December 27, 2000 ST. LOUIS (MD Consult) - Patients receiving antiretroviral therapy for HIV disease are at substantial risk of developing symptomatic hyperlactatemia, according to a recent study in the journal AIDS.
Led by Dr. Yann Gerard of the Centre Hospitalier de Tourcoing, France, the researchers prospectively measured lactate levels in arterial blood in HIV-infected patients receiving antiretroviral therapy who developed unexplained symptoms. Over a 2-year period, this led to the identification of 14 patients with symptomatic hyperlactatemia.
The annual incidence of hyperlactatemia was 0.8%, increasing to 1.2% for patients receiving stavudine. Symptoms associated with hyperlactatemia included abnormal fatigue, tachycardia, weight loss, and peripheral neuropathy. The most specific clinical finding was exercise-induced dyspnea in the presence of effective antiviral therapy. Functional respiratory tests suggested a shift toward anaerobiosis with a high lactate/pyruvate ratios, while muscle biopsy findings were consistent with mitochondrial dysfunction.
One patient died because of severe, refractory lactic acidosis. When nucleoside analog therapy was stopped in 10 patients, their symptoms improved and lactate levels decreased. Fatal lactic acidosis is a known complication of nucleoside analog therapy.
The new findings underscore the importance of monitoring symptoms and blood lactate levels in patients receiving antiretroviral therapy for HIV disease. If the observed hyperlactatemia does result from mitochondrial dysfunction, it may become an increasingly important complication of antiretroviral therapy in the future.
AIDS 14:2723-2730, 2000
December 13, ST. LOUIS (MD Consult) - In a report published in the November issue of the Journal of Rheumatology, adhesive capsulitis of the shoulder appears to be a new side effect of HIV protease inhibitor therapy, particularly in patients receiving the drug Indinavir.
Dr. Anne Grasland and colleagues identified eight HIV-infected patients receiving protease inhibitor therapy who presented with adhesive capsulitis of the shoulder. The patients were treated between July 1996 and December 1999. Of the eight patients, seven were male. The diagnosis of adhesive capsulitis was based on clinical features including shoulder pain and restricted range of motion, both passive and active. No other cause or underlying condition associated with adhesive capsulitis could be identified by the researchers.
According to the report, the onset of symptoms were insidious and all patients complained of shoulder pain upon presentation. In four of the eight cases, the pain was noted to be bilateral and began a mean of 14 months after the initiation of protease inhibitor therapy. In addition, active and passive range of motion during physical examination was noted to be restricted in the glenohumeral joint. In all cases, drug therapy included Indinavir.
The reported symptoms resolved in all eight patients after a mean of 7.4 months, even though patients continued to receive protease inhibitor therapy involving Indinavir. The doctors conclude that more observation of patients will be necessary to confirm adhesive capsulitis as a side effect of HIV protease inhibitor therapy.
ST. LOUIS, August 02 (MD Consult) - A syndrome of hepatic steatosis, lactic acidosis, and myopathy has previously been linked to the use of zidovudine and didanosine in patients infected with human immunodeficiency virus type 1 (HIV-1). Now investigators from the National Institutes of Health report 4 patients with HIV-1 infection who developed this syndrome in association with stavudine. Dr. Kirk D. Miller and colleagues report their findings in the August 1 issue of Annals of Internal Medicine.
The patients (2 men and 2 women) presented with nausea, vomiting, abdominal pain (3 cases), and diffuse myalgias (1 case) of 3 days to 3 months duration. All had been taking stavudine for 3 to 15 months in combination with other antiretroviral drugs, but only 1 patient was also taking didanosine or zidovudine. All patients had severe lactic acidosis and elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Two patients also had pancreatitis and 2 had elevated muscle enzyme levels.
All 4 patients had a complicated hospital course and required treatment in the intensive care unit. The lactic acidosis, hepatic steatosis, and myopathy resolved after stavudine was discontinued, and the syndrome has not recurred.
The authors caution that, although this syndrome is rare, it is life-threatening. Thus physicians who treat patients with HIV-1 infection who are taking stavudine should routinely check the ALT and AST levels every time viral loads and CD4+ T-lymphocytes are assessed (i.e., every 3 to 4 months). Elevated ALT and AST levels warrant further investigation of pancreatic enzyme, serum lactate, and muscle enzyme levels to rule out the development of hepatic steatosis, lactic acidosis, and myopathy.
Until more data are available, the authors suggest that patients with HIV-1 infection who develop persistent hepatic steatosis with stavudine should be switched to another nucleoside analogue. Furthermore, given the increasing number of antiretroviral drugs that have been associated with this life-threatening syndrome, antiretroviral drug therapy should be discontinued temporarily in patients who develop lactic acidosis in association with hepatic steatosis, myopathy, or pancreatitis.
Ann Intern Med 2000; 133: 192-196
ST. LOUIS, Aug 01 (MD Consult) - Glaxo Wellcome has issued a "Dear Health Professional" letter to warn physicians of cases of fatal hypersensitivity reactions in patients reintroduced to the nucleoside analogue reverse transcriptase inhibitor Ziagen (abacavir).
The letter issued by Glaxo Wellcome states:
Dear Health Care Provider:
Glaxo Wellcome Inc., would like to bring to your attention a revised WARNING in the labeling for Ziagen (abacavir sulfate) about fatal hypersensitivity reactions to abacavir in patients presenting with respiratory symptoms. Ziagen is a nucleoside analogue reverse transcriptase inhibitor indicated for use in combination with other antiretroviral drugs for the treatment of HIV-1 infection.
Since its approval in December 1998, the labeling for Ziagen has included a WARNING and description of fatal hypersensitivity reactions to Ziagen. Although presentations vary markedly between patients, frequently occurring features of these hypersensitivity reactions are fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, or abdominal pain) and fatigue or malaise. While respiratory symptoms have been recognized as part of the hypersensitivity reaction in some patients, recent information underscores their importance.
Fatalities in patients treated with Ziagen who developed hypersensitivity reactions in which the initial presentation included respiratory symptoms of dyspnea, cough, or pharyngitis have been reported. Deaths have been reported in patients receiving Ziagen who were initially diagnosed with an acute respiratory disease (pneumonia, bronchitis, or flu-like illness) who were later recognized to have had a hypersensitivity reaction to abacavir that included respiratory symptoms. A delay in diagnosis of hypersensitivity can result in Ziagen being continued or re-introduced, leading to more severe hypersensitivity reactions, including life-threatening hypotension and death.
Review of reports of hypersensitivity in patients receiving Ziagen indicates that respiratory symptoms (including cough, dyspnea, and pharyngitis) have occurred in approximately 20% of patients who have had hypersensitivity reactions. In contrast to some allergic reactions, wheezing or bronchospasm have occurred only infrequently in patients with hypersensitivity reactions to Ziagen.
The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory diseases and other symptoms associated with hypersensitivity to abacavir, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, Ziagen must be permanently discontinued. Ziagen should not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death.
This updated warning about fatal hypersensitivity reactions to abacavir in patients presenting with respiratory symptoms is now included in the revised labeling for Ziagen. In addition, this revised warning is reflected in the Patient Medication Guide and Warning Card and should be discussed with patients treated with Ziagen.
This information is provided to help you in the management of patients prescribed Ziagen Tablets or Ziagen Oral Solution. Please take the time to read the revised package insert, including the revised boxed warning.
ST. LOUIS, July 12 (MD Consult) - Novartis Pharmaceuticals Corporation today announced that the United States Food and Drug Administration (FDA) has requested label changes in the NDA for Mellaril (thioridazine).
In a company press release, Alan L. Bess, M.D., Vice President of Clinical Safety and Epidemiology for Novartis said, "The request is based on data indicating that thioridazine has dose-related effects on ventricular re-polarization leading to QTc interval prolongation, a potentially life-threatening effect." Because of its association with these significant, possibly life-threatening effects, a boxed warning will advise physicians that Mellaril should be held in reserve for patients whose schizophrenia has failed to respond to adequate courses of treatment with other anti-psychotic drugs, either because of inadequate efficacy or intolerable side effects.
Novartis Vice President of Medical Affairs, Stephen Cunningham, M.D. said, "The company will comply with the Agency's request for these label changes. Nevertheless, it should be remembered that Mellaril is still effective and can be used to treat schizophrenia in appropriate circumstances. Like other anti-psychotic drugs in its class, Mellaril can produce a variety of cardiovascular adverse reactions which are already described in the product information."
Mellaril was approved by the FDA for use in anti-psychotic therapy in 1959.
ST. LOUIS, July 12 (MD Consult) - The Food and Drug Administration has announced the nationwide recall of SangCya oral solution, a generic version of the anti-rejection drug cyclosporine (Neoral oral solution), because of clinical evidence that the generic drug's availability is reduced relative to Neoral oral solution if the drug is administered with apple juice. Patients taking cyclosporine capsules are not affected by this recall.
SangStat Medical Corporation claims in a Dear Health Care Professional letter that the recall is limited to the wholesale level and not extended to the pharmacy or the patient. Since it is recognized that some patients may be adversely affected by abruptly changing from SangCya oral solution to another cyclosporine product, the FDA will allow the product to remain in pharmacies and hospitals.
The data from a clinical study recently made available to the FDA showed that taking SangCya oral solution with apple juice diminishes its absorption relative to Neoral oral solution. Because the drug's labeling suggests that it be taken with apple or orange juice, the agency asked the sponsor to recall the product.
According to the Dear Health Care Professional issued by SangStat, the following is recommended until patients can be switched to another cyclosporine product:
The important thing to remember in taking cyclosporine, is to be consistent in the diluents used and in the dosing schedule with respect to meals.
If you should have any questions, please contact SangStat Medical Affairs at 1-87-SANGSTAT (1-877-2647828).
ST. LOUIS, July 10 (MD Consult) - Nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to exert their therapeutic effect by the inhibition of cyclooxygenase-2 (COX-2). However, studies in mice suggest that COX-2 inhibition may have adverse effects on the renal system. Now a study in the July 4 issue of Annals of Internal Medicine indicates that COX-2 inhibitors adversely affect renal function in elderly human patients.
Dr. Suzanne K. Swan and colleagues of Hennepin County Medical Center in Minneapolis and other institutions performed 2 randomized studies in patients 60 to 80 years old who were following a low-salt diet. In the first study, 15 patients received a single dose of either placebo, 75 mg indomethacin, or 250 mg rofecoxib; the dose of rofecoxib used was at least 5 times higher than the recommend dose. Then patients were crossed over to the other treatments. In the second study, 60 patients received 6 days of treatment with either placebo, 50 mg indomethacin t.i.d., or 12.5 or 25 mg/day of rofecoxib.
The authors found that single doses of rofecoxib and indomethacin significantly decreased the glomerular filtration rate (GFR) compared with placebo (by 0.23 and 0.18 ml/sec, respectively). However, GFR did not differ significantly after multiple doses of any of the drugs (decreases of 0.10 to 0.14 ml/sec). There were similar, though less pronounced, changes in creatinine clearance and serum and urinary concentrations of sodium and potassium.
The investigators concluded that COX-2 enzyme inhibitors have an effect on renal function similar to that of COX-1/COX-2-nonspecific NSAIDs. Therefore, COX-2 inhibitors should be used with caution by patients with low effective circulating fluid levels, such as those with congestive heart failure or cirrhosis or who use diuretics.
Ann Intern Med 2000; 133: 1-9
ST. LOUIS, July 10 (MD Consult) - Calcium channel blockers inhibit platelet function and have vasodilatory effects. Some studies have suggested that use of these drugs increases a patient's risk for gastrointestinal (GI) tract bleeding, while others have not confirmed this association. Methodological differences may explain these discrepancies.
In the June issue of the Archives of Internal Medicine, Kaplan and colleagues report the results of a case-control study of the association between the use of calcium channel blockers and the risk of GI tract bleeding. The study included 945 hypertensive patients receiving treatment in a health maintenance organization. Computerized diagnosis codes and medical record review were used to identify 174 hypertensive case patients who were treated for GI tract bleeding between January 1992 and December 1994. The 771 treated hypertensive control patients were selected from other ongoing studies at the study institution. The patients' use of medication and other risk factors for GI tract bleeding were determined from a pharmacy database and medical records.
Patients who used calcium channel blockers had a relative risk (RR) of 2.6 (95% confidence interval [CI], 1.71-3.96) of GI tract bleeding when compared with patients who used ß-blockers; this analysis included adjustments for age, sex, and calendar year. The RR fell to 2.05 (95% CI, 1.33-3.17) when analysis also included adjustments for 4 other factors: number of recent visits, diastolic blood pressure, chronic congestive heart failure, and duration of hypertension. Analysis did not reveal any statistically significant dose-response relationship, and the RRs were similar for verapamil, diltiazem, and nifedipine.
In contrast, users of angiotensin-converting enzyme inhibitors and users of ß-blockers had similar risks of GI tract bleeding (RR, 1.22; 95% CI, 0.75-1.97). Calcium channel blocker use tended to be associated with bleeding in specific anatomical regions: use was more strongly associated with lower GI tract bleeding (RR, 2.56; 95% CI , 1.08-6.05) than with either upper GI tract bleeding (RR, 1.54; 95% CI, 0.91-2.59) or peptic ulcer--related bleeding (RR, 1.17; 95% CI, 0.62-2.21).
The authors conclude that the use of calcium channel blockers may increase the risk of GI tract bleeding in hypertensive patients by approximately 2-fold; however, they advocate randomized clinical trials to confirm these findings.
Arch Intern Med. 2000;160:1849-1855
ST. LOUIS, June 30 (MD Consult) - Glaxo Wellcome Inc. has received reports of prescription dispensing errors involving LAMICTAL (lamotrigine) Tablets and LAMISIL (terbinafine hydrochloride) Tablets resulting in serious adverse events. The error reports involve dispensing Lamictal Tablets when Lamisil Tablets were prescribed and the reverse scenario.
Patients with epilepsy who do not receive their antiepileptic drug LAMICTAL due to a dispensing error would be inadequately treated and could experience serious consequences including status epilepticus. Conversely, patients erroneously receiving Lamictal instead of their antifungal drug LAMISIL would be unnecessarily subjected to a risk of potential side effects (including serious rash). This is especially true if patients receive an initial high dose of Lamictal
LAMICTAL is an antiepileptic drug marketed as 25-, 100-, 150-, and 200-mg six-sided, shield- shaped tablets bearing "Lamictal" and the numeric representation of the strength (e.g., "Lamictal 150"). Lamictal Chewable Dispersible Tablets are 5-mg and 25-mg white tablets engraved with "GX CL2" and "GX CL5," respectively. To initiate therapy with Lamictal, the dose is titrated over a period of several weeks.
LAMISIL is an antifungal drug marketed as 250-mg circular, biconvex, bevelled tablets bearing "Lamisil" on one side and "250" on the other side. The recommended dosage for Lamisil is one 250-mg tablet daily for six or twelve weeks depending on the affected nail. Topical formulations of Lamisil are also available by prescription and over-the-counter.
Pharmacists and are asked to be alert for both written and oral prescriptions for LAMICTAL and LAMISIL, and to promptly share information with their staffs. Measures to avoid dispensing errors should be assessed and implemented as appropriate.
Pharmacists aware of a prescription dispensing error involving these products are asked to contact the appropriate manufacturer:
Glaxo Wellcome Inc.: 1-800-334-4135
Novartis Pharmaceuticals
Corp.: 1-888-669-6682
The USP Medication Errors Reporting Program 1-800-233-7767
The FDA MEDWATCH program
by phone 1-800-FDA-1088
by FAX
1-800-FDA-0178
by internet at www.fda.gov/medwatch
by mail:
MedWatch HF-2
FDA
5600 Fishers Lane
Rockville, MD 20857
For further information on Lamictal, please call 1-888-TALK-2-GW (1-888-825-5249).
ST. LOUIS, May 23 (MD Consult) - For children with Escherichia coli O157:H7 infection, treatment with antibiotics increases the likelihood that hemolytic-uremic syndrome (HUS) will develop, according to an advance report of the New England Journal of Medicine.
The prospective cohort study found that antibiotic treatment was a powerful, independent risk factor for HUS in children with E. coli O157:H7 infection. The editors of NEJM released the study early because of its important clinical implications; the final version will be published in the June 29 issue.
Dr. Craig S. Wong and colleagues of Children's Hospital and Regional Medical Center, Seattle, studied 71 children less than 10 years of age who had diarrhea caused by E. coli O157:H7 infection. Nine children received antibiotic treatment, and 10 developed HUS. Five of the ten patients with HUS had been treated with antibiotics.
Several factors were associated with an increased risk of HUS, including a higher initial white-cell count, prompt stool culture, and antibiotic therapy. On multivariate analysis adjusting for the former two factors, antibiotic treatment remained a significant risk factor: relative risk 17.3, with a 95% confidence interval of 2.2 to 137. The children who did and did not receive antibiotic therapy had similar clinical and laboratory characteristics.
Escherichia coli O157:H7 is a very common cause of GI infection. Hemolytic-uremic syndrome occurs in about 15% of infected children in North America. Previous studies have suggested that antibiotic treatment does not alter the course of E. coli O157:H7 infection. The authors conclude that children with possible E. coli O157:H7 infection should not receive antibiotics, unless stool culture identifies a pathogen for which antibiotic treatment is indicated.
ST. LOUIS, April 21 (MD Consult) - The antiplatelet drug clopidogrel has been associated with several cases of potentially life-threatening thrombotic thrombocytopenic purpura, according to an advance report of the New England Journal of Medicine.
The report describes 11 cases of thrombotic thrombocytopenic purpura occurring during or soon after treatment with clopidogrel. The editors of NEJM released the study early because of its important clinical implications for the recognition and management of this dangerous adverse effect. The final version will be published in the June issue.
The cases, presented by Dr. Charles L. Bennett of the Veterans Affairs Chicago Healthcare System and colleagues, were reported by hematologists, blood banks, and the drug's manufacturer. In 10 of the 11 cases, signs of thrombotic thrombocytopenic purpura--including thrombocytopenia and microangiopathic hemolytic anemia, sometimes with neurologic changes or renal dysfunction--appeared within 2 weeks of starting treatment with clopidogrel. In contrast, cases of thrombotic thrombocytopenic purpura related to ticlopidine usually occur after 2 to 12 weeks of treatment.
The clopidogrel-related cases were slow to respond to plasma exchange. Although 10 of the 11 patients responded to this form of treatment, 2 patients required 20 or more exchanges before clinical improvement appeared. The remaining patient died despite prompt plasma exchange. Five of the patients were also taking cholesterol-lowering "statin" drugs. The potential for adverse interaction between these drugs and clopidogrel is unknown.
Clopidogrel has become a widely used alternative to ticlopidine, mainly because of its better safety profile. Thrombotic thrombocytopenic purpura reportedly occurs in 1 of every 1,600 to 5,000 patients treated with ticlopidine, and is a major reason behind the switch to clopidogrel.
However, the new results suggest that clopidogrel can cause the same complication. Furthermore, the clopidogrel-related cases occur more quickly, are less responsive to plasma exchange, and are more prone to recurrence.
Physicians prescribing clopidogrel are advised to be alert for signs of thrombotic thrombocytopenic purpura. Cardiac or neurologic changes developing after the start of treatment could easily be attributed to the condition for which antiplatelet therapy was prescribed.
ST. LOUIS, March 23 (MD Consult) - The FDA announced on March 23, 2000, that Janssen Pharmaceutica Inc., of Titusville, N.J., will stop marketing Propulsid (cisapride) in the United States as of July 14, 2000. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol.
Cisapride is a prescription drug treatment approved only for severe nighttime heartburn in patients with gastroesophageal reflux disease that does not adequately respond to other therapies.
According to an FDA talk paper, the use of cisapride has been associated with 341 reports of heart rhythm abnormalities including 80 reports of deaths. Most of these adverse events occurred in patients who were taking other medications or suffering from underlying conditions known to increase risk of cardiac arrhythmia associated with cisapride.
Physicians who are treating patients with severely debilitating conditions for whom they believe the benefits of the cisapride may still outweigh its risks are encouraged to contact Janssen at 1-800-JANSSEN.
ST. LOUIS, March 22 (MD Consult) - The Warner-Lambert/Parke-Davis Company announced today that it is voluntarily discontinuing the sale of Rezulin (troglitazone) Tablets, its therapy for the treatment of type 2 diabetes, after the FDA determined it was too dangerous for use. According to a Warner Lambert press release, officials at the company continue to believe that the benefits of the drug outweigh its associated risks.
Patients taking Rezulin should be contacted by their physicians as soon as possible to discuss alternative therapies.
The FDA claims in an official press release that this action was taken after its review of recent safety data on Rezulin and two similar drugs, rosiglitazone (Avandia) and pioglitazone (Actos), showed that Rezulin is more toxic to the liver than the other two drugs. Data to date show that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk. Severe liver toxicity has been shown to occur in patients using Rezulin since 1997. Parke-Davis, under consultation with the FDA, has strengthened the drug's warning labeling several times and has recommended close monitoring of liver function in patients taking Rezulin.
The decision also comes after the American Diabetes Association asked the FDA to expedite it's investigation on the safety of the use of Rezulin. Earlier last week, a national patient advocacy group, Public Citizen's Research Group, petitioned the FDA to investigate Warner Lambert/Parke-Davis on the grounds that the company delayed in reporting to the FDA the complications of 21 patients who developed hepatic abnormalities while taking troglitazone (Rezulin) in clinical trials.
Warner-Lambert claims it will work closely with the Food and Drug Administration and other constituencies to assure a safe and efficient transition for patients as they switch to alternative therapies.
ST. LOUIS, March 07 (MD Consult) - Can the antihistamines found in over-the-counter drugs used to treat allergic rhinitis impair a person's ability to drive a car? These authors used a driving simulator to compare the effects of diphenhydramine (a first-generation antihistamine) and fexofenadine (a second-generation antihistamine) with those of alcohol and placebo on one's ability to perform numerous driving tasks. They report their findings in the March 7 issue of Annals of Internal Medicine.
Dr. John M. Weiler and colleagues of the University of Iowa and Hoechst Marion Roussel, Inc. enrolled 40 licensed drivers 22 to 44 years old who had seasonal allergic rhinitis. Subjects were tested over 4 weeks, on the same day and at the same time each week, with each of the 4 study drugs: 60 mg fexofenadine, 50 mg diphenhydramine, alcohol to reach a blood alcohol concentration of approximately 0.1%), and placebo. Then 2.5 hours after dosing (when the effects of the antihistamines reached their peak), the subjects were tested on a driving simulator to assess their performance on numerous driving tasks.
Coherence was defined as the subjects' ability to match the varying speed of a vehicle they were following. Coherence was significantly worse after diphenhydramine than in the other 3 scenarios. Compared with fexofenadine, diphenhydramine was also associated with significantly greater crossing of the center line (lane excursion) and steering instability (wandering left and right within the lane). In fact, performance after taking diphenhydramine was worse than that after taking alcohol.
Thus, patients who take over-the-counter drugs for allergic rhinitis that contain diphenhydramine should be aware that it can impair their ability to drive a car. The authors also found that the subjects' subjective drowsiness ratings did not correlate with their coherence, and only weakly correlated with lane excursion and steering instability. So a feeling of drowsiness is not a reliable factor by which a person can judge his or her ability to drive.
Ann Intern Med 2000; 132: 354-363
ST. LOUIS, February 23 (MD Consult) - Fungal infections are becoming more common and problematic in intensive care units (ICUs). Over half of all patients with systemic fungal infection will die. Because fluconazole has relatively low toxicity, this agent is increasingly selected to treat nosocomial candidiasis. Treatment is often prophylactic or empirical, although this therapy has not been validated in the ICU population. Furthermore, reports of fluconazole-resistant fungi and a shift toward Candida non-albicans species raise concern about the widespread use of this agent.
In the February issue of Archives of Surgery, Rocco and colleagues report on the effects of fluconazole on patient outcomes and resistance of pathogens. The study included 2 cohorts. In the first cohort (June 1997-January 1999), critically ill ICU patients with documented bacterial infection were randomized: 50 patients received fluconazole treatment, while 49 patients did not. The second cohort (June 1994-December 1998) included 38 patients with Candida species infection; isolates were identified and evaluated for fluconazole susceptibility, using January 1, 1998 as a dividing point.
In the first cohort, both hospital and ICU length of stay were significantly longer for the fluconazole-treated patients. Fluconazole treatment was also associated with administration of a greater number of antibiotics and increased bacterial resistance, noted for 5 different microbes. The hospital mortality rate was also significantly greater for fluconazole-treated patients (40%) than for control patients (20%); concurrent glucocorticoid treatment significantly increased this effect. In the second cohort, C. albicans and Candida glabrata accounted for the majority of isolates, both prior to and during 1998. Prior to 1998, fluconazole resistance was documented for 11% of species; during 1998, resistance was documented for 36% of species. Resistant species shifted from C. albicans and Candida krusei prior to 1998 to C. glabrata and Candida tropicalis during 1998. When trends for the time periods 1994-1997 and 1998 were compared, the number of patients receiving fluconazole increased (191.5 vs. 235 patients/year); the total amount of fluconazole administered increased (383.18 vs. 543.4 g/year); and the prescribed dose per ICU patient increased (2,000.30 vs. 2,312.34 mg/patient).
These findings suggest that widespread fluconazole use in the ICU may be having detrimental effects. The authors recommend that fluconazole treatment should only be used in stable patients with C. albicans colonization or culture-documented infection. Amphotericin B is a better choice for unstable patients with suspected or proven multisite fungal infection. The authors also advocate routine susceptibility testing to tailor appropriate antifungal therapy.
Arch Surg. 2000;135:160-165
ST. LOUIS, February 21 (MD Consult) - Acute arthritis may be added to the list of potential side effects of the antiplatelet drug clopidogrel, according to a report in this week's British Medical Journal.
Dr. Anu Garg and colleagues of Royal Bournemouth Hospital describe two patients--a 76-year-old woman and a 63-year-old man--taking clopidogrel after coronary angioplasty or bypass. The dosage was 75 mg once daily in both patients; one was allergic to aspirin.
Both patients developed arthritic symptoms within 2 weeks. One patient had widespread pruritus with metacarpophalangeal joint pain and swelling. The other had severe knee pain with tenderness, heat, and swelling. Both patients had an increased erythrocyte sedimentation rate but normal uric acid or urate concentration.
In both cases, the symptoms resolved promptly after clopidogrel treatment was stopped. The increased inflammatory markers also resolved.
Clopidogrel is a specific ADP receptor antagonist than can reduce the risk of myocardial infarction, stroke, and cardiovascular causes of death. Added to one case reported to the drug's manufacturer, the new results suggest that acute arthritis and tendinitis are possible side effects of clopidogrel use. The arthritic symptoms disappear when clopidogrel is withdrawn.
BMJ 320:483, 2000
ST. LOUIS, February 21 (MD Consult) - Incomplete exchange of information between patients and physicians is the major cause of misunderstandings regarding prescription medications, reports a study in this week's British Medical Journal.
Led by Dr. Nicky Britten of King's College, London, the researchers performed a qualitative analysis of interactions between patients and general practitioners. Their goal was to identify misunderstandings that could lead to adverse effects on medication use.
Many different categories of misunderstandings were identified. Sometimes patients had information unknown to the physician, or vice versa, or the two parties had conflicting information. Other types of misunderstanding included disagreements about the cause of side effects, failure of communication about the physician's decision, and factors arising from the patient-physician relationship.
However, the common factor was insufficient patient participation in communicating expectations, preferences, or responses to the doctor's decisions. Sometimes patients expressed their concerns, but the physician did not respond adequately. Many patients wanted a prescription, while others did not want a prescription, without saying so to the physician. Even patients who received unwanted prescriptions did not communicate this to the physician.
Exchange of information between patient and physician is essential to shared decision making. The new results suggest that many different types of misunderstandings related to lack of patient participation can lead to potential or actual adverse effects on medication use. The authors plan to incorporate their findings into a new educational intervention for physicians.
BMJ 320:484-488, 2000
ST. LOUIS, February 14 (MD Consult) - The February 12 issue of The Lancet voices concerns over possible drug interactions involving St. John's wort, including one study showing that the popular herbal supplement can reduce levels of the protease inhibitor indinavir.
In a research letter, Dr. Stephen C. Piscelli and colleagues report an open-label study of the effects of St. John's wort on indinavir concentrations in 8 healthy volunteers. None of the study subjects were HIV-infected, nor had they been taking St. John's wort.
The area under the curve of indinavir decreased by a mean of 57% after the subjects started taking St. John's wort. In addition, the extrapolated 8-hour indinavir trough was reduced by 81%. These are substantial reductions in indinavir exposure, which the researchers believe could lead to drug resistance and treatment failure in HIV-infected patients taking this drug.
St. John's wort is thought to induce the 3A4 isoform of the cytochrome P450 system, and the HIV-1 protease inhibitors are substrates of this isoenzyme.
This week's Lancet includes other reports of possible drug interactions with St. John's wort. One study indicates that the herb can interfere with the effectiveness of warfarin; another describes two cases of heart transplant rejection related to reductions of cyclosporin concentration in patients taking St. John's wort. Taken together, these reports highlight the need for increased regulation of St. John's wort and other natural remedies, including warning labels regarding possible drug interactions.
Lancet 355:547, 2000
ST. LOUIS, February 8 (MD Consult) - Intranasal beclomethasone dipropionate (BDP) is often prescribed for children with perennial allergic rhinitis; this corticosteroid is both well tolerated and effective in children age 6 years and older. The systemic effects of BDP, including effects on the hypothalamic-pituitary-adrenal axis, are assumed to be negligible at recommended intranasal doses.
In the February issue of Pediatrics, Skoner and colleagues report on a study of growth in children receiving intranasal BDP. The double-blind study included 100 prepubertal children ages 6 to 9 years with perennial allergic rhinitis. At enrollment, all children were between the 5th and 95th percentile of height for their age and had a skeletal age that was within 2 years of their chronological age. Children were randomized to receive 168 µg of aqueous BDP (n=51) or placebo (n=49) twice daily for 1 year. Short courses of oral prednisolone and dermatologic corticosteroids were permitted, but all other growth-affecting medications were discontinued. After 1, 2, 4, 6, 8, 10, and 12 months of treatment, heights were recorded and the rate of change in standing height was calculated. Basal 8 AM cortisol concentrations and response to 0.25 mg cosyntropin were also measured.
Eighty children completed the entire treatment protocol. Children treated with BDP had a significantly slower growth rate than children treated with placebo, with mean 1-year changes in standing height of 5.0 cm and 5.9 cm, respectively. Growth rates began to diverge after 1 month of treatment. The growth-attenuating effect of BDP occurred across both age and gender subgroups. However, measurements of the hypothalamic-pituitary-adrenocortical axis were similar for BDP- and placebo-treated children. Furthermore, BDP did not produce any significant changes in electrolyte, metabolic, hematologic, and immunologic parameters.
These findings suggest that intranasal BDP has a growth-suppressive action in the absence of measurable adrenal suppression. The authors conclude that further studies are needed to clarify the effect on final height and note that some degree of growth suppression may be acceptable in children with severe rhinitis. In the meantime, physicians should monitor growth in treated children, keep an eye on their total corticosteroid exposure, and treat with the lowest effective doses.
Pediatrics 105; 2000:e23
ST. LOUIS, January 25 (MD Consult) - A Food and Drug Administration (FDA) Talk Paper is advising health care professionals and patients of new recommendations that should be considered prior to any use of the drug cisapride (Propulsid). Cisapride is a treatment for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD). The new measures warn physicians to avoid giving cisapride to patients with cardiac arrhythmias or other cardiovascular irregularities as there is a known risk of rare - but serious - cardiac events associated with the drug.
Continuing reports of heart rhythm disorders and deaths have been associated mostly with the use of the drug in people who are either taking certain other medications or who have certain underlying conditions that are known risk factors. Recent analysis of 270 adverse event reports (including 70 fatalities) revealed that approximately 85% of these cases occurred in patients with these identifiable risks.
This new warning is being announced in conjunction with a "Dear Healthcare Professionals" letter issued by the drug's sponsor, Janssen Pharmaceutica of Titusville, NJ, that summarizes the updates being made to the warnings and precautions sections of the drug's label. The changes include recommending that physicians perform an electrocardiogram and certain blood tests prior to prescribing the drug.
The revised labels also list the contraindicated drugs and underlying conditions which put patients at increased risk. Cisapride should not be used by patients taking some of the following types of medications:
It is also advised that patients with any of the following conditions not take the drug:
Unlike drugs that reduce stomach acid, cisapride works by a prokinetic mechanism that moves the harmful acids through the digestive tract thus preventing its painful reflux into the esophagus. Healthcare providers are encouraged to report any adverse events related to cisapride to Janssen Pharmaceutica (800-526-7736) or the FDA. Reports may be submitted to FDA by telephone (800-FDA-1088), fax (800-FDA-0178), online at www.fda.gov/medwatch/ or by mail to:
MedWatch (HF-2)
Food and Drug Administration
5600 Fishers
Lane
Rockville, MD 20857
ST. LOUIS, January 21 (MD Consult) - Isotretinoin (trade name Accutane; Roche Laboratories, Nutley, N.J.) is an oral drug that effectively treats severe acne, yet can also cause congenital malformations in infants of women who use it during their first trimester. Because of this teratogenicity, in 1988 the manufacturer began an extensive pregnancy prevention program (PPP) that included educational materials for physicians and patients and print, television, and radio advertisements that still continues. Yet despite this extensive campaign, isotretinoin exposure during pregnancy still occurs; and in March 1999 the Centers for Disease Control and Prevention interviewed 14 women who took isotretinoin during their pregnancy to learn more about how to prevent such exposures.
All 14 of the respondents (median age 25.5 years) said that they knew isotretinoin should not be used during pregnancy, but none of the respondents said they had seen all of the components of the PPP, and none had been referred for contraceptive counseling during their isotretinoin therapy. Contraceptive failures did occur, yet equally as important were failures to use contraceptives properly during drug therapy. The following factors were identified as the main contributors to isotretinoin exposure during pregnancy:
Using the drug outside of a clinical setting (i.e., using leftover medication from an earlier prescription was also responsible for some of these exposures.
The authors suggest that another contributor to isotretinoin exposure during pregnancy may be increased patient demand for the drug. Half the respondents said they had seen an advertisement for acne treatment before they talked with their doctor about beginning isotretinoin therapy. But half of the respondents also said that they did not meet the criteria on the warning label for its use (i.e., women of childbearing potential should not use isotretinoin unless the she has severe, disfiguring nodular acne that is recalcitrant to standard therapies). The prescription of isotretinoin for conditions other than cystic acne may contribute to the problem of isotretinoin exposure during pregnancy.
The authors make the following recommendations:
MMWR 2000; 49: 28-31
ST. LOUIS, January 18 (MD Consult) - Troglitazone, the first of the thiazolidinediones approved as oral hypoglycemic agents, has previously been shown to cause hepatotoxicity. Now another drug of this class, rosiglitazone maleate, has been linked with hepatic injury and hepatic failure in 2 cases reported in the January 18 issue of Annals of Internal Medicine.
In the first case, Dr. Lisa M. Forman and colleagues at the Hospital of the University of Pennsylvania describe a 69-year-old man with newly diagnosed type 2 diabetes mellitus who began taking rosiglitazone, 4 mg/day. In the second case, Dr. Jameela Al-Salman and colleagues of MCP-Hahnemann University describe a 61-year-old man with poorly controlled type 2 diabetes mellitus who had begun taking rosiglitazone, 4 mg/day, 2 weeks earlier.
Both patients began experiencing nausea, anorexia, and abdominal pain within 8 days of starting rosiglitazone therapy. Dosing continued for 21 and 14 days, respectively, before the patients presented for evaluation of abdominal pain. Upon presentation, both patients had highly abnormal liver enzyme levels, yet imaging studies and extensive blood testing could not identify the cause of these abnormal results. The first patient was discovered to have hepatic failure, while the second patient experienced severe hepatocellular injury. Both patients quickly recovered with supportive care after the drug was discontinued.
Given these findings, the authors suggest that liver enzyme levels be closely monitored in patients taking rosiglitazone, especially those who are just starting therapy. Patients who report anorexia, fatigue, abdominal pain, nausea, or jaundice after beginning rosiglitazone therapy should be immediately examined for signs of hepatic dysfunction.
Ann Intern Med 2000; 132: 118-121
Ann Intern Med 2000; 132:
121-124
ST. LOUIS, January 14 (MD Consult) - On January 12, 1999, the Food and Drug Administration (FDA) issued a Public Health Advisory on the safe and appropriate use of influenza drugs. Due to the fact that influenza is now occurring in many areas of the country, the FDA is reminding prescribers of important clinical decisions that need to be made when considering use of anti-viral drugs for treatment of patients with signs and symptoms of influenza. Major points from the advisory include:
All health care professionals are encouraged to report any serious adverse event associated with the use of anti-viral drugs for influenza to the FDA's MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178).
ST. LOUIS, January 10 (MD Consult) - A case of acute renal failure related to topical use of the nonsteroidal anti-inflammatory drug ketoprofen is reported in this week's British Medical Journal.
Dr. T. Krummel and colleagues of Hôpitaux Universitaires, Strasbourg, France, treated a 62-year-old woman for inflammatory arthritis of the ankle. The patient had polycystic kidney disease and chronic renal failure. However, she was in stable condition, with a creatinine concentration of 360 µmol/L, on treatment. Her ankle arthritis was treated with colchicine and topical ketoprofen twice daily for 5 days.
Over the 5 days of treatment, the patient's serum creatine concentration rose from 390 to 673 µmol/L. Serum urea increased from 25 to 38 mmol/L. Functional acute renal failure was diagnosed on the basis of drops in urinary sodium and fractional sodium excretion. The patient was taken off ketoprofen, enlapril, and furosemide immediately, resulting in recovery of renal function.
Although acute renal failure is a known complication of oral NSAID treatment, topical NSAID administration is generally considered safe. In this case, ketoprofen clearance was reduced because of the patient's underlying renal failure, leading to systemic effects despite topical treatment. The patient's age and treatment with angiotensin-converting enzyme inhibitors and diuretics were probably contributing factors. Topical NSAIDs should be used cautiously in patients with risk factors for renal failure.
BMJ 320:93, 2000
ST. LOUIS, January 5 (MD Consult) - A new study indicates that adults with human immunodeficiency virus (HIV) infection who take the antiretroviral drug ritonavir are at increased risk of hepatotoxicity. However, no increased risk of hepatotoxicity was found with the other protease inhibitors tested (indinavir, nelfinavir, saquinavir) or with nucleoside analogs. Dr. Mark S. Sulkowski and colleagues of Johns Hopkins University report their findings in the January 5 issue of the Journal of the American Medical Association.
Over a 2-year period, the investigators studied 298 patients with HIV who received a new antiretroviral therapy. Treatments involved combination therapy with protease inhibitors (211 patients; median follow-up, 182 days) or therapy with dual nucleoside analogs (87 patients; median follow-up, 167 days). Additionally, 154 of the patients in the protease inhibitor group (52%) and 8 of the patients in the nucleoside analog group (9.2%) had chronic hepatitis B or C infections.
Hepatotoxicity was defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase after therapy. The authors discovered that severe hepatotoxicity developed in 31 of the 298 patients (10.4%). Patients who received ritonavir had a significantly higher incidence of hepatotoxicity (30%). None of the other drugs studied was associated with a significantly increased hepatotoxicity risk.
Severe hepatotoxicity developed in 12.2% of the patients with chronic hepatitis C. However, coinfection with hepatitis B or C was not significantly associated with hepatotoxicity risk in multiple regression analyses: the only significant independent predictors of hepatotoxicity risk were the use of ritonavir (adjusted odds ratio 8.6) and an increase in the CD4 cell count of > 0.05 x 109cell/L (adjusted odds ratio 3.6).
Despite the strong association between ritonavir and hepatotoxicity, none of the outcomes was irreversible. The authors suggest that antiretroviral therapy involving ritonavir should be avoided in patients with HIV, but none of the evidence suggests an increased hepatotoxicity risk with other protease inhibitors (indinavir, nelfinavir, saquinavir) or with the nucleoside analogs tested. Furthermore, based on these data, protease inhibitor therapy does not increase the risk of hepatotoxicity in patients with HIV who are coinfected with hepatitis B or C virus.
JAMA 2000; 283:74-80
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