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On December 10, 2010, the FDA approved new labeling for Zerit capsules and Zerit for oral solution. The revisions to the Dosage and Administration, Warnings and Precautions, Adverse Reaction sections in both package inserts are outlined below.
Other important changes include conversion of the package insert to physicians labeling rule (PLR) format), and conversion of the patient package insert to Medication Guide. Minor changes to the package inserts were made for consistency.
Summary of Revisions:
Under Dosage and Administration, Dosage Adjustment (Section 2.3) was modified to remove statements for dose reductions for peripheral neuropathy because dose reductions for peripheral neuropathy have not been established, and importantly dose reduction is less relevant in the current setting of HIV infection and multiple available HIV treatment options.
Warnings and Precautions (Section 5.5 ) for Fat Redistribution was modified in both package inserts as shown below. The changes reflect the strong causal relationship of lipodystrophy with stavudine demonstrated in clinical trials. Data from longitudinal clinical trials in both antiretroviral naïve and treatment-experienced patients demonstrate a higher frequency of clinical lipoatrophy in subjects receiving stavudine-containing regimens compared to regimens containing other nucleotides, specifically tenofovir or abacavir (Haubrich RH AIDS 2009, Podzamczer D AIDS 2007). Additionally, stavudine use was associated with decreases in limb fat compared to increases in limb fat observed with other nucleotides. Other published reports indicate lipoatrophy did not completely resolve following stavudine discontinuation, although modest increase in limb fat was observed after discontinuation (Carr A JAMA 2002, Martin A AIDS 2004).
Section 5.5 Fat Redistribution:
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving ZERIT should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using ZERIT including lipoatrophy and lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.
Adverse Reactions (Section 6.3 ) were modified to include neutropenia, lipoatrophy, and lipodystrophy under Postmarketing Events in the package inserts.
The revised labeling will be posted soon at Drugs@FDA.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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