Updates Label Information for Stavudine (Zerit)
Last week the U.S. Food and Drug Administration
(FDA) updated the product label information for
(d4T, Zerit) to reflect current information
about adverse side effects. The new label contains
a stronger warning about body fat changes including
peripheral lipoatrophy, and noted that there is
no conclusive evidence that stavudine dose reduction
can help reduce peripheral neuropathy.
is the text of an FDA email announcement describing the changes.
labeling for Zerit capsules and Zerit for oral solution
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
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 naive 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
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.
Klein and K Struble. New labeling for Zerit capsules and Zerit
for oral solution. HIV/AIDS Update. December 10, 2010.