FDA Safety Labeling Changes: Emtriva, FazaClo, Climara/Climara Pro

Yael Waknine

September 14, 2005

Sept. 14, 2005 — The U.S. Food and Drug Administration (FDA) approved safety labeling revisions in June to advise that discontinuation of emtricitabine therapy may cause severe hepatitis B virus exacerbations in coinfected HIV patients; patients receiving clozapine therapy should be monitored regularly for granulopoietic suppression; and estradiol and estradiol/levonorgestrel transdermal therapies have been linked to an increased risk of adverse cardiovascular events.

Discontinuation of Emtricitabine (Emtriva) Linked to Severe HBV Exacerbations

On June 13, the FDA approved revisions to the safety labeling for emtricitabine (Emtriva capsules, made by Gilead Sciences, Inc.) to warn that its safety and efficacy have not been established in patients coinfected with HIV-1 and hepatitis B virus (HBV).

The FDA has received reports of severe acute HBV exacerbations in coinfected patients upon discontinuation of emtricitabine therapy, underscoring the need for close monitoring of hepatic function with both clinical and laboratory follow-up for a period of several months. The FDA notes that initiation of anti-HBV therapy may be warranted.

Emtricitabine is indicated for use in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in adults. It is not indicated for the treatment of chronic HBV infection.

Clozapine (FazaClo) Therapy Requires Monitoring for Granulopoietic Suppression

On June 8, the FDA approved revisions to the safety labeling for clozapine orally disintegrating tablets (FazaClo ODT, made by Alamo Pharmaceuticals, LLC) to advise of strategies for managing the significant risk of agranulocytosis associated with its use.

Patients receiving clozapine must undergo a baseline white blood cell (WBC) count and absolute neutrophil count (ANC) prior to initiation of therapy, as well as regular evaluations during treatment that continue for at least four weeks after discontinuation of treatment.

The WBC count and ANC should be performed on a weekly basis for the first six months of therapy; if acceptable counts (3,500 cells/mm3 or greater and 2,000 cells/mm3 or greater, respectively) have been maintained during this period, monitoring can be performed every two weeks for the next six months. Patients who have maintained acceptable counts for one year of continuous therapy can be evaluated once monthly thereafter.

Further information regarding therapy discontinuation due to granulopoietic suppression and the possibility of clozapine rechallenge in certain patients is available on the FDA Web site at https://www.fda.gov/medwatch/safety/2005/Jun_PI/FazaClo_PI.pdf.

Clozapine is available only through a distribution system that ensures monitoring of WBC count and ANC according to this schedule prior to delivery of the next supply of medication.

Clozapine ODT is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard medical therapy, and for reducing the risk of recurrent suicidal behavior in at-risk patients with schizophrenia or schizoaffective disorder.

Estradiol, Estradiol/Levonorgestrel Patches (Climara, Climara Pro) Linked to Increased Risk of CV Events

On June 22, the FDA approved revisions to the safety labeling for estradiol and estradiol/levonorgestrel transdermal systems (Climara and Climara Pro, made by Berlex, Inc.) to warn of the increased risks of cardiovascular events associated with their use.

Results from the five-year Women's Health Initiative (WHI) study in 27,000 postmenopausal women have linked estrogen and estrogen/progestin therapies to an increased risk of myocardial infarction, stroke, and venous thromboembolism (VTE; deep vein thrombosis [DVT] and pulmonary embolism [PE]). Treatment should be discontinued if any of these occur or are suspected.

Data from the conjugated estrogens/medroxyprogesterone acetate substudy of the WHI showed relative risks of 1.29 for coronary heart disease (95% confidence interval [CI], 1.02 - 1.63); 1.41 for stroke (95% CI, 1.07 - 1.85), 2.13 for PE (95% CI, 1.39 - 3.25), and 2.07 for DVT (95% CI, 1.49 - 2.87) compared with placebo.

During treatment, risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (eg, personal or family history, obesity, and systemic lupus erythematosus) should be managed appropriately.

The estradiol transdermal system is indicated for the treatment of moderate to severe vasomotor symptoms and symptoms of vulvovaginal atrophy associated with menopause. Secondary indications include hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and the prevention of postmenopausal osteoporosis.

The estradiol/levonorgestrel transdermal system is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus.

Reviewed by Gary D. Vogin, MD


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