, with mean survival rates ranging from approximately 6 months to 6 years for the different classifications of MDS. Patients with MDS must often rely on blood transfusions to manage symptoms of anemia and fatigue and may develop life-threatening iron overload or toxicity from frequent transfusions, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.
Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with MDS and involve a deletion in all or part of 1 or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20% to 30% of all patients with MDS. The World Health Organization has also recently identified a unique subset of MDS patients with a "5q-Syndrome," in which the only chromosomal abnormality is a specific portion of the 5q chromosome.
RevAssist is a proprietary risk-management restrictive distribution program, tailored specifically for Revlimid patients, to prevent the potential for human birth defects and to ensure prompt and convenient access to Revlimid. For more information about Revlimid and the RevAssist program, visit REVLIMID.com or call 1-888-4CELGENE. Full prescribing information is available at celgene.com/PDF/RevlimidPI.pdf.
December 28, 2005
ST. LOUIS (MD Consult) - Bristol-Myers Squibb Company announced on December 23, 2005, that the US Food and Drug Administration (FDA) has approved Orencia (abatacept), the first selective modulator of a costimulatory signal required for full T-cell activation, for the treatment of rheumatoid arthritis.
Rheumatoid arthritis is a systemic, chronic, autoimmune disease characterized by inflammation in the synovium, causing joint damage with chronic pain, stiffness, and swelling. Rheumatoid arthritis causes limited range of motion and decreased function as a result of affected joints losing their shape and alignment. The condition is estimated to affect approximately 1% of the world's population, including more than 2 million people in the United States. It is more common in women than in men by a ratio of 3:1.
Orencia is indicated for reducing the signs and symptoms of rheumatoid arthritis, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to 1 or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) or tumor necrosis factor (TNF) antagonists. Orencia may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. Orencia should not be administered concomitantly with TNF antagonists and is not recommended for use concomitantly with anakinra.
Orencia was studied in patients with an inadequate response to DMARDs. Specifically, it is the first approved agent to demonstrate efficacy and safety in patients with an inadequate response to TNF antagonists, as well as those with an inadequate response to MTX. Methotrexate is the most widely used nonbiologic DMARD for rheumatoid arthritis, and TNF antagonists are the most widely used biologic therapies for rheumatoid arthritis. Orencia is also the first in a new class of agents for the treatment of rheumatoid arthritis that selectively modulates a costimulatory signal required for full T-cell activation.
"In clinical trials, Orencia significantly reduced the signs and symptoms of rheumatoid arthritis among patients who had inadequate response to DMARDs such as methotrexate and/or anti-TNF therapy when compared to placebo," said Mark Genovese, MD, associate professor of medicine at the Stanford University School of Medicine, Palo Alto, Calif.
The efficacy and safety profiles of Orencia have been studied through a rigorous clinical trial program that included more than 2,600 patients. More than 3,800 person-years of experience were included across the placebo-controlled and open-label extension periods of the clinical trials.
The phase III trial program included 3 major double-blind randomized placebo-controlled studies: AIM (Abatacept in Inadequate responders to Methotrexate), which compared Orencia in combination with MTX to MTX alone; ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders), which compared Orencia in combination with nonbiologic DMARDs to nonbiologic DMARDs alone in patients with an inadequate efficacy response to the TNF antagonists etanercept and infliximab; and ASSURE (Abatacept Study of Safety in Use with other RA thErapies), which studied the safety of Orencia compared with placebo when used in combination with a variety of biologic and nonbiologic DMARDs.
In both pivotal phase III efficacy studies (AIM and ATTAIN), Orencia demonstrated significant and sustained improvement of the signs and symptoms of rheumatoid arthritis as measured by American College of Rheumatology (ACR) 20, 50, and 70 scores, with significant difference from placebo by day 15 for ACR 20 in some patients, which was the first follow-up visit after the first dose. In both trials, significant improvements in physical function were noted, compared with placebo. Health-related quality of life was assessed by the Short Form 36 (F-36) questionnaire; improvements were observed in the patients treated with Orencia compared with placebo in all 8 domains of the SF-36. ACR responses and improvements in physical function were maintained up to 3 years in a phase II trial of patients with inadequate response to MTX.
Additionally, a significant proportion of patients taking Orencia plus MTX achieved a major clinical response, defined as maintaining an ACR 70 score for 6 consecutive months, compared with those treated with MTX alone in AIM (14% vs 2%; P < .001).
In AIM, structural damage was slowed in patients treated with Orencia plus MTX compared with those treated with MTX alone.
Concurrent therapy with Orencia and a biologic DMARD is not recommended. In controlled clinical trials, patients receiving concomitant Orencia and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared with patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy.
Caution should be exercised in patients with a history of infection or underlying conditions that predispose them to infections. Treatment with Orencia should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis, and if the result is positive, should be treated with standard medical practice before receiving therapy with Orencia.
Less than 1% of patients treated with Orencia experienced hypersensitivity reactions, including 2 cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of patients treated with Orencia and generally occurred within 24 hours of an infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available.
Live vaccines should not be given concurrently with Orencia or within 3 months of its discontinuation.
Patients with chronic obstructive pulmonary disease (COPD) who are treated with Orencia developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of Orencia in patients with rheumatoid arthritis and COPD should be undertaken with caution, and such patients should be monitored for worsening of their respiratory status.
Orencia should be used during pregnancy only if clearly needed. Rats treated every 3 days with abatacept during early gestation throughout the lactation period showed no adverse effects in the offspring at doses up to 45 mg/kg. At a dose of 200 mg/kg, alterations of immune function consisted of a 9-fold increase in the T-cell–dependent antibody response in female pups and inflammation of the thyroid in 1 female of the 10 male and 10 female pups evaluated. Whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept has not been determined.
Nursing mothers should discuss with their health care practitioners the risks and benefits of continued breast-feeding or discontinuation of the drug.
The most serious adverse reactions were serious infections (3% with Orencia vs 1.9% placebo) and malignancies (1.3% Orencia vs 1.1% placebo).
The overall frequency of malignancies was similar in patients treated with Orencia and placebo-treated patients. However, more cases of lung cancer were observed in patients treated with Orencia (0.2%) than placebo-treated patients (0%). A higher rate of lymphoma was seen compared with the general population; however, patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of Orencia in the development of malignancies in humans is unknown.
The most frequent adverse events occurring in ≥10% of patients treated with Orencia were headache, upper respiratory tract infection, nasopharyngitis, and nausea.
Orencia is administered as a 30-minute intravenous infusion at a fixed dose based on weight range approximating 10 mg/kg at day 0, 2 weeks, 4 weeks, and every 4 weeks thereafter. Infusion reactions were experienced in 9% of patients treated with Orencia and in 6% of patients treated with placebo. The most frequently reported events (1% to 2%) were dizziness, headache, and hypertension. In clinical trials, premedications were not required. However, appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction.
Orencia is expected to be available for initial commercial use by the end of February 2006.
For prescribing information, visit the Orencia Web site.
December 22, 2005
ST. LOUIS (MD Consult) - On December 20, 2005, the US Food and Drug Administration approved Nexavar (sorafenib tosylate), a new anti-cancer medicine used to treat adults with advanced renal cell carcinoma, the most common type of kidney cancer.
In the United States, kidney cancer accounts for approximately 3% of all adult cancers. According to the American Cancer Society, about 32,000 new cases are diagnosed and about 12,000 people die from the disease annually. Kidney cancer occurs most often in people between the ages of 50 and 70 years, affects men almost twice as often as women, and, if detected early enough, may be curable surgically. However, tumors that are advanced (ie, those that cannot be surgically removed or have spread to other parts of the body) are difficult to treat.
Two studies in patients with advanced kidney cancer have shown that patients treated with Nexavar had more time before tumor progression or death. In the larger study, most patients had previously received treatment with interleukin-2 or interferon. The median time to tumor progression or death in the Nexavar-treated arm was 167 days compared with 84 days in people not treated with the drug.
Some common temporary adverse effects reported with Nexavar are rash, diarrhea, increases in blood pressure, and redness, pain, swelling, or blisters on the palms of the hands or soles of the feet.
Nexavar will be distributed and marketed by Bayer Pharmaceuticals Corporation of Westhaven, Conn.
November 4, 2005
ST. LOUIS (MD Consult) - On November 3, 2005, pharmaceutical company Novartis announced the approval of Exjade (deferasirox) by the US Food and Drug Administration (FDA). Exjade, the first once-daily oral iron chelator, has been approved for the treatment of chronic iron overload due to blood transfusions in adults and children aged 2 years and older.
Exjade is the only iron chelator administered as a drink (the tablets are dispersed in a glass of orange juice, apple juice, or water), compared with the current standard of care, which often requires a subcutaneous infusion lasting 8 to 12 hours per night, for 5 to 7 nights per week for as long as the patient continues to receive blood transfusions or has excess iron within the body. As a result, many patients may have stopped or avoided iron chelation therapy, thus risking the toxic effects of iron overload.
The approval of Exjade is expected to greatly enhance the acceptance of iron chelation therapy, especially for children, and offer a new alternative to the burdensome continuous infusion therapy.
Iron overload is a potentially life-threatening and unavoidable consequence of frequent blood transfusions used to treat certain types of rare chronic blood disorders, including thalassemia and sickle cell disease, as well as other rare anemias and myelodysplastic syndromes. Signs of iron overload may be detected after transfusion of about 20 units of blood. If left undiagnosed or untreated, the excess iron in the body is likely to lead to damage to the liver, heart, and endocrine glands. The body has no inherent mechanism to remove excess iron, so iron chelation is used as an effective treatment for transfusion-related iron overload.
Exjade was approved after being granted priority review by the FDA and also after the Blood Products Advisory Committee to the FDA voted unanimously to give Exjade a positive recommendation for approval.
The Exjade filings were based on the results of a clinical trials program that included a phase III trial, which showed that after 1 year Exjade produced reductions in liver iron concentration.
The clinical trials, which included more than 1,000 adults and children, were part of the largest prospective global clinical trials program ever implemented for an investigational iron chelator. Liver iron concentration is an indicator for body iron content in patients receiving blood transfusions. It is a measure of iron accumulation in the liver. The studies demonstrated that Exjade, given at 20 to 30 mg/kg/day, led to the maintenance or reduction of iron burden in transfused patients with thalassemia and sickle cell disease as well as other rare anemias and myelodysplastic syndromes. In the clinical studies, Exjade was generally well tolerated, with the most frequently reported adverse events being nausea, vomiting, diarrhea, abdominal pain, skin rash, and increases in serum creatinine. As with deferoxamine (Desferal), cases of ocular and auditory disturbances have been reported.
Mild, nonprogressive increases in serum creatinine, mostly within the normal range, occur in about one third of patients treated with Exjade. These increases are dose dependent, often resolve spontaneously, and can sometimes be alleviated by reducing the dose. Serum creatinine should be assessed before initiating therapy and should be monitored monthly thereafter to determine whether dose modification or discontinuation is necessary. Liver function should be monitored monthly, and if there is an unexplained, persistent, or progressive increase in serum transaminase levels, Exjade administration should be interrupted or discontinued.
In iron chelation, an agent binds to iron in the body and tissues and helps remove it through the urine, feces, or both. The goal of iron chelation therapy is to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden. In many patients, the need for transfusions may be lifelong. To date, only deferoxamine is globally available for the first-line treatment of transfusion related iron overload. And although deferoxamine is effective, its relatively burdensome administration leads some patients to abandon iron chelation therapy, exposing themselves to the dangers of iron overload.
For more information about Exjade, visit novartis.com.
November 1, 2005
ST. LOUIS (MD Consult) - On October 31, 2005, the US Food and Drug Administration (FDA) announced the approval of Arranon (nelarabine) for marketing in the United States. This is a new drug to treat adults and children with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed after at least 2 chemotherapy regimens. Arranon is the first drug to treat this limited population of patients.
Arranon is a cancer chemotherapy drug that kills cancer cells by blocking the cell's ability to reproduce. Rapidly dividing cancer cells are more sensitive to cancer chemotherapy drugs than are more slowly dividing normal cells.
This new medication was approved under the FDA's accelerated approval program, which allows the agency to approve products for cancer and other serious or life-threatening diseases based on early evidence of a product's effectiveness. In this case, this evidence consisted of complete disappearance of cancer cells in some patients, although in most cases the cancer later returned. In those patients whose conditions responded to Arranon, the disappearance of cancer cells was sometimes accompanied by a return of normal blood cell counts. As required under the FDA's accelerated approval program, the sponsor will be completing further studies to verify Arranon's clinical benefit.
Arranon also received orphan drug designation, which is granted by the FDA to products indicated to treat rare diseases (those that affect fewer than 200,000 people in the United States). The Orphan Drug Act provides a 7-year period of exclusive U.S. marketing to the first sponsor that obtains marketing approval for a designated orphan drug. Approximately 1,600 patients are newly diagnosed with T-ALL/T-LBL each year in the United States. Of those, an estimated 500 patients per year have relapsed or refractory T-ALL/T-LBL, with approximately 200 of these patients being children.
ALL is an aggressive disease that progresses rapidly without effective therapy. Each year, an estimated 2,400 children and 1,200 adults are diagnosed with ALL in the United States, of whom approximately 700 have T-ALL. LBL represents approximately 30% of childhood and 3% of adult non-Hodgkin's lymphoma.
An estimated 50,000 patients are diagnosed with non-Hodgkin's lymphoma each year, of whom approximately 900 have T-LBL.
The safety and efficacy of this product were demonstrated in 2 clinical studies, one conducted in children and the other in adults. Both studies enrolled patients with relapsed or refractory T-ALL/T-LBL. All patients received Arranon. Among the 39 pediatric patients treated, 23% had a complete disappearance of their cancer. Complete disappearance lasted from 3.3 to 9.3 weeks. Of the 28 adult patients treated, the rate of complete disappearance was 21% and lasted from 4 to more than 195 weeks.
Common adverse effects reported with Arranon treatment are fatigue, nausea, vomiting, and diarrhea.
Arranon will be distributed and marketed by GlaxoSmithKline of Research Triangle Park, North Carolina. For full prescribing information, visit us.gsk.com/products/assets/us_arranon.pdf.
September 30, 2005
ST. LOUIS (MD Consult) - On September 29, 2005, Schering AG announced that the US Food and Drug Administration (FDA) has approved Angeliq (drospirenone and estradiol) to treat moderate to severe menopausal symptoms. The medication relieves the occurrence of vasomotor symptoms such as hot flashes and other symptoms of menopausal estrogen withdrawal, generally within 4 weeks of therapy initiation.
Angeliq is different from other available hormone replacement therapies in that it contains the anti-aldosterone progestin drospirenone. Anti-aldosterone activity has been shown to counter the excess water and sodium retention sometimes caused by estrogen. In addition, Angeliq contains estradiol, the same estrogen produced by a woman's body prior to menopause.
Angeliq was studied in large-scale clinical trials involving 1,759 women that established safety and efficacy in providing endometrial protection and an acceptable bleeding profile among postmenopausal women.
Angeliq will be available in the United States by mid-2006 in a preparation containing 0.5 mg drospirenone and 1 mg estradiol.
September 12, 2005
ST. LOUIS (MD Consult) - On September 9, 2005, Biovail Corporation announced that its new drug application for a once-daily formulation of tramadol hydrochloride (Tramadol ER) has received final approval from the US Food and Drug Administration (FDA).
Tramadol ER has been approved for the treatment of moderate to moderately severe chronic pain in once-daily 100-, 200-, and 300-mg doses. Biovail is the first company to submit an application to the FDA for approval of a once-daily formulation of tramadol.
Biovail has said it anticipates the commercial launch of Tramadol ER to occur in early 2006. A trade name is still being finalized for the product, so the FDA-approved label refers to the product as "Tradename ER."
For more information about pharmaceutical company Biovail, visit its Web site at biovail.com.
September 7, 2005
ST. LOUIS (MD Consult) - Merck & Co, Inc, announced on September 6, 2005, that the US Food and Drug Administration has approved the combination vaccine Proquad (measles, mumps, rubella, and varicella virus vaccine live) for simultaneous vaccination against measles, mumps, rubella, and varicella in children aged 12 months to 12 years. Proquad is the first vaccine approved in the United States to help protect against these 4 diseases in a single shot. Proquad is also approved for use in children 12 months to 12 years of age if a second dose of measles, mumps, and rubella vaccine is to be administered.
Proquad combines two well-established Merck vaccines M-M-R II (measles, mumps, and rubella virus vaccine live) and Varivax (varicella virus vaccine live [Oka/Merck]). Vaccination with M-M-R II has contributed to a greater than 99% reduction in the United States in the incidence of measles, mumps, and rubella—diseases that have been associated with serious complications and once claimed tens of thousands of lives each year in the United States alone. Since its licensure in 1995, Varivax has contributed to a significant reduction in the number of chickenpox cases in the United States. Chickenpox-related hospitalizations and deaths have also declined over the past decade in the United States.
Leading US authorities on vaccination such as the American Academy of Pediatrics, American Academy of Family Physicians, and the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recommend routine vaccination against measles, mumps, rubella, and varicella. As a combination vaccine indicated for simultaneous vaccination against all 4 of these diseases in children aged 12 months to 12 years, Proquad may help physicians meet these vaccination recommendations. And according to the report "Combination Vaccines for Childhood Immunization," issued by the ACIP in 1999, "the use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines."
Potential advantages of combination vaccines include reducing multiple injections, improving timely vaccination coverage, reducing the costs of stocking and administration of separate vaccines for health care providers, and reducing health care costs for extra health visits, according to the report.
Merck's Biologics License Application for Proquad included results from studies that evaluated the immunogenicity, antibody persistence, and safety of Proquad compared with its component vaccines.
Immunogenicity was studied in 5,835 healthy children aged 12 months to 6 years of age with a negative clinical history of measles, mumps, rubella, and varicella who participated in 5 randomized trials. In these trials, the immunogenicity of Proquad was similar to that of its individual component vaccines, M-M-R II, and Varivax.
In 4 randomized trials in which 5,446 healthy children aged 12 to 23 months received Proquad, vaccine response rates for Proquad were similar to the rates induced by the concomitant administration of single doses of M-M-R II and Varivax at separate injection sites in 2,038 children. Results showed that, after a single dose of Proquad, the immune response rates were 97.4% for measles, 95.8% to 98.8% for mumps, 98.5% for rubella, and 91.2% for chickenpox. The duration of protection from measles, mumps, rubella, and chickenpox infections after vaccination with Proquad is unknown.
In 2 of the 4 trials, 1,035 of the 5,446 children administered a single dose of Proquad received a second dose of Proquad approximately 3 months after the first dose. The proportion of initially seronegative vaccinees with positive serologic responses after 2 doses were 99.4% for measles, 99.9% for mumps, 98.3% for rubella, and 99.4% for chickenpox. The rates of adverse experiences after the second dose were generally similar to or lower than those seen with the first dose. The fever rate was lower after the second dose of Proquad than after the first dose.
The immunogenicity of Proquad was also evaluated in a clinical trial of 799 healthy children aged 4 to 6 years who had received M-M-R II and Varivax as primary vaccination against measles, mumps, rubella, and chickenpox at least 1 month before study entry. In this study, 399 children received Proquad and placebo, 205 received M-M-R II and placebo concomitantly at separate injection sites, and 195 children received M-M-R II and Varivax concomitantly at separate injection sites. After the dose of Proquad, seropositivity rates were 99.2% for measles, 99.5% for mumps, 100% for rubella, and 98.9% for varicella. The rates of adverse experiences, including the most commonly reported adverse experiences of injection site reactions, nasopharyngitis and cough, were generally similar among the 3 treatment groups.
Formal studies to evaluate the clinical efficacy of Proquad have not been performed. Efficacy of the measles, mumps, rubella, and chickenpox components of Proquad was previously established in a series of clinical studies with the monovalent vaccines. A high degree of protection from infection was demonstrated in these studies.
In clinical trials, the safety of Proquad was compared with the safety of M-M-R II and Varivax given concomitantly at separate injection sites. Proquad was administered to 4,497 children aged 12 to 23 months without concomitant administration with other vaccines. Children in these studies were monitored for up to 42 days postvaccination. The safety profile for Proquad was similar to the component vaccines. Injection-site adverse experiences reported in greater than or equal to 1% of children 12 to 23 months of age who received 1 dose of Proquad were as follows: pain/tenderness/soreness (22%); erythema (14.4%); swelling (8.4%); ecchymosis (1.5%); and rash (2.3%). Pain/tenderness/soreness at the injection site was reported at a statistically lower rate in persons who received Proquad than in those who received M-M-R II and Varivax concomitantly at separate injection sites.
Systemic vaccine-related adverse experiences reported in greater than or equal to 1% of children 12 to 23 months of age who received 1 dose of Proquad were fever higher than 102°F (21.5%), irritability (6.7%), measles-like rash (3%), varicella-like rash (2.1%), rash not otherwise specified (1.6%), upper respiratory infection (1.3%), viral exanthema (1.2%), and diarrhea (1.2%). The only systemic vaccine-related adverse experiences reported at a significantly greater rate in persons who received Proquad than those who received M-M-R II and Varivax concomitantly at separate injection sites were fever (higher than 102°F) and measles-like rash. Both fever and measles-like rash usually occurred within 5 to 12 days after vaccination, were of short duration, and resolved with no long-term issues.
The persistence of antibody 1 year after vaccination was evaluated in 2,107 children enrolled in clinical trials. Antibody persistence rates 1 year after a single dose of Proquad were 98.9% against measles, 96.7% against mumps, 99.6% against rubella, and 97.5% against chickenpox. These persistence rates are similar to those observed at 1 year with the individual component vaccines, M-M-R II and Varivax.
No clinical data are available on the safety, immunogenicity, and efficacy of Proquad in children younger than 12 months of age. At least 1 month should elapse between a dose of a measles-containing vaccine, such as M-M-R II, and a dose of Proquad. If for any reason a second dose of varicella-containing vaccine is required, at least 2 months should elapse between administration of the 2 doses.
Proquad should not be administered to persons with a history of anaphylactic reactions to neomycin. It should also not be administered to those with a history of hypersensitivity to any component of the vaccine, including gelatin. Proquad should not be administered to persons with certain medical conditions, including blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system, or persons with any immunodeficient condition or receiving immunosuppressive therapy. The vaccine also should not be used in those with active untreated tuberculosis or active febrile illness with fever (higher than 101.3°F) or those who are pregnant. Proquad may be used in persons who are receiving topical corticosteroids or low-dose corticosteroids for asthma prophylaxis or replacement therapy (eg, for Addison's disease), but it should not be given to those receiving immunosuppressive doses of corticosteroids.
Vaccination with Proquad may not offer 100% protection from measles, mumps, rubella, and varicella infection. Caution should be exercised in administering Proquad to persons with a history of cerebral injury, individual or family history of convulsions, or any other condition in which stress due to fever should be avoided. The vaccination history of a prospective vaccine recipient should be obtained to determine whether the person had any previous reactions to any vaccine including Proquad, Varivax, or any measles-, mumps-, or rubella-containing vaccines.
For more information on Merck & Co, Inc, visit merck.com.
Full prescribing information for Proquad is available at merck.com/product/usa/pi_circulars/p/proquad/proquad_pi.pdf.
September 1, 2005
ST. LOUIS (MD Consult) - On August 31, 2005, Tercica, Inc, announced that the US Food and Drug Administration (FDA) has approved Increlex (mecasermin [rDNA origin] injection) for the long-term treatment of growth failure in children with severe primary insulin-like growth factor–1 deficiency (IGFD) or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone. The FDA also designated Increlex as an orphan drug for severe primary IGFD.
Insulin-like growth factor–1 (IGF-1) is the direct mediator of growth hormone's effect on statural growth and must be present for children's bones, cartilage, and organs to grow normally. Severe primary IGFD is a growth hormone–resistant state characterized by abnormally low blood IGF-1 levels in the presence of normal or elevated growth hormone, which afflicts approximately 6,000 children in the United States.
"For more than 30 years, growth hormone has been the only treatment option endocrinologists have had for children with short stature due to hormonal deficiency," said Philippe Backeljauw, MD, Division of Endocrinology, Cincinnati Children's Hospital and a coinvestigator in the phase III trial conducted for Increlex. "The availability of Increlex will enable physicians to offer a more specific treatment for children whose growth failure is linked to abnormally low blood IGF-1 levels."
The active ingredient of Increlex is identical to the natural hormone, IGF-1, which the body produces in response to stimulation by growth hormone. Without adequate IGF-1, children cannot achieve height within the normal range. Tercica acquired exclusive rights to develop, commercialize and manufacture Increlex from Genentech, Inc.
Children with severe primary IGFD have height and serum IGF-1 levels that are more than 3 standard deviations below normal. They are not growth hormone deficient, and, because they are resistant to the effects of growth hormone, they cannot be expected to respond adequately to growth hormone therapy. In both children and adults, severe primary IGFD can lead to a range of other metabolic disorders including lipid abnormalities, decreased bone density, obesity, and insulin resistance.
The FDA's approval of Increlex is based on clinical trial data from 71 patients. Data reported at the 2004 Annual Meeting of the Endocrine Society demonstrated a statistically significant increase (P < .001) in growth rate over an 8-year period in response to therapy. Compared with pretreatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of 8 years. In addition, an analysis of safety concluded that long-term treatment with Increlex appears to be well tolerated and has an acceptable safety profile. The most common adverse events were hypoglycemia, lipohypertrophy, and tonsillar hypertrophy. Adverse effects were generally mild to moderate in nature, and no patients withdrew from the study as a result of them.
For further information on Tercica, which is based in Brisbane, Calif, please visit tercica.com.
September 1, 2005
ST. LOUIS (MD Consult) - GlaxoSmithKline announced on August 31, 2005, that the US Food and Drug Administration (FDA) has approved its influenza vaccine, Fluarix (influenza virus vaccine) for distribution in time for the 2005-2006 influenza season. Indicated for adults aged 18 years and older to combat influenza disease, Fluarix will be available exclusively in prefilled Tip-Lok syringes.
The FDA reviewed safety and immunogenicity data from a phase III clinical trial that studied Fluarix in approximately 1,000 adults in the United States aged 18 to 64 years. This randomized, double-blind, placebo-controlled study showed Fluarix to be safe and immunogenic.
Influenza is a highly contagious and potentially fatal virus that affects 5% to 20% of the total US population during each influenza season. Between 1990 and 1999, approximately 36,000 persons died annually in the United States from complications of influenza infection; more than 90% of these deaths occurred in persons 65 years of age and older. Influenza can reach epidemic levels and poses a significant threat to public health, particularly among the nation's oldest and youngest citizens. Influenza vaccination is the primary method for preventing influenza and its severe complications.
Many respiratory diseases occur every winter, but influenza is one of the most severe. The illness is easily passed from one person to another through the air by tiny droplets released when an infected person coughs or sneezes. Most persons recover fully within a week or 2, but the risk of complications is elevated in very young, very old, and chronically ill persons. Because the prevalent strains of influenza can change from season to season, the composition of the vaccine is adjusted yearly to match the recommendations of the FDA and the Centers for Disease Control and Prevention (CDC). As a result of these changes in the influenza virus, the CDC recommends annual vaccination, particularly for groups at high risk of complications.
Although epidemics of influenza happen in most years, the beginning, severity, and length of the epidemic can vary widely from year to year. Before a season begins, it is not possible to accurately predict the features of any season. Although October or November is the best time to get vaccinated, getting influenza vaccine in December or even later can be beneficial in most years. Flu season can begin as early as October and last as late as May. Persons who should receive the influenza vaccine include the very young, persons 50 years of age or older, the chronically ill, women who will be pregnant during influenza season, and all health care workers.
In addition to the public health threat influenza poses, the disease has economic repercussions. An average of approximately 226,000 influenza-related excess hospitalizations occurred per year in the United States between 1979 and 2001. Influenza epidemics can have a significant impact on the US economy because influenza infection results in an average of 2.8 lost workdays per episode, or $398 in lost wages for the average worker. Recent estimates put the cost of influenza epidemics to the economy at $71 to $167 billion per year.
Fluarix should not be administered to anyone with known systemic hypersensitivity reactions to eggs, egg products, egg or chicken proteins, or any component of Fluarix, nor to anyone who has had a life-threatening reaction to previous administration of any influenza vaccine. The most common adverse event in a clinical trial was pain at the injection site. Less common adverse events were muscle aches, fatigue, and headache. Most adverse events in clinical trials were mild and self-limiting. As with any vaccine, vaccination with Fluarix may not protect 100% of susceptible persons.
For information on GlaxoSmithKline, visit gsk.com.
August 30, 2005
ST. LOUIS (MD Consult) - On August 23, 2005, Alcon, Inc, announced that the US Food and Drug Administration (FDA) has approved its new drug application for Nevanac (nepafenac ophthalmic suspension) 0.1% for the treatment of pain and inflammation associated with cataract surgery. The approval came after a priority 6-month review.
Nevanac suspension contains a novel prodrug that rapidly penetrates ocular tissues. It is the first ophthalmic nonsteroidal anti-inflammatory prodrug to receive FDA approval. Alcon expects Nevanac suspension to be commercially available in the autumn of 2005.
"Nevanac suspension provides unique, target-specific activity that promotes penetration into the ocular tissues of most concern to ophthalmologists. This maximizes efficacy at the target sites of pain and inflammation following cataract surgery," said Richard L. Lindstrom, MD, adjunct professor emeritus, Department of Ophthalmology, University of Minnesota, and founder of Minnesota Eye Consultants.
The approval is based on results of 2 multicenter, placebo-controlled studies involving over 680 patients. In these clinical trials, Nevanac suspension was dosed 3 times per day, beginning 1 day before cataract surgery and continuing on the day of surgery and for 14 days postoperatively. Patients were evaluated at baseline and at 1, 3, 7, and 14 days after surgery. Patients treated with Nevanac suspension were found to have significantly less ocular pain and inflammation in the early postoperative period through the end of treatment.
In these studies, more than 80% of patients treated with Nevanac suspension were pain free the day after surgery, compared with less than 50% in the placebo group. After 2 weeks of treatment with Nevanac suspension, approximately 95% of patients were pain free, compared with 45% of patients in the placebo group. Additionally, 91% of patients treated with Nevanac suspension had no clinically significant inflammation at day 14, compared with approximately 47% of patients in the placebo group. In the studies, Nevanac suspension was shown to be safe and well tolerated with no unexpected adverse events reported.
In controlled clinical studies, the most frequently reported ocular adverse events after cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These events occurred in approximately 5% to 10% of patients. These events were similar to those reported with placebo and may be the consequence of the cataract surgery procedure.
A cataract is the clouding of the eye's natural lens that results in a loss or degradation of vision. The vast majority of cataracts are the result of the natural aging process. Cataract surgery is the removal of the clouded natural lens and replacement of it with an artificial lens. Surgeons will perform an estimated 2.8 million cataract surgeries in the United States in 2005. Anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs and corticosteroids, are commonly used by eye care professionals after ophthalmic surgery.
August 18, 2005
ST. LOUIS (MD Consult) - On August 16, 2005, Upsher-Smith Laboratories, Inc, announced the launch of new Fortical calcitonin-salmon (rDNA origin) Nasal Spray, an effective treatment option for postmenopausal osteoporosis in women more than 5 years postmenopause with low bone mass relative to healthy premenopausal women.
Calcitonin-salmon has been proved to produce statistically significant increases in lumbar vertebral bone mineral density (BMD) at just 6 months compared with placebo, with persistence at this level for up to 2 years of observation. Calcitonin-salmon has also been shown to increase hip BMD at 12 months compared with placebo.
"Fortical represents a pharmaceutically equivalent nasal calcitonin-salmon that provides a significant cost savings compared to the existing therapy," said Phill Dritsas, Vice President of Marketing and Sales for Upsher-Smith. "Fortical will conveniently fit into a woman's normal routine and can be taken before, during, or even after meals."
According to Mark Evenstad, Vice Chairman and President of Upsher-Smith Laboratories, "Fortical is manufactured with a unique, patented recombinant DNA technology and safely treats postmenopausal osteoporosis with no reported serious drug-related gastrointestinal or esophageal adverse events."
Fortical Nasal Spray is available with a prescription and is recommended in conjunction with adequate intake of calcium and vitamin D. Periodic nasal examinations are recommended; if nasal ulceration occurs, treatment should be discontinued until the ulcer heals. Because calcitonin-salmon is a protein, the possibility of systemic allergic reaction exists.
For more information on Fortical Nasal Spray, including complete product information, visit upsher-smith.com or call 1-800-654-2299.
Upsher-Smith is located in Minneapolis, Minn, and Denver, Colo. Fortical was developed and will be manufactured for Upsher-Smith by Unigene Laboratories, Inc, a biopharmaceutical company based in Fairfield, New Jersey.
July 28, 2005
ST. LOUIS (MD Consult) - QLT Inc announced on July 7, 2005, that it has received final approval from the US Food and Drug Administration (FDA) to market Aczone (dapsone) Gel, 5%, for the topical treatment of acne vulgaris. Aczone is the only topical formulation of dapsone available.
Patients will need to be screened to detect whether they are predisposed to hemolytic anemia because of a specific enzyme deficiency, glucose 6-phosphate dehydrogenase (G6PD) deficiency. Patients who have this enzyme deficiency will need to be monitored with regular blood counts. In the Aczone clinical trial program, 1.4% of approximately 3,500 patients had this disorder, which is consistent with the incidence in the general North American population. Certain populations, mainly males of African American descent, have a higher reported incidence of approximately 10% to 14%. QLT will undertake a postapproval phase IV study in 50 acne patients who have G6PD deficiency and perform follow-up with them for 6 months, after which the company expects to submit an application to the FDA to reevaluate the Aczone label.
Aczone is an aqueous topical gel containing 5% dapsone. Combining dapsone in a solvent microparticulate gel enables the agent to be applied topically and safely. In 2 randomized double-blind, vehicle-controlled clinical studies involving 3,000 patients with acne, Aczone Gel achieved a statistically significant reduction in the number of acne lesions and a better success rate on the Global Acne Assessment Score. The most common adverse events reported from controlled clinical trials include oiliness/peeling, dryness, and erythema. There were no significant differences in the adverse event rates between Aczone Gel and vehicle control–treated patients.
For more information on QLT Inc, visit the company Web site at qltinc.com.
July 26, 2005
ST. LOUIS (MD Consult) - Takeda Pharmaceuticals North America, Inc, announced on July 22, 2005, that the US Food and Drug Administration has approved Rozerem (ramelteon) 8-mg tablets for the treatment of insomnia characterized by difficulty with sleep onset. The approval allows physicians to prescribe Rozerem for long-term use in adults.
Rozerem is the first prescription sleep medication to show no evidence of abuse and dependence and, as a result, it has not been designated as a controlled substance by the US Drug Enforcement Administration (DEA). With the exception of Rozerem, all prescription medications indicated for insomnia are classified as Schedule IV controlled substances by the DEA. In addition, Rozerem is the first prescription insomnia medication with a new therapeutic mechanism of action in 35 years. The drug is expected to be available for patients by late September 2005.
"People with insomnia are not only affected by their sleeplessness at night; insomnia's impact is also in how they feel and function the next day," said Thomas Roth, PhD, director of the Sleep Disorders and Research Center, Detroit, Mich. "Current therapies often used for insomnia work by broadly inhibiting the activity of neurons in the brain. Ramelteon treats insomnia by specifically affecting the activity of neurons in an area of the brain involved in the sleep-wake process, and has been shown to carry no risks of abuse, withdrawal, or dependency, and negligible risk for next-day ‘hangover’ effects."
Rozerem has a unique therapeutic mechanism of action that selectively targets two receptors located in the brain's suprachiasmatic nucleus (SCN). The SCN is known as the body's "master clock" because it regulates circadian rhythms including the sleep-wake cycle.
The Rozerem new drug application, submitted in September 2004 by Takeda Global Research & Development Center, Inc, was based on data collected from an extensive clinical research program, including recently completed clinical studies with more than 4,200 patients aged 18 to 93 years. In one study, 472 patients received single daily doses of Rozerem for up to 1 year. Also, based on recently presented clinical trials, Rozerem has been shown to be safe for older adults, as well as those who have mild to moderate chronic obstructive pulmonary disease (COPD) and mild-to-moderate sleep apnea.
Approximately 60 million people in the United States suffer from insomnia, yet the vast majority remain undiagnosed and untreated. Insomnia is characterized by difficulty falling asleep, difficulty staying asleep, or poor-quality sleep, leading to impairment of next-day functioning.
Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. According to the US Surgeon General, nearly $15 billion annually is spent on health care related to insomnia, and $50 billion is lost in productivity.
Rozerem should not be used in patients with hypersensitivity to ramelteon or any components of the formulation. The drug can be prescribed for long-term use; however, failure of insomnia to remit after a reasonable period of time, worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities after taking Rozerem should be evaluated because such symptoms may be the result of an unrecognized underlying medical disorder. In primarily depressed patients, worsening of depression, including suicidal ideation, has been reported in association with the use of hypnotics.
Rozerem should not be used by patients with severe hepatic impairment or in patients in combination with fluvoxamine.
Rozerem has not been studied in subjects with severe sleep apnea or severe COPD and is not recommended for use in those populations. Patients should be advised to exercise caution if they consume alcohol in combination with this medication.
Because Rozerem has been associated with decreased testosterone levels and increased prolactin levels, health care professionals should be mindful of any unexplained symptoms possibly associated with such changes in these hormone levels. The drug has not been studied in children or adolescents, and the effects in these populations are unknown.
Rozerem should be taken within 30 minutes before going to bed, and activities should be confined to those necessary to prepare for bed. The medication should not be taken with or immediately after a high-fat meal. Engaging in hazardous activities that require concentration (eg, operating a motor vehicle or heavy machinery) after taking Rozerem should be avoided.
The most common adverse events seen with Rozerem that had greater than 2% incidence difference from placebo were somnolence, dizziness, and fatigue. For complete prescribing information, visit ROZEREM.com.
Takeda Pharmaceuticals North America, Inc, is based in Lincolnshire, Ill, and is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. More information about the company are available at tpna.com.
July 25, 2005
ST. LOUIS (MD Consult) - On July 21, 2005, Micro Therapeutics, Inc, announced that it has been granted premarket application approval from the US Food and Drug Administration (FDA) to commercialize its Onyx Liquid Embolic System for the treatment of arteriovenous malformations (AVMs), a vascular disorder in the brain.
AVMs are blood vessel networks that abnormally connect arteries to veins. As a result of high blood flow and pressure imbalances, AVMs in the brain are at risk of hemorrhage, which can lead to stroke, severe disability, and even death. Treatment options for AVMs include catheter-based therapies, surgery, radiation therapy, or a combination of these treatments. Catheter-based treatments involve the delivery of embolic materials to occlude the abnormal blood vessels composing the AVM.
Onyx is a liquid embolic material that is delivered by neurovascular specialists through Micro Therapeutics' proprietary micro catheters directly into a vascular defect, such as a brain aneurysm or AVM, in a very controlled manner. After delivery of the embolic material, the liquid quickly transforms into a solid polymer cast, thereby sealing off the vessels in the AVM from blood flow and reducing the risk of rupture. In the United States, Onyx is indicated for use in the presurgical embolization of brain AVMs. Endovascular embolization can reduce the size and vascularity of the AVM, thereby facilitating safer and easier surgical resection.
Micro Therapeutics expects to introduce Onyx to US markets immediately. Onyx has been under development by Micro Therapeutics since 1995 and has been distributed in international markets since 2002 by Micro Therapeutics' majority stockholder, ev3 Inc.
June 27, 2005
ST. LOUIS (MD Consult) - NitroMed, Inc, announced on June 23, 2005, that the US Food and Drug Administration (FDA) has approved BiDil (isosorbide dinitrate/hydralazine hydrochloride) for the treatment of heart failure in self-identified black patients, representing a step toward the promise of personalized medicine.
BiDil is indicated to improve survival, prolong time to hospitalization for heart failure, and improve patient-reported functional status, as an adjunct to current standard heart failure therapy.
Heart failure is a condition in which the heart is weakened and does not pump enough blood. It can be caused by a variety of damage to the heart, including heart attacks, high blood pressure, and infections.
The approval of BiDil was based in part on the results of the African-American Heart Failure Trial (A-HeFT). The study, which involved 1,050 self-identified black patients with severe heart failure who had already been treated with the best available therapy, was conducted because 2 previous trials in the general population of severe heart failure patients found no benefit, but suggested a benefit of BiDil in black patients. Patients on BiDil experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared with placebo, as well as a decrease of their symptoms of heart failure.
"Today's approval of a drug to treat severe heart failure in self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients," said Dr. Robert Temple, FDA Associate Director of Medical Policy. "The information presented to the FDA clearly showed that blacks suffering from heart failure will now have an additional safe and effective option for treating their condition. In the future, we hope to discover characteristics that identify people of any race who might be helped by BiDil."
Heart failure affects approximately 5 million Americans, including an estimated 750,000 African Americans, according to NitroMed. There is currently no cure for this disease, and more than 50% of patients die within 5 years of diagnosis. Black persons are affected at a rate greater than that of the corresponding non-black population, presenting with the disease earlier and dying sooner. According to the US Centers for Disease Control and Prevention, African Americans between the ages of 45 and 64 years are 2.5 times more likely to die from heart failure than white persons in the same age range.
BiDil is a combination of 2 older drugs, neither of which is approved for heart failure—hydralazine and isosorbide dinitrate. As an antihypertensive agent, hydralazine relaxes the arteries and decreases the work of the heart. The antianginal agent, isosorbide dinitrate, relaxes the veins as well as the arteries. Isosorbide seems to work by releasing nitric oxide at the blood vessel wall, but its effect usually wears off after half a day. Hydralazine may prevent this loss of effect. But how the two drugs work together is not fully known.
BiDil treatment is orally administered and is initiated at a dose of 1 tablet taken 3 times per day. This dosage can be increased to a maximum of 2 tablets 3 times per day, based on patient tolerance. Adjustments to maximum dosage may occur in 3 to 5 days; however, adverse side effects, which may include headaches and dizziness, may require that some patients take more time to reach their highest tolerated dose.
Common side effects with the use of BiDil are headache and dizziness.
BiDil is marketed by NitroMed, Inc, of Lexington, Mass. For full prescribing information, visit BiDil.com.
June 24, 2005
ST. LOUIS (MD Consult) - On June 23, 2005, Boehringer Ingelheim Pharmaceuticals, Inc, announced that the US Food and Drug Administration (FDA) has granted accelerated approval of Aptivus (tipranavir) capsules. Accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses that provide meaningful benefit to patients over existing treatments. This approval is based on 24-week data from ongoing studies. Longer-term data will be needed before the FDA can consider traditional approval for Aptivus. There are no study results demonstrating the effect of Aptivus on clinical progression of HIV-1.
The approved dose of Aptivus is 500 mg taken with 200 mg of ritonavir (Aptivus/r) twice daily. Aptivus must be coadministered with ritonavir to boost the therapeutic levels of Aptivus; otherwise, levels of Aptivus will be insufficient to inhibit HIV replication. Aptivus/r must be taken in combination with other anti-HIV medications. Boehringer Ingelheim expects that Aptivus 250-mg soft gel capsules will be available in pharmacies nationwide within 2 weeks of FDA approval.
Aptivus is a nonpeptidic protease inhibitor that works by inhibiting protease, an enzyme needed to complete the HIV replication process. Aptivus is able to enter infected immune cells and inhibit HIV replication for many strains of HIV that are resistant to other commercially available protease inhibitors.
Drug resistance is one of the major challenges that patients and physicians face in the treatment of HIV. Resistance develops when the virus mutates and is no longer suppressed by drugs that were once effective. Boehringer Ingelheim pointed out that the prevalence of drug-resistant HIV emphasizes the need for new treatments.
Aptivus, coadministered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1–infected adult patients with evidence of viral replication, who are highly treatment experienced or have HIV-1 strains resistant to multiple protease inhibitors. This indication is based on analyses of plasma HIV-1 RNA levels in 2 controlled studies of Aptivus of 24 weeks' duration. Both studies were conducted in clinically advanced, 3-class antiretroviral treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The use of other active agents with Aptivus/r is associated with a greater likelihood of treatment response. Genotypic or phenotypic testing and/or treatment history should guide the use of Aptivus/r. The number of baseline primary protease inhibitor mutations affects the virologic response to this treatment regimen. Liver function testing should be performed at initiation of therapy with these drugs and monitored frequently throughout the duration of treatment.
Patients enrolled in the Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir (RESIST) studies were failing their current protease inhibitor–based regimen, had received at least 2 previous protease inhibitor–based regimens, had received prior treatment from at least 3 classes of antiretroviral agents, and had documented protease inhibitor resistance. These trials examined the treatment response at 24 weeks of Aptivus/r versus a comparator group in which patients received one of several marketed ritonavir-boosted PIs. Investigators selected a comparator protease inhibitor that offered patients the best opportunity for treatment response based on resistance testing. The comparator protease inhibitors were lopinavir, indinavir, saquinavir, and amprenavir. In addition, patients in both arms of the trial received an optimized background regimen of other antiretroviral drugs. Patients in these trials were highly treatment experienced, and the majority were at least possibly resistant to the comparator protease inhibitor chosen. The median baseline viral load and CD4+ count were 4.82 log10 copies/mL and 155 cells/mm3, respectively.
The results of the RESIST studies showed that a statistically significant greater percentage of HIV-positive patients taking Aptivus/r achieved a treatment response versus the comparator group (40% vs 18%). Treatment response was defined as a confirmed 1 log10 or greater decrease in viral load from baseline.
In addition, a significantly greater proportion of patients receiving regimens that contained boosted Aptivus were able to reduce the amount of HIV in their blood to undetectable levels than in the boosted comparator group. At 24 weeks, 34% of patients in the Aptivus/r group and 16% of patients in the boosted comparator group achieved a viral load of less than 400 copies/mL, and 23% versus 9% achieved less than 50 copies/mL.
Patients treated with Aptivus/r also experienced greater increases in their immune cells than those treated with a ritonavir-boosted comparator protease inhibitor. The median change from baseline in CD4+ cell count at week 24 was +34 cells/mm3 in patients receiving Aptivus/r (n = 582) versus +4 cells/mm3 in the comparator group of ritonavir-boosted protease inhibitors (n = 577).
Caution should be used when prescribing Aptivus/r to patients with elevated transaminases, hepatitis B or C coinfection, or other underlying hepatic impairment. Aptivus coadministered with 200 mg of ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. All patients should be followed up closely with clinical and laboratory monitoring. Liver function tests should be performed before initiating therapy with Aptivus/r and frequently throughout the duration of treatment. Patients who develop symptoms of liver problems, such as fatigue, loss of appetite, yellowing of the eyes or skin, or liver tenderness, should stop taking Aptivus/r treatment. Patients with moderate to severe hepatic insufficiency should not take Aptivus/r.
The extensive drug-drug interaction potential of Aptivus/r when coadministered with multiple classes of drugs must be considered before and during Aptivus/r use. Aptivus/r has an effect on the way some medications are eliminated by the body, and if these medications are combined with Aptivus/r, an elevation of their level may occur, which can lead to serious and/or life-threatening adverse effects. Some medications from the following drug classes must not be taken with Aptivus/r: antiarrhythmics, antihistamines, ergot derivatives, gastrointestinal motility agents, neuroleptics, and sedatives/hypnotics.
Other medications taken with Aptivus/r may require a dose adjustment or additional monitoring, including reverse transcriptase inhibitors, protease inhibitors, antifungals, antimycobacterials, calcium channel blockers, antidepressants, HMG-CoA reductase inhibitors, hypoglycemics, immunosuppressants, narcotic analgesics, estrogens, PDE5 inhibitors, anticoagulants, antibiotics, and drugs to treat alcohol dependence. Patients should discuss the potential for drug interactions with their health care providers.
Aptivus, a sulfa-containing drug, should be used with caution in patients with a known sulfa allergy. Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving Aptivus/r. In phase 2 and 3 trials, rash was observed in 14% of female patients and in 8% to 10% of male patients receiving Aptivus/r. Additionally, in 1 drug interaction trial in healthy female volunteers who were administered a single dose of ethinyl estradiol followed by Aptivus/r, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized itching has been reported in both men and women receiving Aptivus/r. Women taking estrogen-containing medications with Aptivus/r have an increased risk of developing a rash.
Like other protease inhibitors, Aptivus/r may be associated with the development or worsening of diabetes, elevations in cholesterol and triglycerides, abnormal distribution of body fat, immune-related inflammatory response to infections, and increased bleeding in hemophiliacs.
Aptivus does not cure HIV infection/AIDS or prevent the transmission of HIV to others. Patients taking the drug may continue to develop opportunistic infections and other complications associated with HIV disease. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. Aptivus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The long-term effects of Aptivus are unknown at this time.
The most commonly (≥2%) reported adverse effects of at least moderate intensity in patients enrolled in the RESIST studies taking Aptivus/r are gastrointestinal, including diarrhea (10.9%), nausea (6.7%), vomiting (3.4%), and abdominal pain (2.8%). Fever (4.6%), fatigue (4%), headache (3.1%), bronchitis (2.9%), depression (2%), and rash (2%) also occurred. The most common (=2%) moderate to severe laboratory abnormalities in patients enrolled in the RESIST studies taking Aptivus/r are elevated triglycerides (45.1%), elevated liver enzymes (17.5%), elevated cholesterol (14.6%), decreased white blood cell count (3.6%), and elevated amylase (2.9%).
Boehringer Ingelheim has announced that it is undertaking studies to evaluate the safety and efficacy of Aptivus. The drug's safety and efficacy in pediatric patients and in treatment-naive adults have not been established; phase 2 and 3 studies in these populations are fully enrolled and ongoing. In addition, the company plans to continue to study Aptivus in women and hepatitis-coinfected patients and to conduct further pharmacokinetic interaction studies of the drug.
June 20, 2005
ST. LOUIS (MD Consult) - Novo Nordisk announced on June 17, 2005, that the US Food and Drug Administration (FDA) has granted marketing authorization for Levemir (insulin detemir), the company's long-acting insulin analog for the treatment of diabetes.
Levemir is a soluble, long-acting basal human insulin analog with a relatively flat action profile and prolonged duration of action of up to 24 hours. Levemir is engineered to bind to human albumin, which provides slow absorption and prolonged action.
Levemir is indicated for once- or twice-daily subcutaneous administration in the treatment of adult patients with diabetes mellitus who require basal insulin for the control of hyperglycemia. Levemir can be used as the basal component of basal-bolus therapy in type 1 and type 2 diabetes and as add-on therapy in people with type 2 diabetes that is inadequately controlled with oral antidiabetic agents.
The safety and efficacy of Levemir given once or twice daily was compared to NPH human insulin or insulin glargine in controlled clinical studies involving a total of 6,004 patients with diabetes (3,724 with type 1 and 2,280 with type 2). One study, a treat-to-target efficacy study of 475 patients using Levemir or NPH insulins, showed that patients taking Levemir had mean A1C levels at the end of the study of approximately 6.6%, which meets the target level recommended by the American Diabetes Association. There was no significant difference between the 2 treatment arms. In other studies, Levemir achieved a level of glycemic control similar to that provided by other basal insulins, as measured by A1C.
Levemir is contraindicated in patients hypersensitive to insulin detemir or its excipients.
The most common adverse effect of Levemir is hypoglycemia. In clinical trials, the overall rates of hypoglycemia with Levemir and NPH insulin were similar. Analysis of nocturnal hypoglycemia is type 1 diabetes showed a significantly lower risk of minor nocturnal hypoglycemia than with NPH insulin, whereas no difference was seen in type 2 diabetes.
Levemir is associated with no weight gain in people with type 1 diabetes and significantly less weight gain compared with NPH insulin in people with type 2 diabetes, according to Novo Nordisk. The company stated that this result has been consistently observed over both 6 and 12 months in all phase 3 trials.
Adjustment of dosage of Levemir may be necessary if the patient undertakes increased physical activity, changes his or her usual diet, or experiences concomitant illness. Self-monitoring of blood glucose should be carried out regularly and frequently, as with other regimens.
The medication's use in pediatric patients is under review with the FDA, and a decision is expected before the end of 2005.
Denmark-based Novo Nordisk expects to introduce Levemir in the US market within the next 12 months.
For more details on Levemir, including prescribing information, visit novonordisk.com/diabetes/hcp/pharmaceuticals/Levemir.
June 17, 2005
ST. LOUIS (MD Consult) - Wyeth Pharmaceuticals announced on June 15, 2005, that the US Food and Drug Administration (FDA) has approved Tygacil (tigecycline), an intravenous antibiotic with a broad spectrum of antimicrobial activity, including activity against the drug-resistant bacteria methicillin-resistant Staphylococcus aureus (MRSA). Tygacil is indicated for the treatment of complicated intraabdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI) in adults. Approval of this first-in-class product comes at a time when the need for new antibiotic options to combat serious, resistant infections is increasing.
Tygacil can be used as an empiric monotherapy to treat a variety of cIAI and cSSSI, both hospital- and community-acquired, including complicated appendicitis, infected burns, intra-abdominal abscesses, deep soft tissue infections, and infected ulcers. Tygacil provides clinicians with a novel, broad-spectrum option that can be used at the onset of treatment when the specific bacteria present are not yet known. In addition, Tygacil does not require dosage adjustment in patients with impaired renal function and is administered every 12 hours.
According to the US Centers for Disease Control and Prevention (CDC), persons infected with drug-resistant organisms are more likely to have longer hospital stays and require treatment with multiple drugs. The increasing prevalence of resistant bacteria often necessitates the use of combinations of antibiotics to fight infections. Antibiotic resistance costs Americans between $4 billion and $5 billion annually. The CDC further states that antibiotic resistance has become so widespread that many significant bacterial infections in the world are becoming resistant to commonly used antibiotics.
Additionally, few broad-spectrum antibiotic agents are currently in development. Antibiotic development has slowed to the point that the FDA has had few opportunities to approve new agents. In fact, development and approvals of new antibacterial agents have decreased by 56% over the past 20 years (1998-2002 vs 1983-1987). New classes of antibiotics are needed to address increasing antibiotic resistance among common pathogens.
Tygacil, the first antibiotic approved in a new class called glycylcyclines, was developed by Wyeth to overcome key mechanisms of resistance that have affected antibiotic use. The drug is approved for adults with cSSSI caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp (includes S anginosus, S intermedius, and S constellatus), Streptococcus pyogenes, and Bacteroides fragilis.
Tygacil is also approved for adults with cIAI caused by Citrobacter freundii, Enterobacter cloacae, E coli, Klebsiella oxytoca, Klebsiella pneumoniae, E faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible isolates only), S anginosus grp (includes S anginosus, S intermedius, and S constellatus), B fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
The new drug application for Tygacil included data from 4 pivotal phase III studies examining the safety and efficacy of Tygacil for the treatment of cIAI and cSSSI. The submission also included in vitro data showing activity against both gram-negative and gram-positive bacteria, anaerobes, and certain drug-resistant pathogens.
In clinical trials, empiric monotherapy with Tygacil provided comparable clinical cures rates in cSSSI to vancomycin and aztreonam, a combination treatment. Empiric monotherapy with Tygacil also provided clinical cure rates comparable to imipenem/cilastatin, an empiric treatment for cIAI. The overall discontinuation rate for Tygacil (5.0%) was comparable to vancomycin and aztreonam (5.3%) and imipenem/cilastatin (4.4%).
Tygacil is contraindicated in patients with known hypersensitivity to tigecycline. The drug should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics; similar adverse effects to those elicited by that class may result. In clinical trials, the most common treatment-emergent adverse events in patients treated with Tygacil were nausea (29.5%) and vomiting (19.7%).
Tygacil may cause fetal harm when administered to a pregnant woman. The safety and effectiveness of the medication in patients younger than 18 years and lactating women have not been established. Use of Tygacil during tooth development may cause permanent discoloration of the teeth.
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life-threatening. Monotherapy should be used with caution in patients with clinically apparent intestinal perforation.
Tygacil prescribing information is available at wyeth.com.
June 14, 2005
ST. LOUIS (MD Consult) - Pfizer Inc announced on June 13, 2005, that the US Food and Drug Administration (FDA) has approved Zmax (azithromycin extended release) for oral suspension. The single-dose treatment is indicated for mild to moderate acute bacterial sinusitis and community-acquired pneumonia in adults.
In the first 24 hours after a 2-g dose of Zmax, the amount of drug that gets into the tissue is 3 times higher than a standard dose of immediate-release azithromycin. Immediate-release azithromycin has been available in the United States since 1992 under the trade name Zithromax. This "front loading" of Zmax provides high drug levels earlier in the course of infection, when the bacterial burden is likely to be highest. Dr. Joseph Feczko, chief medical officer at Pfizer, stated, "Results showed that 1 dose of Zmax was as effective as currently available treatments that must be taken for 7 to 10 days."
Zmax is released in the small intestine rather than in the stomach, which results in a favorable side-effect profile. In addition, the high tissue penetration and long half-life of azithromycin make it possible to deliver the entire course of therapy as a single dose, which is helpful in dealing with compliance issues and may decrease the emergence of resistance to antibiotics.
Zmax is indicated for treatment of acute bacterial sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae and community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy.
The Zmax adult clinical research program included outpatients with mild to moderate acute bacterial sinusitis and community-acquired pneumonia, as well as acute bacterial exacerbations of chronic bronchitis (AECB).
Pfizer withdrew its application for the treatment of AECB while the FDA reevaluates how it reviews investigational antibiotics for this indication.
Zmax offers a safety profile comparable to other antibiotic treatments for certain types of sinusitis and pneumonia and is generally well tolerated. Adverse effects were generally mild to moderate. Overall in the pivotal studies, the most common treatment-related adverse reactions in adult subjects receiving a single (2-g) dose of Zmax were diarrhea/loose stools (11.6%), nausea (3.9%), abdominal pain (2.7%), headache (1.3%), and vomiting (1.1%). In the majority of Zmax-treated patients, diarrhea resolved within 2 days.
Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any other macrolide or ketolide antibiotic. If an allergic reaction occurs, administration of the drug should be discontinued and appropriate therapy instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy for the allergic reaction is discontinued. Pseudomembranous colitis has been reported with nearly all antibacterial agents. It is important to consider this diagnosis in patients who present with diarrhea.
Full prescribing information for Zmax is available at pfizer.com/pfizer/download/uspi_zmax.pdf.
June 7, 2005
ST. LOUIS (MD Consult) - Pfizer Inc announced on June 6, 2005, that the US Food and Drug Administration (FDA) has approved Revatio (sildenafil citrate) as a treatment for pulmonary arterial hypertension (PAH), a rare, aggressive, and life-shortening vascular disease. Sildenafil citrate is also the active ingredient in Viagra, Pfizer's erectile dysfunction medication.
PAH is characterized by dangerously high pressure in the blood vessels that lead from the heart to the lungs. It is estimated to affect approximately 100,000 people worldwide. Symptoms include difficulty breathing, dizziness, and fatigue. Left untreated, patients have an average survival time of less than 3 years from the time of diagnosis.
The FDA granted Revatio a priority review. The FDA approval was based on results of a large randomized, double-blind, placebo-controlled study involving 277 patients with PAH. The study measured the exercise capability of patients after 12 weeks of treatment. Patients were randomly assigned to receive Revatio—20, 40, or 80 mg 3 times daily—or placebo. All 3 treatment groups showed highly significant improvements in the 6-minute walk distance, the standard measure of efficacy in PAH trials, compared with patients who received placebo. No differences were observed among the Revatio doses studied; therefore, the approved dosage is limited to 20 mg 3 times/d.
Patients taking Revatio also showed improvements in mean pulmonary artery pressure and other measures of cardiac function. A long-term non–placebo-controlled extension trial was also conducted. At the end of 1 year, walk distance and functional class were stable, and 94% of patients were still alive.
Revatio is the first oral treatment for PAH to be approved for patients with an early stage of the disease, allowing physicians to treat patients earlier in this progressive disorder.
Revatio was generally well tolerated at all doses studied. The most common adverse effects were headache, dyspepsia, flushing, epistaxis, and insomnia.
The Revatio 20-mg pill is white and round, to distinguish it from Viagra's blue diamond-shaped pill for erectile dysfunction. Pfizer expects Revatio to be available in retail pharmacies in mid-July 2005.
Revatio is indicated for the treatment of PAH to improve exercise ability. The efficacy of Revatio has not been evaluated in patients currently receiving bosentan therapy.
The use of Revatio or Viagra and organic nitrates in any form, at any time, is contraindicated. Adverse effects were similar to the established safety profile of Viagra used for the treatment of erectile dysfunction.
The most common adverse effects of Viagra are headache, facial flushing, and upset stomach. Less commonly, bluish vision, blurred vision, or sensitivity to light may briefly occur.
For more information regarding Pfizer and its products, visit pfizer.com.
June 6, 2005
ST. LOUIS (MD Consult) - On June 3, 2005, Biovail Corporation and Depomed, Inc, announced that they have received approval from the US Food and Drug Administration (FDA) for Glumetza (metformin hydrochloride), a once-daily, extended-release formulation for the treatment of type II diabetes.
Glumetza may offer potential advantages such as less frequent dosing and proven effectiveness in combination with other diabetes drugs. Glumetza also offers excellent tolerability that allows physicians to more quickly administer a large enough dose to provide glycemic control without significantly increasing the incidence of nausea, diarrhea, and other adverse effects that are sometimes caused by metformin products.
The 500-mg dosage strength was developed using Depomed's Gastric Retention drug-delivery technology. The 1,000-mg dosage strength was developed using Biovail's Smartcoat delivery technology.
"Glumetza has excellent tolerability, which is important because side effects, such as nausea and diarrhea, are thought to be a primary reason that 60% of patients prescribed metformin are no longer taking their medication as prescribed after the first year," said Dr. Sherwyn Schwartz, endocrinologist and a principal investigator in the phase III clinical trials of Glumetza. "Additionally, a phase III clinical trial confirmed Glumetza's effectiveness in combination with the sulfonylurea glyburide, another diabetes drug that is frequently prescribed with metformin. Glumetza's effectiveness in combination with other diabetes drugs is key because the American College of Endocrinology and American Association of Clinical Endocrinologists recently recommended that physicians aggressively treat diabetes early, often with 2 or more drugs."
Diabetes mellitus is a condition characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin activity, or both. Metformin is indicated for the control of hyperglycemia in metformin-responsive, stable, mild, non–ketosis prone maturity-onset type of diabetes (type II) that cannot be controlled by proper dietary management, exercise, and weight reduction and when insulin therapy is not appropriate.
Diabetes affects an estimated 18 million Americans and is increasing by approximately 1 million new cases each year in the United States alone. Approximately 90% of persons with diabetes have type II, the most common metabolic disease in the world and the fifth-deadliest disease in the United States. Diabetes is the leading cause of blindness, end-stage renal disease, and nontraumatic loss of limb and can also lead to heart disease, stroke, high blood pressure, kidney disease, and other serious conditions.
Glumetza should not be administered to patients with kidney problems, heart failure that is treated with medicine, or metabolic acidosis, including diabetic ketoacidosis, which should be treated with insulin.
Glumetza can cause lactic acidosis, a rare but serious condition. Patients should stop taking this medication and call their doctors right away if they feel very weak or tired; feel dizzy or lightheaded; have a slow or irregular heartbeat, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, or diarrhea; feel cold, especially in the arms and legs; or if a medical condition suddenly changes.
The most common adverse effects of Glumetza include diarrhea, nausea, and upset stomach.
For more information about Depomed, visit depomedinc.com. Additional information about Biovail is available at biovail.com.
June 2, 2005
ST. LOUIS (MD Consult) - BioMarin Pharmaceutical Inc announced on June 1, 2005, that the US Food and Drug Administration (FDA) has granted marketing approval for Naglazyme (galsulfase), the first specific therapy approved for the treatment of mucopolysaccharidosis VI (MPS VI). Naglazyme has been shown to improve walking and stair-climbing capacity in patients with this condition.
As postmarketing clinical commitments, BioMarin has agreed with the FDA to evaluate the effect of Naglazyme treatment on skeletal dysplasia in patients younger than 1 year of age and to maintain a clinical surveillance program to monitor patients receiving commercial therapy; no extension study of phase 3 patients was required.
MPS VI (also known as Maroteaux-Lamy syndrome) is a debilitating, life-threatening genetic disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase. This enzyme deficiency leads to the accumulation of glycosaminoglycans (GAGs) in the lysosomes, giving rise to progressive cellular, tissue, and organ system dysfunction. An estimated 1,100 persons in the developed world have MPS VI. The majority of persons with MPS VI die from disease-related complications between childhood and early adulthood. Additional information can be found at mpsvi.com.
Clinical trials have demonstrated that Naglazyme provides clinically important benefits for MPS VI patients—specifically, improved endurance as demonstrated by the 12-minute walk test and the 3-minute stair climb. Naglazyme reduced the excess carbohydrates—GAGs—that are excreted in the urine of patients with MPS VI, an indication of enzymatic bioactivity.
BioMarin completed a 24-week, phase 3, multicenter double-blind placebo-controlled trial involving 39 patients. Patients were randomly assigned, on a 1-to-1 basis, into a treatment group or a placebo control group that received a weekly intravenous infusion of 1.0 mg/kg of Naglazyme or placebo solution, respectively. During the 24-week period, 19 patients received Naglazyme and 20 patients received placebo infusions. One patient in the placebo group dropped out of the trial for reasons unrelated to treatment. All 38 patients who completed the trial elected to receive Naglazyme in an ongoing open-label extension study.
After 24 weeks of treatment, patients receiving Naglazyme demonstrated a statistically significant improvement (P = .025) in endurance compared with patients receiving placebo, as measured by the change relative to baseline in the distance walked in 12 minutes. The Naglazyme-treated group showed greater mean increase in distance walked in 12 minutes compared with the placebo group. The model-derived mean difference measured as a change from baseline between patients receiving Naglazyme and patients receiving placebo after 24 weeks was 92 ± 40 m. After an additional 24 weeks of treatment with Naglazyme in the extension study, patients demonstrated further improvement in endurance as measured by the change in distance walked in 12 minutes, relative to baseline. From week 24 to week 48, patients receiving Naglazyme since week 1 of the trial improved their mean walk distance an additional 36 ± 97 m.
After 24 weeks of treatment, patients receiving Naglazyme demonstrated an improvement (P = .053) in stair-climbing ability compared with patients receiving placebo as measured by the change relative to baseline in the number of stairs climbed per minute. The Naglazyme-treated group showed greater mean increase in the rate of stairs climbed in 3 minutes compared with the placebo group. The model-derived mean difference measured as a change from baseline between patients receiving Naglazyme and patients receiving placebo after 24 weeks was 5.7 ± 2.9 stairs/min. After an additional 24 weeks of treatment with Naglazyme in the extension study, from week 24 to week 48, patients receiving Naglazyme since week 1 of the trial improved their mean number of stairs climbed per minute by an additional 3 ± 7 stairs.
After 24 weeks of treatment, patients receiving Naglazyme experienced a statistically significant reduction (P < .001) of GAGs excreted in the urine compared with patients receiving placebo. The average urinary GAG reduction in patients receiving Naglazyme after 24 weeks was 75.5%. This initial reduction in urinary GAG levels was maintained after an additional 24 weeks of treatment in the extension study.
While in the extension study, patients who received placebo solution during the initial 24-week trial demonstrated an improvement in endurance after 24 weeks of treatment with Naglazyme as measured by the change in distance walked in 12 minutes, relative to baseline. From week 24 to week 48, the original placebo group demonstrated a mean increase of 65 m relative to week-24 values. These patients also demonstrated an average improvement in stair-climbing ability as measured by stairs climbed in 3 minutes, relative to baseline, of 5.7 stairs/min after 24 weeks of treatment with Naglazyme. Additionally, patients initially receiving placebo demonstrated a reduction in urinary GAG levels after 24 weeks of treatment with Naglazyme comparable to that observed for those treated in the initial 24-week, double-blind portion of the trial.
Data from the phase 3 clinical trial and extension study indicate that Naglazyme was generally safe. The most common adverse events observed in clinical trials in Naglazyme-treated patients were headache, fever, arthralgia, vomiting, upper respiratory infections, abdominal pain, diarrhea, ear pain, cough, and otitis media. Over 95% of the infusion-related adverse events were considered mild or moderate and were easily managed. Infusion-related adverse events commonly included fever, chills/rigors, headache, rash, and mild to moderate urticaria. Severe reactions included angioneurotic edema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria. No patients discontinued Naglazyme infusions for adverse events, and all patients who completed the double-blind portion of the trial continue to receive weekly infusions of Naglazyme. Nearly all patients developed antibodies as a result of treatment, but the level of the immune response did not correlate with adverse events or affect the improvements experienced in endurance. Evaluation of airway patency should be considered before the initiation of treatment. Consideration to delay Naglazyme infusion should be given when treating patients who present with an acute febrile or respiratory illness.
Naglazyme has been granted orphan drug status in the United States, which confers 7 years of market exclusivity. BioMarin plans to launch Naglazyme in the United States in July 2005.
For more information on BioMarin and its products, visit BMRN.com.
May 23, 2005
ST. LOUIS (MD Consult) - Depomed, Inc, announced on May 20, 2005, that it has received approval from the US Food and Drug Administration (FDA) for Proquin XR, a once-daily, extended-release formulation of ciprofloxacin hydrochloride for the treatment of uncomplicated urinary tract infections (UTIs). Proquin XR is the first version of ciprofloxacin with nausea and diarrhea listed as "uncommon" adverse events in its label, rather than "common" adverse events. As a class of compounds, ciprofloxacin and other fluoroquinolones are cited in literature as causing nausea and diarrhea, and these types of adverse effects are reportedly the most frequent reason that patients discontinue ciprofloxacin treatment.
According to Depomed's dissolution studies, Cipro (Bayer Corp) and generic equivalents release their entire dosage within approximately 30 minutes, and once-daily Cipro XR releases its dosage within approximately 2 hours, whereas Proquin XR is designed to gradually release the drug over 6 hours. This extended release avoids large quantities of drug being deposited into the patient's intestinal system, where it can cause adverse effects or interactions with gastrointestinal drugs. In a randomized, double-blind, phase III clinical trial of 1,037 patients with uncomplicated UTIs, Proquin XR eradicated Escherichia coli, the bacteria most commonly responsible for causing UTIs, comparably to twice-daily Cipro.
Patients should not take Proquin XR if they are allergic to, or have ever had a severe reaction to, ciprofloxacin or to any other "quinolone" antibiotics. Proquin XR is generally well tolerated. The most common adverse effects with Proquin XR include vaginal yeast infection and headache.
For additional information on Proquin XR, call the product information hotline at 800-206-2945. More information about Depomed can be found at its Web site: depomedinc.com.
May 10, 2005
ST. LOUIS (MD Consult) - On May 9, 2005, London-based pharmaceutical company SkyePharma PLC announced that the US Food and Drug Administration has approved Triglide, its novel formulation of fenofibrate. The main drawback of fenofibrate is insolubility in water, resulting in variable uptake from the stomach and requiring the patient to take the tablets with food. Triglide has a comparable absorption under fed and fasting conditions and therefore allows patients to take the drug at any time, improving compliance and simplicity for both patients and prescribers.
Fenofibrate is an oral treatment for lipid disorders such as elevated cholesterol and triglycerides.
A study involving the administration of fenofibrate in patients with severe renal impairment showed a greatly reduced rate of clearance of fenofibric acid, warranting a dosage minimization of the medication in this cohort. However, no modification of dosage is required in patients having moderate renal impairment.
Hepatocellular, chronic active, and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic hepatitis. Regular periodic monitoring of liver function, including serum alanine aminotransferase, should be performed for the duration of therapy with fenofibrate, and therapy should be discontinued if enzyme levels persist above 3 times the normal limit.
Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.
Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time. In addition, the combined use of fenofibrate and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.
Fenofibrate has not been investigated in adequate and well-controlled trials in pediatric patients.
For more information, visit skyepharma.com. The drug label for Triglide is available at fda.gov/cder/foi/label/2005/021350lbl.pdf.
May 5, 2005
ST. LOUIS (MD Consult) - On May 4, 2005, Cangene Corporation announced that the US Food and Drug Administration (FDA) has approved Cangene's Vaccinia immune globulin (VIG) for use in counteracting certain adverse reactions to smallpox vaccination.
The product was developed under a supply and development contract with the United States Centers for Disease Control and Prevention (CDC) as part of the US government's smallpox vaccination program in an effort to prepare for potential bioterrorism threats. The contract is for a 5-year period to supply a maximum of 100,000 doses of VIG. The CDC will order product under these guidelines on an as-needed basis.
VIG is a hyperimmune product to be used in treating and preventing a type of severe reaction that may be brought on by administration of the smallpox vaccine. Cangene stated that its newly approved product is considered to be an important component to smallpox vaccination programs. Hyperimmune products are highly purified specialty antibodies made from human plasma.
Founded in 1984, biotechnology company Cangene is headquartered in Winnipeg, Manitoba. The corporation has manufacturing facilities in Winnipeg and in Baltimore, Md. Product information is available at cangene.com.
May 2, 2005
ST. LOUIS (MD Consult) - Amylin Pharmaceuticals, Inc, and Eli Lilly and Company announced on April 29, 2005, that the US Food and Drug Administration (FDA) has approved Byetta (exenatide) injection as adjunctive therapy to improve blood sugar control in patients with type 2 diabetes who have not achieved adequate control by taking metformin and/or a sulfonylurea, two common oral diabetes medications.
In addition to approving the new drug for use as an adjunct to existing oral medicines, the FDA also stated that Byetta is approvable as a monotherapy for patients with type 2 diabetes. Any additional data submitted to support a monotherapy indication is expected to receive a 6-month review.
Byetta is formulated for self-administration as a fixed dose, subcutaneous injection given before the morning and evening meals. Byetta will be made available in both 5- and 10-µg doses in prefilled pen-injector devices.
Byetta, made from the saliva of the Gila monster lizard, is the first in a new class of medicines known as incretin mimetics, a new class of therapeutics for use in treating type 2 diabetes. An incretin mimetic works to mimic the antidiabetic or glucose-lowering actions of naturally occurring human hormones (incretins), leading to better long-term control as measured by hemoglobin A1C levels. These actions include the stimulation of insulin secretion only when blood sugar is high and the restoration of the first-phase insulin response, an activity of the insulin-producing cells in the pancreas that is lost in persons who have type 2 diabetes.
In three 30-week controlled trials, adverse events associated with Byetta were generally mild to moderate in intensity. The most frequently reported adverse event was mild-to-moderate dose-dependent nausea. With continued therapy in most patients who initially experienced nausea, the frequency and severity decreased over time.
Patients receiving Byetta in combination with a sulfonylurea have an increased risk of hypoglycemia. To reduce this risk, reduction in the dose of the sulfonylurea should be considered. In the 30-week controlled clinical trials, hypoglycemia appeared to be dependent on the doses of both Byetta and a sulfonylurea. Most episodes of hypoglycemia were mild to moderate in intensity, and all were resolved with oral administration of carbohydrate. No increased risk of hypoglycemia was observed in the 30-week controlled studies with Byetta when used in combination with metformin compared with placebo.
Patients should also be advised that treatment with Byetta may result in a reduction in appetite, food intake, or body weight and that there is no need to modify the dosing regimen due to such effects.
Byetta should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, nor is this medication a substitute for insulin in patients requiring insulin. Use of Byetta is not recommended in patients with end-stage renal disease or severe renal impairment, nor in patients with severe gastrointestinal disease. The drug should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption.
According to the International Diabetes Federation Diabetes Atlas and the US Centers for Disease Control and Prevention (CDC), diabetes affects an estimated 194 million adults worldwide and more than 18 million in the United States. Approximately 90% to 95% of those affected have type 2 diabetes, a condition in which the body does not produce enough insulin and/or the cells in the body do not respond normally to insulin. The American Diabetes Association states that diabetes is the fifth leading cause of death by disease in the United States. Type 2 diabetes usually occurs in adults over the age of 40 but is increasingly common in younger people.
According to the CDC's National Health and Nutrition Examination Survey, approximately 60% of diabetes patients do not achieve target hemoglobin A1C levels (less than 7%, according to American Diabetes Association guidelines) with their current treatment regimen.
Amylin stated that Byetta will be available to pharmacies by June 2005. Full prescribing information is available at www.byetta.com.
April 18, 2005
ST. LOUIS (MD Consult) - On March 28, 2005, ISTA Pharmaceuticals, Inc, announced that the U.S. Food & Drug Administration has approved Xibrom (bromfenac ophthalmic solution) 0.09% for the treatment of ocular inflammation after cataract surgery.
Xibrom is the first twice-daily ophthalmic nonsteroidal anti-inflammatory solution (NSAID) to be approved in the United States. Approved doses of other ophthalmic NSAIDs involve administration 4 times daily.
Xibrom 0.09% is a sterile, topical, nonsteroidal anti-inflammatory compound. ISTA completed 2 pivotal phase III clinical studies of the drug involving 527 patients. In these studies, a statistically significant proportion of the patients treated with Xibrom achieved treatment success, defined as the complete absence of ocular inflammation, compared with those patients who received placebo. This effect was evident in the Xibrom group as early as day 3 following initiation of treatment.
ISTA, based in Irvine, Calif, is a specialty pharmaceutical company focused on the development and commercialization of ophthalmic products. The company expects to launch Xibrom during the second quarter of 2005. For additional information on ISTA and Xibrom, visit istavision.com.
April 12, 2005
ST. LOUIS (MD Consult) - On April 11, 2005, Rochester, New York–based Bausch & Lomb announced that the U.S. Food and Drug Administration (FDA) has approved Retisert (fluocinolone acetonide intravitreal implant), 0.59 mg, for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. Uveitis is a sight-threatening inflammatory disease that primarily afflicts people between the ages of 20 and 50 years.
Retisert is the first intravitreal drug implant approved for the treatment of this condition that affects an estimated 175,000 people in the United States and an estimated 800,000 people worldwide. The product received FDA "Fast Track" status, designed to allow for priority review of novel therapies for serious diseases for which there is an unmet medical need. The company said it plans to make the drug available by mid-year, 2005.
Retisert's drug-delivery method consists of a tiny drug reservoir designed to deliver sustained levels of the anti-inflammatory corticosteroid fluocinolone acetonide for 30 months directly to the back of the eye.
FDA approval of the single-indication orphan drug was based on 34-week results from two 3-year randomized, double-masked, multicenter clinical studies demonstrating that, in eyes treated with Retisert, the following occurred:
The most common adverse events include cataract progression, which is managed by standard cataract surgery; increased intraocular pressure (IOP), which is managed with the use of IOP-lowering eye drops or filtering surgery; and procedural complications and eye pain. Bausch & Lomb pointed out that these adverse effects were anticipated, given the nature of the disease and the type of drug used.
Full prescribing information is available via the manufacturer's Web site: www.bausch.com/retisert_pi.pdf.
April 1, 2005
ST. LOUIS (MD Consult) - On March 31, 2005, Schering-Plough Corporation announced that, after a long regulatory delay, the U.S. Food and Drug Administration (FDA) has approved the use of Asmanex Twisthaler 220 mcg (mometasone furoate inhalation powder) for the first-line maintenance treatment of asthma as preventive therapy in patients 12 years of age and older. Asmanex is also the only inhaled asthma controller therapy approved for once-daily initiation and management of asthma in patients previously treated with bronchodilators alone or inhaled corticosteroids. Clinical studies with Asmanex have shown substantial improvement in lung function, decreased use of rescue medication, decreased incidence of nighttime awakenings, and significant improvements in daytime symptoms such as coughing and wheezing.
In a clinical trial, Asmanex showed substantial improvement in lung function and decreased albuterol (rescue medication) use compared with placebo, as evidenced by a 12-week, multicenter, randomized, double-blind, placebo-controlled study of 400 patients with persistent asthma previously dependent on inhaled corticosteroid therapy. At the trial's end point, patients who received Asmanex had a significant improvement in nighttime awakenings and daytime symptoms.
The National Asthma Education and Prevention Program asthma treatment guidelines recommend single-ingredient, low-dose inhaled corticosteroid as the foundation of therapy for mild persistent asthma management.
Asthma is a chronic inflammatory lung disease that affects a growing number of Americans each year. According to the Global Initiative for Asthma, the number of cases has grown steadily in the past 20 years, making it one of the leading public health problems in the United States. The U.S. Centers for Disease Control and Prevention estimate that as many as 20 million people currently have asthma. On an annual basis, this leads to at least 2 million emergency room visits and more than 5,000 deaths. Additionally, the American Lung Association states that this accounts for an annual direct cost of treatment of $9.4 billion. Asthma symptoms such as coughing, wheezing, and shortness of breath occur during the day and night, affecting multiple aspects of patients' lives. Daytime symptoms can affect activities ranging from exercise to going to school or work. Nighttime symptoms can interfere with patients' ability to sleep.
In clinical trials with Asmanex, adverse events were generally mild to moderate in severity. The following incidence of common adverse experiences is based on double-blind data from 10 placebo-controlled clinical trials involving a total of 2,809 patients previously maintained on inhaled steroids and/or bronchodilators (1,140 male, 1,669 female; aged 12-83 years) who were treated for up to 12 weeks with Asmanex, an active comparator, or placebo. Adverse events were generally mild to moderate in severity and included headache, allergic rhinitis, pharyngitis, upper respiratory infection, sinusitis, oral candidiasis, dysmenorrhea, musculoskeletal pain, back pain, dyspepsia, myalgia, abdominal pain, and nausea.
Asmanex offers an effective inhaled corticosteroid to control asthma symptoms in an easy-to-use device. The Asmanex Twisthaler uses an inhalation-driven device that does not use a propellant, thus eliminating the need for hand-breath coordination, and it includes a numeric dose counter that provides a visual indication of the remaining doses.
The recommended starting dose of Asmanex is 1 inhalation daily in the evening for patients previously treated with bronchodilators alone or inhaled corticosteroids. For patients who previously took oral corticosteroids, the recommended starting dose of Asmanex is 2 inhalations twice daily.
Asmanex is expected to be available in the United States in the autumn of 2005.
Full prescribing information is available at spfiles.com/piasmanex.pdf.
March 31, 2005
ST. LOUIS (MD Consult) - On March 29, 2005, the U.S. Food and Drug Administration approved Baraclude (entecavir) for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histologic, virologic, biochemical, and serologic responses after 1 year of treatment in nucleoside-treatment-naive and lamivudine-resistant adult patients with hepatitis B e antigen (HBeAg)-positive, or HBeAg-negative chronic HBV infection with compensated liver disease. Also taken into consideration were more limited data in adult patients with HIV/HBV coinfection who have received prior lamivudine therapy.
Study AI463038 was a randomized, double-blind, placebo-controlled study of Baraclude versus placebo in 68 patients coinfected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral therapy (HAART) regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine, 300 mg/d) and were assigned to add either Baraclude 1 mg once daily (51 patients) or placebo (17 patients) for 24 weeks followed by an open-label (nonblinded) phase for an additional 24 weeks during which all patients received Baraclude.
At baseline, patients had a mean serum HBV DNA level by polymerase chain reaction of 9.13 log10 copies/mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. The median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy.
The proportion of HIV/HBV-coinfected patients with HBV DNA < 300 copies/mL was 6% for the group receiving Baraclude 1 mg versus 0% for the placebo group. The mean change from baseline for HBV DNA was -3.65 log10 copies/mL for those receiving Baraclude 1 mg versus +0.11 log10 copies/mL for the placebo group. Thirty-four percent of patients in the Baraclude 1 mg group had ALT normalization (-1 × upper limit of normal) compared with 8% of patients in the placebo group.
There are no data for patients with HIV/HBV coinfection who have not received prior lamivudine therapy.
New York-based Bristol-Myers Squibb, manufacturer of Baraclude, advises that people taking Baraclude should tell their health care providers right away if they feel very weak or tired, have unusual muscle pain, have trouble breathing, have stomach pain with nausea and vomiting, feel cold (especially in their arms and legs), feel dizzy or lightheaded, or have a fast or irregular heartbeat; these could be signs of lactic acidosis. Lactic acidosis is a medical emergency and must be treated in the hospital. Some people who have taken medicines like Baraclude have developed serious liver problems including hepatotoxicity. This may occur with hepatomegaly and steatosis. People should contact their health care providers immediately if they experience any of the following signs of liver problems: jaundice, darkening of the urine, lightening in the color of stools, loss of appetite for several days or longer, nausea, or lower stomach pain. Lactic acidosis and hepatotoxicity have occurred in some people taking medicines like Baraclude.
In some people, hepatitis B symptoms may get worse or become very serious when they stop taking Baraclude. Patients should not stop taking Baraclude without discussing with their health care providers. Health care providers will need to follow up with their patients and do blood tests to check the liver when Baraclude administration is stopped. In addition, health care providers should be notified if patients have or develop kidney problems because tests may be necessary to determine whether a lower dose is needed.
It is not known whether Baraclude is safe to use during pregnancy, nor is it not known whether this medication helps to prevent a pregnant mother from passing HBV to her baby. Women should not breast-feed if they are taking Baraclude.
For more details on Baraclude, including full prescribing information, visit baraclude.com. Limited data about Baraclude in patients with HIV/HBV coinfection who received prior lamivudine therapy are presented in the drug label. The Special Population section under Description of Clinical Studies includes information on HIV/HBV coinfected patients.
March 18, 2005
ST. LOUIS (MD Consult) - Fujisawa Healthcare, Inc, announced on March 16, 2005, that the U.S. Food and Drug Administration (FDA) has approved the antifungal product Mycamine (micafungin sodium for injection) for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and the treatment of esophageal candidiasis.
According to a recent study, invasive candidiasis kills 10% to 40% of infected immunocompromised patients. "Immunocompromised patients whose white blood cell contents are lowered are highly susceptible to candida infections," said Ira D. Lawrence, MD, Senior Vice President, Research and Development at Fujisawa. "Mycamine can be an effective preventive therapy for immunocompromised patients who undergo bone marrow or stem cell transplants and are highly susceptible to candida fungal infections."
The FDA approval is based on 32 clinical studies conducted in the United States, Canada, Japan, South America, Europe, and Africa. The clinical development program included data from 2,402 subjects. Subjects in the Mycamine studies included a broad range of persons who had a confirmed, or were at risk for, candida fungal infections, including patients with hematologic malignancies, bone marrow transplant recipients, and HIV-positive patients. In 3 large, well-controlled, clinical trials, Mycamine was shown to have an overall safety profile and discontinuation rate similar to that of fluconazole.
Mycamine is a member of a new class of antifungal agents, the echinocandins, which inhibit cell-wall synthesis. The novel mechanism of action of echinocandins specifically targets the wall of fungal cells to treat the infection. Mycamine is contraindicated in patients with hypersensitivity to any component of the product. Patients receiving Mycamine have reported isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock), significant hemolysis, and hemolytic anemia. The most common side effects experienced in the clinical trials included changes in liver and renal function. Possible histamine-mediated symptoms have been reported with Mycamine, including rash, pruritus, facial swelling, and vasodilatation. Injection site reactions, including phlebitis and thrombophlebitis, have been reported at Mycamine doses of 50 to 150 mg/d.
Fujisawa Healthcare, Inc, headquartered in Deerfield, Ill, is a subsidiary of Fujisawa Pharmaceutical Co, Ltd, based in Osaka, Japan. Additional information can be found at www.fujisawa.com.
March 18, 2005
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) approved Symlin (pramlintide acetate), an injectable medicine to control blood sugar for adults with type 1 and type 2 diabetes, on March 17, 2005. Symlin is to be used in addition to insulin therapy in patients who cannot achieve adequate control of their blood sugar levels with intensive insulin therapy alone.
Symlin will be the only therapy for the treatment of type 1 diabetes other than insulin. Patients with type 2 diabetes already have several other types of oral therapies available.
The safety and efficacy of Symlin were studied in approximately 5,000 patients. Overall, Symlin therapy was associated, in patients with both types of diabetes, with improvements in the control of blood glucose and with weight loss. So-called "tight" control of blood sugar is desirable in all patients with diabetes to reduce risks for long-term adverse consequences of the disease, including blindness, kidney disease, and vascular disease.
Symlin is to be used only in combination with insulin to help decrease blood sugar levels during the 3 hours after meals. Symlin will be accompanied by an FDA-approved patient medication guide and a risk minimization action plan due to 3 areas of concern: First, the principle risk associated with Symlin therapy is hypoglycemia, and this risk is greatest in patients with type 1 diabetes or gastroparesis. Second, the potential for medication errors, specifically mixing of Symlin with insulin in the same syringe, which can alter the activity of the insulin, is addressed in the medication guide and in physician-directed drug labeling. Finally, the potential for off-label use in patients for whom the benefit/risk profile has not been characterized or demonstrated is also a concern and will be monitored by the drug's sponsor.
The medication guide informs patients that Symlin should only be used if (1) they are already using their insulin as prescribed but still need better blood sugar control; (2) they will follow their doctors' instructions exactly; (3) they will follow up with their doctors often; (4) they will test their blood sugar levels before and after every meal and at bedtime; and (5) they understand how to adjust Symlin and insulin doses.
Symlin should not be used if patients cannot tell when their blood sugar is low, if they have gastroparesis, or if they are allergic to pramlintide acetate, metacresol, D-mannitol, acetic acid, or sodium acetate.
Adverse effects associated with Symlin include but are not limited to nausea, vomiting, abdominal pain, headache, fatigue, and dizziness. The drug has not been evaluated in the pediatric population.
Symlin is manufactured by Amylin Pharmaceuticals, Inc, of San Diego, Calif. For more information, including full prescribing details, visit symlin.com.
February 22, 2005
ST. LOUIS (MD Consult) - Medicis announced on February 18, 2005, that the U.S. Food and Drug Administration (FDA) has approved Ammonul (sodium phenylacetate and sodium benzoate) as an adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. The FDA granted Ammonul orphan drug status with 7 years of exclusivity based on long-term compassionate patient use in patients with urea cycle disorder (UCD). UCD is an inherited, inborn error of metabolism. Patients with UCD lack one of the key enzymes that compose the urea cycle, which can result in the life-threatening condition of hyperammonemia.
Ammonul is a hospital product administered intravenously as a rescue medication when a UCD patient progresses into a hyperammonemic crisis. Ammonul works by scavenging ammonia directly from the bloodstream, independent of the defective urea cycle. Buphenyl (sodium phenylbutyrate), another Medicis prescription product indicated for UCD, is the only FDA-approved drug for maintenance treatment of UCD patients in the United States. Buphenyl tablets and powder are used for daily, lifelong maintenance in UCD patients and work much the same as Ammonul by scavenging ammonia from the bloodstream.
The annual incidence rate of UCD in the United States is approximately 1 in 30,000 live births. Historically, less than 5% of UCD patients survived the disorder, as the infant patient would appear simply septic. With the increasing awareness of UCD and the availability of Ammonul as a rescue medication, statistics have improved drastically to a survival rate greater than 90%.
Ammonul is available by prescription and administered intravenously in the hospital setting. Although rare, vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment have been reported with sodium phenylacetate and sodium benzoate therapy. Ammonul is contraindicated for use by patients with known hypersensitivity to sodium phenylacetate and sodium benzoate. When used as directed, Ammonul is safe and efficacious as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.
Full prescribing information for Ammonul can be obtained by contacting Medicis. The company's Web site is available at www.medicis.com/index.html.
February 18, 2005
ST. LOUIS (MD Consult) - On February 14, 2005, Medicis Pharmaceutical Corporation announced that the U.S. Food and Drug Administration (FDA) has approved its new drug application for Vanos (fluocinonide), a class I corticosteroid, for the treatment of plaque-type psoriasis.
Vanos is a patented corticosteroid formulation that embodies the heritage of Lidex. The formulation of Vanos provides doctors and patients with a new, high-potency vehicle in the form of a cream for once or twice daily application.
Vanos is available by prescription and comes in 30- and 60-g containers. The most common adverse events associated with the use of Vanos are headache and burning at the application site. Vanos is contraindicated for use by patients with a history of hypersensitivity to its components. When used as directed, Vanos is safe and efficacious for the treatment of plaque-type psoriasis.
Vanos is manufactured by Patheon, Inc, in Canada. Full prescribing information for Vanos can be obtained by contacting Medicis at 602-808-8800 or media_relations@medicis.com.
Medicis, based in Scottsdale, Ariz, is an independent pharmaceutical company specializing in the treatment of dermatological and podiatric conditions and aesthetics medicine. For more information, visit the company's website at medicis.com.
Medicis anticipates launching Vanos to dermatologists in the quarter beginning April 2005.
January 31, 2005
ST. LOUIS (MD Consult) - On December 2, 2004, Inamed Corporation and Genzyme Corporation announced that the U.S. Food and Drug Administration has granted market approval for Captique Injectable gel, a new dermal filler product based on Genzyme's proprietary non-animal stabilized hyaluronic acid (HA) technology.
Captique is the newest HA entry into the U.S. dermal filler marketplace. It is indicated for the correction of moderate to severe facial wrinkles and is manufactured by Genzyme.
"This is the first of our non-animal stabilized HA pipeline products and an excellent complement to our existing Hylaform and Hylaform Plus product line in the U.S.," said Hani Zeini, Executive Vice President, Inamed Aesthetics. Inamed's Aesthetics is the company's division dedicated to the facial aesthetics and plastic surgery markets.
Inamed is a global health care company based in Santa Barbara, Calif. The company's Web site is Inamed.com. Genzyme Corporation is a global biotechnology company headquartered in Cambridge, Mass. Visit genzyme.com. The two companies are partnering to market and distribute Captique in the United States.
January 18, 2005
ST. LOUIS (MD Consult) - Sanofi pasteur, the vaccines segment of the sanofi-aventis Group, announced on January 17, 2005, that the U.S. Food and Drug Administration (FDA) has licensed Menactra (meningococcal [groups A, C, Y, and W-135] polysaccharide diphtheria toxoid conjugate vaccine) for protection against meningococcal disease in adolescents and adults aged 11 to 55 years.
Menactra vaccine is the first quadrivalent conjugate vaccine licensed in the United States for the prevention of meningococcal disease and is designed to offer protection against 4 serogroups of Neisseria meningitidis (A, C, Y, W-135), the bacterium that causes meningococcal infection.
The Advisory Committee on Immunization Practicies (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC) has formed a working group that is updating the recommendations for the prevention and control of meningococcal disease, including routine meningococcal vaccination of one or more birth cohorts (eg, 11- to 12-year-olds) and of selected college students. The ACIP is expected to approve any changes in recommendations during the February 2005 committee meeting.
Although meningococcal disease rates are highest in infants, rates begin to rise again in early adolescence and peak between the ages of 15 and 24 years. During the 1990s, one study reported substantially increased incidence among 15- to 24-year-olds. In addition to the increased incidence, the fatality rate was over 22% in this age group, over 5 times that seen in younger persons. Up to 83% of the cases reported in this study were caused by the potentially vaccine-preventable serogroups that are included in Menactra vaccine.
"In 2001, members of the CDC's Active Bacterial Core Surveillance Team called upon the pharmaceutical industry to create a conjugate vaccine for protection against multiple serogroups of Neisseria meningitidis to combat the increased risk for disease in the adolescent population," said Michael Decker, MD, MPH, vice president, scientific and medical affairs at sanofi pasteur, the human vaccines business of sanofi-aventis Group. He stated the company's development of Menactra was in response to this challenge.
The FDA's decision to license Menactra vaccine was based on safety and immunogenicity data from 6 pivotal studies including more than 7,500 adolescents and adults receiving Menactra vaccine. Menactra vaccine induced the production of functional antibodies specific to the capsular polysaccharides of the 4 serogroups (A, C, Y, and W-135) found in the vaccine. All vaccine immunogenicity measurements demonstrated strong immune responses to a single dose of Menactra vaccine that were equivalent to a single dose of sanofi pasteur's Menomune-A/C/Y/W-135 (meningococcal polysaccharide vaccine, groups A, C, Y, and W-135 combined).
Additional findings demonstrated 98% to 100% of seronegative adolescents were found to elicit 4-fold increases in antibody titers to all 4 meningococcal serogroups. In seronegative adults, this range was 91% to 100%.
There are risks associated with all vaccines. The most common adverse reactions to Menactra vaccine may include pain, redness, and induration at the site of injection, headache, fatigue, and malaise. Menactra vaccine is contraindicated in persons with known hypersensitivity to any component of the vaccine or to latex, which is used in the vial stopper.
Sanofi pasteur has said it plans to work closely with the CDC in an effort to ensure production schedules that will support an orderly implementation of the anticipated new immunization recommendations. In early 2005, the company plans to apply for supplemental licensure in the United States for use of Manactra vaccine in children younger than 11 years.
In general, the benefits of a successful conjugate vaccine include improved duration of protection, induction of immunologic memory, booster responses and reduction in nasopharyngeal bacterial carriage. These characteristics have been recognized with Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae conjugate vaccines. In 1987, sanofi pasteur licensed in the United States the first conjugate vaccine for protection against Hib—ProHIBit (Hib and diphtheria conjugate vaccine [diphtheria toxoid-conjugate]). Since the introduction of Hib conjugate vaccines, such as ProHIBit, the incidence of Hib invasive disease among children aged 4 years or younger has declined by 98%.
Meningococcal disease is a rare but serious bacterial infection that strikes between 1,500 and 3,400 Americans every year, causing meningitis or sepsis in the majority of cases. Approximately 10% of persons who contract meningococcal disease will die. Of those who survive, up to 1 in 5 suffer permanent disabilities such as hearing loss, neurologic damage, and limb amputations. Meningococcal disease often begins with symptoms that can be mistaken for common viral illnesses, such as the flu. But unlike more common infections, meningococcal disease can progress very rapidly and kill an otherwise healthy young person in 48 hours or less.
January 11, 2005
ST. LOUIS (MD Consult) - American Pharmaceutical Partners, Inc, and American Bioscience, Inc, announced on January 7, 2005, that the U.S. Food and Drug Administration (FDA) has approved Abraxane for injectable suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound). Abraxane is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
The approval marks a new class of "protein-bound particle" drugs, made possible by American Bioscience, Inc's proprietary nanoparticle albumin-bound (nab) technology. Abraxane is the first in this new class of drugs.
Abraxane, consisting only of albumin-bound paclitaxel nanoparticles, is free of toxic solvents and demonstrated a superior response rate with an almost doubling of the reconciled target lesion response rate compared with the solvent-based Taxol (paclitaxel; Bristol-Myers Squibb) in a prospectively randomized trial of 460 patients with metastatic breast cancer. Because it contains no toxic solvents, this next-generation taxane product enables the administration of 50% more chemotherapy with a well-tolerated safety profile, requires no premedication to prevent hypersensitivity reactions, and can be given over the course of 30 minutes using standard IV tubing.
The compound paclitaxel is considered one of the most effective anti-cancer compounds ever discovered. However, due to its water-insoluble nature, it has been necessary, until now, to use the toxic solvent Cremophor-EL (BASF Aktiengesellschaft) to put the compound into solution in order to administer it intravenously (IV). In patients, Cremophor is known to cause life-threatening allergic reactions despite premedication and lowering of the white blood cell count. In animals, Cremophor has also been shown to cause nerve and brain damage.
In addition to these toxicities, solvents also leach plasticizers from the IV tubing. To administer solvent-containing drugs to patients, specialized IV tubing is thus required.
Furthermore, studies have shown that solvents may minimize anti-tumor activity by entrapping the active compound in the bloodstream, rendering it less available to the tumor cell where it is needed to effect its anti-tumor activity.
Abraxane, having eliminated the risks of toxic solvents, requires no premedication and can deliver a 50% higher dose of chemotherapy than with Taxol. Inadvertent substitution of solvent-based Taxol at 260 mg/m2 without steroid premedication over 30 minutes could pose significant risk to the patient, potentially resulting in fatal hypersensitivity reactions, a high incidence of severe neutropenia, and a possibility for severe, prolonged peripheral neuropathy.
"Abraxane... is an active new class of drugs that addresses the toxicities associated with solvents in taxane-based chemotherapy, namely hypersensitivity reactions, severe myelosuppression, prolonged peripheral neuropathy and severe edema," said Edith Perez, MD, Professor of Medicine, Mayo Clinic College of Medicine, and Chair of the Breast Committee, North Central Cancer Treatment Group. "Grade 4 neutropenia occurred in less than 10% of the patients. In the patients who developed grade 3 peripheral neuropathy, rapid improvement occurred after a median of only 22 days. It is significant that Abraxane can be safely administered to both young and elderly patients. Plans currently are underway to study this next-generation taxane in combination with other chemotherapeutic agents in the treatment of front-line metastatic breast cancer."
The new drug application reviewed by the FDA included data from 106 patients in 2 single-arm open-label studies and from 1 randomized comparative study of 460 women with metastatic breast cancer. This randomized trial was designed to compare Abraxane at a dose of 260 mg/m2 given as a 30-minute infusion without premedication versus paclitaxel injection (Taxol) at 175 mg/m2 given as a 3-hour infusion with standard steroid and antihistamine premedication. Fourteen percent of patients did not receive prior chemotherapy; 27% received chemotherapy in the adjuvant setting; 40% in the metastatic setting, and 19% in both metastatic and adjuvant settings. Of the patient population, 41% were first-line patients and 59% received study drug as second- or greater-than-second-line therapy. Seventy-seven percent of patients had been previously exposed to anthracyclines.
The prospectively defined end point for this study was a protocol-specific target lesion response rate based on data from the first 6 cycles of therapy using an independent radiologic review reconciled with the investigator response assessment. It is well established that independent radiologically reviewed response rates are lower than the investigator-reported response rates that are typically reported in the scientific literature.
This reconciled target lesion response rate for the 233 patients in the Abraxane treatment arm of the trial was superior at 21.5% (95% confidence interval, 16.9% to 26.7%) compared with 11.1% (95% confidence interval, 6.94% to 15.1%) for the 227 patients in the Taxol treatment arm (P = .003). In this study, the investigator response rates for Abraxane and Taxol were 33% and 19%, respectively (as reported at the San Antonio Breast Cancer Symposium in December 2003).
Despite a 50% higher dose of chemotherapy infused over 30 minutes without premedication for hypersensitivity, Abraxane was well tolerated in the pivotal phase III trial. Neutropenia (all grades) was experienced by 80% of patients treated with Abraxane and 82% of patients treated with Taxol. Less grade 4 neutropenia was experienced by patients taking Abraxane despite the 50% higher dose administered (9% of Abraxane patients vs 22% of Taxol patients).
No patients taking Abraxane experienced severe hypersensitivity reactions. Premedications required with Taxol are not needed with Abraxane.
Sensory neuropathy (all grades) occurred in 71% of patients treated with Abraxane and 56% treated with Taxol. Grade 3 sensory neuropathy symptoms were observed in 10% of Abraxane patients versus 2% of Taxol patients. There were no episodes of grade 4 neuropathy in this study. Of the patients who developed grade 3 peripheral sensory neuropathy while taking Abraxane, 58% (14 of 24) had documented rapid improvement in symptoms after a median of 22 days, and 42% of patients (10 of 24) were able to resume treatment at a reduced dose. Only 3% of patients receiving Abraxane discontinued treatment due to peripheral neuropathy.
Nail changes were uncommon in both arms of treatment. No patients in the study had severe edema. No increased toxicity was seen in elderly patients receiving Abraxane compared with younger patients.
Other clinically important adverse events (all grades) included, anemia (33% with Abraxane and 25% with Taxol), infections (24% and 20%, respectively), hypersensitivity reactions (4% and 12%), edema (10% and 8%), nausea (30% and 21%), vomiting (18% and 9%), diarrhea (26% and 15%), and mucositis (7% in both arms). Severe adverse events included myalgia/arthralgia (8% with Abraxane and 4% with Taxol) and vomiting (4% and 1%, respectively).
According to the American Cancer Society, although early detection efforts have decreased mortality rates, an estimated 215,990 women are expected to have been diagnosed in 2004 with breast cancer that had already spread. Breast cancer is still the leading overall cause of death in women between the ages of 20 and 59 years, with 40,110 deaths estimated in 2004. One of every 3 cases of cancer diagnosed in the United States is breast cancer, and excluding skin cancer, it is the most common cancer among women.
For full prescribing information for Abraxane, visit ABRAXANE.com.
January 7, 2005
ST. LOUIS (MD Consult) - Biopharmaceutical company CoTherix, Inc, announced on December 29, 2004, that the U.S. Food and Drug Administration (FDA) has approved Ventavis (iloprost) Inhalation Solution for the treatment of pulmonary arterial hypertension (PAH) in patients with New York Heart Association (NYHA) class III or IV symptoms. PAH is a highly debilitating and potentially fatal disease characterized by high blood pressure in the pulmonary arteries of the lungs.
"This approval provides PAH patients with a non-invasive treatment option that avoids the complications associated with intravenous or subcutaneous prostacyclin delivery," said Donald J. Santel, Chief Executive Officer of CoTherix.
A randomized, double-blind, multicenter, placebo-controlled trial was conducted in 203 adult patients (inhaled Ventavis, n = 101; placebo, n = 102) with NYHA class III or IV PAH (World Health Organization [WHO] group I; idiopathic in 53%, associated with connective tissue disease, including CREST and scleroderma, in 17%, or associated with anorexigen use in 2%) or pulmonary hypertension related to chronic thromboembolic disease (WHO group IV; 28%). The primary clinical end point for the trial was a composite of the following: (1) an improvement in NYHA functional class, (2) an increase in the distance walked in 6 minutes of at least 10%, and (3) no clinical deterioration or death. The response rate for the primary efficacy end point among patients with PAH was 19% for patients treated with Ventavis compared with 4% for the placebo-treated patients (P = .0033). All 3 components of the composite end point favored Ventavis. The absolute change in 6-minute walk distance measured 30 minutes after inhalation among patients with PAH was greater in the Ventavis group compared with the placebo group at all time points, including week 12, with a placebo-corrected difference of 40 m (P < .01).
Ventavis is generally well tolerated. The most common adverse effects include flushing, increased cough, hypotension, headaches, nausea, spasm of the jaw muscles that causes trouble opening the mouth, and syncope. Other serious adverse events reported with the use of inhaled Ventavis include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.
PAH affects an estimated 50,000 patients in the United States, with only about 15,000 diagnosed and under treatment. Its cause may be unknown, or it may result from other diseases that cause a restriction of blood flow to the lungs, including scleroderma, HIV, and lupus. Symptoms of the disease include fatigue, shortness of breath on exertion, chest pain, and dizziness. Left untreated, the median survival time after diagnosis can be as short as 3 years.
Ventavis is currently marketed by Schering AG in several European countries and Australia. CoTherix licensed exclusive rights to develop and commercialize Ventavis in the United States from Schering AG in October 2003 and filed a new drug application in June 2004. In August 2004, CoTherix's application was accepted by the FDA and granted priority review. In addition, Ventavis received orphan drug designation in August 2004 to treat PAH.
For more information, visit cotherix.com.
January 4, 2005
ST. LOUIS (MD Consult) - Pfizer Inc announced on December 31, 2004, that it has received approval from the U.S. Food and Drug Administration (FDA) to market Lyrica (pregabalin capsules) for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN). Lyrica is the first FDA-approved treatment for both of these neuropathic pain states, which are distinctly different from arthritis or musculoskeletal pain.
Contrary to Pfizer's expectations, however, the FDA decided to classify the drug as a controlled substance. This designation can affect sales because it imposes additional requirements on doctors and pharmacists administering the drug.
Neuropathic pain, one of the most debilitating forms of pain, is caused by nerve damage that can result from underlying conditions, such as diabetes or shingles. According to Pfizer, nearly half of the 18 million Americans with diabetes will develop some form of diabetic neuropathy over the course of their disease, and about 1 in 6 patients with diabetes will experience painful diabetic neuropathy. The pain of DPN is often described as burning, tingling, sharp, stabbing, or pins and needles in the feet, legs, hands, or arms.
PHN is a complication of shingles, a painful outbreak of rash or blisters on the skin caused by a reactivation of the same virus that causes chicken pox. Each year, about 150,000 Americans develop PHN, which is often characterized as constant stabbing, burning, or electric shock–like sensation.
The efficacy of Lyrica was established in 6 double-blind, placebo-controlled trials, 3 involving patients with DPN and 3 involving patients with PHN. Lyrica provided rapid and clinically meaningful pain reduction in a significant portion of patients, with pain relief beginning as early as the first week of treatment in some patients. Pain relief was sustained in studies of up to 12 weeks' duration.
The safety of Lyrica was established in more than 9,000 patients. In all clinical trials, adverse events were mild to moderate. The most common adverse effects associated with Lyrica compared with placebo included dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight gain, and difficulty with concentration/attention. The discontinuation rate due to adverse effects was low.
The FDA's classification of Lyrica as a controlled substance is likely to delay the product's launch date because Pfizer must wait for the Drug Enforcement Administration (DEA) to conduct a formal review of the drug. A Pfizer spokeswoman said that the DEA review could take as short as a few weeks or as long as several months. A launch date won't be announced until the review is completed, she said.
For more information, visit lyrica.com.
December 30, 2004
ST. LOUIS (MD Consult) - On December 28, 2004, Genzyme Corporation was granted approval from the U.S. Food and Drug Administration (FDA) to market Clolar (clofarabine) for the treatment of pediatric patients (aged 1-21 years) with refractory or relapsed acute lymphoblastic leukemia (ALL). Clolar is the first new leukemia treatment approved specifically for children in more than a decade.
In 2005, an estimated 3,400 new cases of pediatric acute leukemia will be diagnosed in the United States, according to Cancer Metric. ALL is the most common form of pediatric leukemia, and children who do not respond to initial therapy, or those who relapse, have a very poor survival prognosis.
Clolar is indicated for the treatment of patients 1 to 21 years old with relapsed or refractory ALL after at least 2 prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
Clolar has received "orphan drug" designation for adult and pediatric acute lymphoblastic leukemia. Clolar will now have 7 years of market exclusivity in pediatric ALL patients. The FDA also recently granted 6 months of extended market exclusivity to Clolar under the Best Pharmaceuticals for Children Act.
Clolar was approved under the FDA's accelerated approval process, which was established for serious or life-threatening diseases such as ALL when a product may provide meaningful therapeutic benefit to patients over existing treatments. Approvals can be granted on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate end point reasonably likely to predict clinical benefit. Postmarketing studies to verify clinical benefit are required under this mechanism. Genzyme has announced its commitment to continue postmarketing evaluation of Clolar in pediatric ALL and has submitted a pediatric development plan that includes further study of Clolar in combination with existing therapies.
Clolar's approval was based on results from a pivotal phase II trial involving 49 heavily pretreated children with relapsed or refractory ALL; prior to treatment with Clolar the patients' conditions had failed to respond to an average of 3 other regimens. Patients received 52 mg/m2 of Clolar intravenously for 1 to 2 h/d for 5 consecutive days. This process was repeated for 2 to 6 cycles every 28 days depending on response to treatment and blood count recovery.
In the study a 30% response rate was achieved, with 20% of all patients achieving a complete remission (CR) or a complete marrow remission in the absence of platelet recovery (CRp) and 10% of all patients achieving a partial response. Seven patients (14%) went on to receive bone marrow or stem cell transplants after treatment with Clolar.
Results of 12 additional patients were recently presented at the American Society of Hematology 46th Annual Meeting and Exposition in San Diego and supported a 30% response rate in this same patient population.
Clolar has also been studied in children with relapsed or refractory acute myeloid leukemia (AML). A phase II study to date has shown a 26% response rate in 42 children with this leukemia, with one CRp and 10 partial remissions. In addition, 12 patients (34%) treated with clofarabine received transplant. On December 1, 2004, the Oncologic Drugs Advisory Committee of the FDA advised conducting additional studies in this group before recommending an AML approval. Plans are currently underway to further support Clolar in this setting.
Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and may increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Assessment of respiratory status and blood pressure monitoring during infusion with Clolar is recommended. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, and appropriate supportive care measures should be initiated. The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leucopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection. Careful hematologic monitoring during therapy is important.
Hepatic and renal function should be assessed before and during treatment with Clolar because the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Cardiac disorders included tachycardia, pericardial effusion, and left ventricular systolic dysfunction in up to 35% of patients. However, the presence of these disorders in patients before Clolar administration or previous therapy, as well as concurrent illness in patients receiving Clolar, make the etiology of these disorders unclear.
Genzyme is based in Cambridge, Mass. The biotechnology company expects to make Clolar commercially available as quickly as possible in January 2005.
For more information about Clolar, call 1-800-RX-CLOLAR or visit genzymeoncology.com.
December 29, 2004
ST. LOUIS (MD Consult) - On December 28, 2004, Elan Corporation, PLC, announced that the U.S. Food and Drug Administration (FDA) has approved Prialt (ziconotide intrathecal infusion) for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.
FDA approval of Prialt was based on the treatment of more than 1,200 patients and 3 phase III clinical trials, which evaluated the efficacy and safety of IT Prialt in patients with severe chronic pain that was not adequately managed despite a regimen of systemic and/or IT analgesic and other drugs. Severe chronic pain is defined as pain lasting longer than 6 months and having multiple causes, such as failed back surgery, injury, accident, cancer, AIDS, and other nervous system disorders.
Prialt, developed at Dublin-based Elan, is in a class of nonopioid analgesics known as N-type calcium channel blockers. Prialt is the synthetic equivalent of a naturally occurring conopeptide found in a marine snail known as Conus magus. Research suggests that Prialt's novel mechanism of action works by targeting and blocking N-type calcium channels on nerves that ordinarily transmit pain signals.
"Taken together, the findings from the Prialt clinical trials are conclusive evidence that this therapy represents a significant treatment option for patients who do not have adequate pain relief from other therapies," said Mark Wallace, MD, Associate Professor of Clinical Anesthesiology, Department of Anesthesiology, University of California San Diego; Director, Center for Pain and Palliative Medicine; and an investigator for Prialt pivotal studies. "Furthermore, Prialt is not associated with the risk of addiction."
The approval of Prialt was based on 3 independent pivotal trials, which successfully used the Visual Analog Scale of Pain Intensity (VASPI) as the primary end point in each study.
The most recent phase III trial was conducted in response to the FDA's approvable letter in 2001, which requested additional data using lower doses and a slower titration. This randomized double-blind, placebo-controlled study was conducted at 39 sites in the United States. Two hundred twenty adults with opioid-resistant, severe chronic pain were enrolled into this study for up to 9 weeks. Most of the patients had neuropathic pain. All patients had programmable IT infusion systems and were randomly assigned to receive IT Prialt (n = 112) or placebo (n = 108). At baseline, the mean VASPI score (the most commonly used pain assessment scale for clinical trials) for both placebo and Prialt groups was 80.7 mm (VASPI score of 0 mm = no pain; 100 mm = worst possible pain). Treatment was initiated at 2.4 mcg/d (0.1 mcg/h) and was increased by less than or equal to 2.4 mcg/d (less than or equal to 0.1 mcg/h), no more than 2 to 3 times a week for 3 weeks.
The primary efficacy measure was mean percent change in the VASPI score at week 3, which showed statistically significant improvement in patients receiving Prialt versus placebo (P = .036). Improvement in VASPI score was seen as early as week 1. The mean dose at week 3 was 6.9 mcg/d (0.29 mcg/h). The majority of secondary efficacy end points also showed statistically significant improvement in patients receiving Prialt.
The majority of adverse events were mild or moderate. The 4 most frequently reported adverse events in this clinical trial were dizziness, ataxia, confusion, and abnormal gait. Study discontinuation among participants in the Prialt group due to adverse events was comparable with that for placebo (5.4% and 4.6%, respectively).
In 2 other phase III clinical trials, IT-administered Prialt was found to significantly reduce severe chronic pain in a variety of opioid-resistant patient populations with neuropathic pain and pain related to cancer and AIDS. The results of the first fast-titration study were published in January 2004 in The Journal of the American Medical Association.
Prialt has been evaluated as an IT infusion in more than 1,200 patients participating in chronic pain trials. The longest treatment duration to date is more than 7 years. Severe psychiatric symptoms and neurologic impairment may occur during treatment with Prialt. Patients with a preexisting history of psychosis should not be treated with Prialt. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Prialt therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurologic or psychiatric signs or symptoms.
The 4 most frequently reported adverse events associated with Prialt were dizziness, nausea, confusion, and headache. When Prialt was used with an external pump, there was a higher incidence of meningitis.
Information about Prialt, including prescribing information and comprehensive support services, is available by calling 1-888-PRIALT-1 or visiting PRIALT.com. The drug is expected to be available to physicians and patients in the United States in late January 2005.
December 28, 2004
ST. LOUIS (MD Consult) - On December 23, 2004, Swiss pharmaceutical company Novartis Pharma AG announced that the U.S. Food and Drug Administration (FDA) has approved Enablex (darifenacin) extended-release tablets (7.5 and 15 mg) for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency.
Enablex, a once-daily medication, works by blocking the M3 receptor, which is primarily responsible for bladder muscle contraction. It is a potent muscarinic receptor antagonist that helps reduce incontinence episodes, increases the amount of urine the bladder can hold, reduces the frequency of urination episodes, and decreases the pressure or urgency associated with the urge to urinate.
The FDA approval of Enablex was based on efficacy data from 4 pivotal studies and safety data from studies in which more than 7,000 patients with a mean age of 58 years were treated with varying doses of Enablex. In these studies, patients taking Enablex experienced decreased frequency of incontinence and urination episodes, increased bladder capacity, and decreased feelings of urgency. Enablex was shown to reduce weekly incontinence episodes by up to 83%, and results were seen within 2 weeks of beginning treatment. Efficacy was sustained throughout the 12-week treatment period, and long-term safety was studied for up to 1 year.
OAB, a condition that affects an estimated 33 million Americans, is caused by the untimely contraction of the bladder muscle. According to Novartis, at least 16% of the population over the age of 40 years experience OAB. Although prevalence increases with age, the problem affects people of all ages. People with OAB often limit travel, social, and even work activities to avoid potentially embarrassing episodes that can occur with this condition.
In total, Enablex has been studied in 98 clinical trials involving more than 10,000 people. In clinical trials, the most frequently reported adverse events associated with Enablex were dry mouth and constipation; however, patient discontinuation rates due to these events were low. The majority of adverse events in Enablex-treated subjects were mild or moderate and mostly occurred during the first 2 weeks of treatment. As with other OAB medications, Enablex is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Enablex is also contraindicated in patients with known hypersensitivity to the drug or its ingredients.
Enablex is expected to launch in the United States in early 2005.
For further details, including full prescribing information, visit enablex.com.
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