Included as part of the PRECAUTIONS section.
Lactic Acidosis/Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of nucleoside analogues
alone or in combination, including stavudine and other antiretrovirals.
Although relative rates of lactic acidosis have not been assessed in
prospective well-controlled trials, longitudinal cohort and retrospective
studies suggest that this infrequent event may be more often associated with
antiretroviral combinations containing stavudine. Female gender, obesity, and
prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has
been reported in pregnant individuals who received the combination of stavudine
and didanosine with other antiretroviral agents. Coadministration of ZERIT and
didanosine is contraindicated [see CONTRAINDICATIONS and Use In Specific
Particular caution should be exercised when administering
ZERIT to any patient with known risk factors for liver disease; however, cases
of lactic acidosis have also been reported in patients with no known risk
factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal
pain, and unexplained weight loss); respiratory symptoms (tachypnea and
dyspnea); or neurologic symptoms, including motor weakness [see Neurologic Symptoms] might be indicative of the development of symptomatic
hyperlactatemia or lactic acidosis syndrome.
Treatment with ZERIT should be suspended in any patient
who develops clinical or laboratory findings suggestive of symptomatic
hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Permanent discontinuation of ZERIT should be considered for patients with
confirmed lactic acidosis.
The safety and efficacy of ZERIT have not been
established in HIV-infected patients with significant underlying liver disease.
During combination antiretroviral therapy, patients with preexisting liver
dysfunction, including chronic active hepatitis, have an increased frequency of
liver function abnormalities, including severe and potentially fatal hepatic
adverse events, and should be monitored according to standard practice. If
there is evidence of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death
were reported during postmarketing surveillance in HIV-infected patients
treated with hydroxyurea and other antiretroviral agents.
Fatal hepatic events were reported most often in patients
treated with the combination of hydroxyurea, didanosine, and stavudine.
Coadministration of ZERIT and didanosine is contraindicated; and the
combination of ZERIT and hydroxyurea should be avoided [see CONTRAINDICATIONS
and DRUG INTERACTIONS].
Use With Interferon And Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the
phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although
no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of HIV-1/HCV
virologic suppression) interaction was seen when ribavirin was coadministered
with stavudine in HIV-1/HCV co-infected patients [see DRUG INTERACTIONS],
hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected
patients receiving combination antiretroviral therapy for HIV-1 and interferon
and ribavirin. Patients receiving interferon with or without ribavirin and
stavudine should be closely monitored for treatment-associated toxicities,
especially hepatic decompensation. Discontinuation of stavudine should be
considered as medically appropriate. Dose reduction or discontinuation of
interferon, ribavirin, or both should also be considered if worsening clinical
toxicities are observed, including hepatic decompensation (eg, Child-Pugh
>6) (see the full prescribing information for interferon and ribavirin).
Motor weakness has been reported rarely in patients
receiving combination antiretroviral therapy including ZERIT. Most of these
cases occurred in the setting of lactic acidosis. The evolution of motor
weakness may mimic the clinical presentation of Guillain-Barré syndrome
(including respiratory failure). If motor weakness develops, ZERIT should be
discontinued. Symptoms may continue or worsen following discontinuation of
Peripheral sensory neuropathy, manifested by numbness,
tingling, or pain in the hands or feet, has been reported in patients receiving
ZERIT therapy. Peripheral neuropathy, which can be severe, is dose-related and
occurs more frequently in patients with advanced HIV-1 disease, a history of
peripheral neuropathy, or in patients receiving other drugs that have been
associated with neuropathy [see DRUG INTERACTIONS].
Patients should be monitored for the development of
peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if
therapy is withdrawn promptly. If peripheral neuropathy develops permanent
discontinuation of ZERIT should be considered. In some cases, symptoms may
worsen temporarily following discontinuation of therapy.
Fatal and nonfatal pancreatitis have occurred during
therapy when ZERIT was part of a combination regimen that included didanosine
in both treatment-naive and treatment-experienced patients, regardless of
degree of immunosuppression. The combination of ZERIT and any other agents that
are toxic to the pancreas should be suspended in patients with suspected
pancreatitis. Coadministration of ZERIT and didanosine is contraindicated [see
CONTRAINDICATIONS]. Reinstitution of ZERIT after a confirmed diagnosis of
pancreatitis should be undertaken with particular caution and close patient
In randomized controlled trials of treatment-naive
patients, clinical lipoatrophy 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 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 and questioned about body changes related to
lipoatrophy. Given the potential risks of using ZERIT including lipoatrophy, a
benefit-risk assessment for each patient should be made and an alternative
antiretroviral should be considered.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including ZERIT.
During the initial phase of combination antiretroviral treatment, patients
whose immune system responds may develop an inflammatory response to indolent
or residual opportunistic infections (such as Mycobacterium avium infection,
cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or
tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease,
polymyositis, and Guillain-Barré syndrome) have also been reported to occur in
the setting of immune reconstitution; however, the time to onset is more
variable, and can occur many months after initiation of treatment.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Inform patients of the
importance of early recognition of symptoms of symptomatic hyperlactatemia or
lactic acidosis syndrome, which include unexplained weight loss, abdominal
discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in
whom these symptoms develop should seek medical attention immediately.
Discontinuation of ZERIT therapy may be required. Advise pregnant
individuals of the potential risks of lactic acidosis syndrome/hepatic
steatosis syndrome [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS
and Use In Specific Populations].
Inform patients that hepatotoxicity, which may be fatal,
may occur in patients treated with ZERIT in combination with didanosine and
hydroxyurea. ZERIT is contraindicated in combination with didanosine [see CONTRAINDICATIONS].
Avoid coadministration of ZERIT with hydroxyurea [see WARNINGS AND
PRECAUTIONS and DRUG INTERACTIONS].
Inform patients that an important toxicity of ZERIT is
peripheral neuropathy. Make patients aware that peripheral neuropathy is
manifested by numbness, tingling, or pain in hands or feet, and that these
symptoms should be reported to their physicians. Counsel patients that
peripheral neuropathy occurs with greatest frequency in patients who have
advanced HIV-1 disease or a history of peripheral neuropathy, and
discontinuation of ZERIT may be required if toxicity develops.
Instruct caregivers of young children receiving ZERIT
therapy regarding detection and reporting of peripheral neuropathy [see WARNINGS
Inform patients that an increased risk of pancreatitis,
which may be fatal, may occur in patients treated with the combination of ZERIT
and didanosine. ZERIT is contraindicated in combination with didanosine [see CONTRAINDICATIONS].
Closely monitor patients for symptoms of pancreatitis such as severe abdominal
pain, nausea and vomiting, and fever.
Instruct patients to avoid alcohol while taking ZERIT.
Alcohol may increase the patient’s risk of pancreatitis or liver damage [see WARNINGS
Inform patients that loss of body fat (e.g., loss of fat
from arms, legs, or face) may occur in individuals receiving ZERIT. Monitor
patients receiving ZERIT for clinical signs and symptoms of lipoatrophy.
Patients should be questioned routinely about body changes related to
lipoatrophy [see WARNINGS AND PRECAUTIONS].
Inform patients that there is an antiretroviral pregnancy
registry to monitor fetal outcomes of pregnant individuals exposed to ZERIT [see
Use In Specific Populations].
Advise mothers with HIV-1 not to breastfeed because HIV-1
can be passed to the baby in breast milk [see Use In Specific Populations].
Sucrose In ZERIT For Oral Solution
Inform patients with diabetes that ZERIT for oral
solution contains 50 mg of sucrose per mL.
Instruct patients not to miss a dose but if they do,
patients should take ZERIT as soon as possible.
Inform patients that it is important to take ZERIT on a
regular dosing schedule and to avoid missing doses as it can result in
development of resistance.
Patients should be instructed if they take too much
ZERIT, they should contact a poison control center or emergency room right
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In 2-year carcinogenicity studies in mice and rats,
stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and
168 times, respectively, human exposure at the recommended clinical dose.
Benign and malignant liver tumors in mice and rats and malignant urinary
bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732
(rats) times human exposure at the recommended clinical dose.
Stavudine was not mutagenic in the Ames, E. coli reverse
mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with
and without metabolic activation. Stavudine produced positive results in the in
vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in
vivo mouse micronucleus test. In the in vitro assays, stavudine elevated the
frequency of chromosome aberrations in human lymphocytes (concentrations of 25
to 250 μg/mL, without metabolic activation) and increased the frequency of
transformed foci in mouse fibroblast cells (concentrations of 25 to 2500
μg/mL, with and without metabolic activation). In the in vivo micronucleus
assay, stavudine was clastogenic in bone marrow cells following oral stavudine
administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days.
No evidence of impaired fertility was seen in rats with
exposures (based on AUC) up to 137 times human exposure at the RHD.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in individuals exposed to ZERIT during pregnancy. Healthcare
providers are encouraged to register patients by calling the Antiretroviral
Pregnancy Registry (APR) at 1-800-258-4263.
Fatal lactic acidosis has been reported in pregnant
individuals who received the combination of stavudine and didanosine with other
antiretroviral agents. It is unclear if pregnancy augments the risk of lactic
acidosis/hepatic steatosis syndrome reported in non-pregnant individuals
receiving nucleoside analogues [see WARNINGS AND PRECAUTIONS]. The
combination of ZERIT and didanosine is contraindicated [see CONTRAINDICATIONS].
Prospective pregnancy data from APR are not sufficient to
adequately assess the risk of major birth defects, miscarriage or adverse
developmental outcomes. Available data from the APR show no increase in overall
risk of major birth defects compared with 2.7% in the U.S. reference population
of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of
miscarriage is not reported in the APR. In the U.S. general population, the
estimated background risks of miscarriage in clinically recognized pregnancies
is 15 to 20%.
In animal reproduction studies, no adverse developmental
effects were observed with oral administration of stavudine at clinically
relevant exposures. No developmental toxicities were observed in rats and
rabbits at systemic exposures 112 (AUC) and 183 (Cmax) times, respectively, the
exposures in humans at the recommended human dose (RHD) of ZERIT (see Data).
Maternal Adverse Reactions
Cases of lactic acidosis syndrome, sometimes fatal have
occurred in pregnant individuals using ZERIT in combination with didanosine.
ZERIT is associated with an increased risk of lactic acidosis syndrome/hepatic
steatosis syndrome [see WARNINGS AND PRECAUTIONS].
Based on prospective reports to the APR of live births
following exposure to stavudine-containing regimens during pregnancy (including
811 exposed in the first trimester and 196 exposed in the second/third
trimester), the prevalence of birth defects in live births for stavudine was
2.6% (95% CI: 1.6 % to 3.9%) with first trimester exposure and 3.1% (95% CI:
1.1% to 6.5%) with second/third trimester exposure compared to the background
birth defect rate of 2.7% in the U.S. reference population of the MACDP.
Prospective reports from the APR of overall major birth
defects in pregnancies exposed to ZERIT is compared with a U.S. background
major birth defect rate. Methodological limitations of the APR include the use
of MACDP as the external comparator group. Limitations of using an external
comparator include differences in methodology and populations, as well as
confounding due to the underlying disease.
Stavudine was administered orally to pregnant rats (0,
50, 250, and 1000 mg/kg/day from gestation day 6 to 17) and rabbits (0, 60,
150, 300 and 600 mg/kg/day from gestation day 6 to 18). In rats, fetal skeletal
variations, including increased unossified or incomplete ossification of sternebra,
were observed at the highest dose (1000 mg/kg/day) (approximately 488 times
human AUC exposure at the RHD). In rabbits, there were no developmental effects
up to the highest dose of 600 mg/kg (approximately 183 times human Cmax exposure
at the RHD).
In the pre/post-natal development study, stavudine was
administered orally to rats at 0, 50, 250, and 1000 mg/kg/day from gestation
day 17 to postnatal day 21. Post-implantation loss and an increase in early
neonatal mortality was observed at 1000 mg/kg/day (approximately 488 times human
AUC exposure at the RHD). No developmental effects were observed at 250
mg/kg/day (approximately 112 times human AUC exposure at the RHD).
Stavudine was transferred to the fetus through the
placenta in rats with concentrations in fetal tissues approximately half the
concentration detected in maternal plasma.
The Centers for Disease Control and Prevention recommend
that HIV-infected mothers not breastfeed their infants to avoid risking
postnatal transmission of HIV.
Based on limited data, stavudine has been detected in
human milk. No data are available regarding the effects of stavudine on the
breastfed infant, or the effects on milk production.
Because of the potential for (1) HIV transmission (in
HIV-negative infants), (2) developing viral resistance (in HIV-positive
infants) and (3) adverse reactions in breastfed infants similar to those seen
in adults, instruct mothers not to breastfeed if they are receiving ZERIT.
Use of stavudine in pediatric patients from birth through
adolescence is supported by evidence from adequate and well-controlled studies
of stavudine in adults with additional pharmacokinetic and safety data in
pediatric patients [see DOSAGE AND ADMINISTRATION and ADVERSE
Adverse reactions and laboratory abnormalities reported
to occur in pediatric patients in clinical studies were generally consistent
with the safety profile of stavudine in adults. These studies include ACTG 240,
where 105 pediatric patients ages 3 months to 6 years received ZERIT 2
mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185
newborns received ZERIT 2 mg/kg/day either alone or in combination with
didanosine from birth through 6 weeks of age; and a clinical trial where 8
newborns received ZERIT 2 mg/kg/day in combination with didanosine and
nelfinavir from birth through 4 weeks of age.
Stavudine pharmacokinetics have been evaluated in 25
HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and
in weight from 2 to 43 kg after IV or oral administration of single doses and
twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in
age from birth to 4 weeks after oral administration of twice-daily regimens [see
CLINICAL PHARMACOLOGY, Â Table 9)].
Clinical studies of ZERIT (stavudine) did not include
sufficient numbers of patients aged 65 years and over to determine whether they
respond differently than younger patients. Greater sensitivity of some older
individuals to the effects of ZERIT cannot be ruled out.
In a monotherapy Expanded Access Program for patients
with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic
symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice
daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the
approximately 12,000 patients enrolled in the Expanded Access Program,
peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of
patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice
daily. Elderly patients should be closely monitored for signs and symptoms of
ZERIT is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely to have
decreased renal function, it may be useful to monitor renal function. Dose
adjustment is recommended for patients with renal impairment [see DOSAGE AND
Data from two studies in adults indicated that the
apparent oral clearance of stavudine decreased and the terminal elimination
half-life increased as creatinine clearance decreased. Based on these
observations, it is recommended that the ZERIT dosage be modified in patients
with reduced creatinine clearance and in patients receiving maintenance
hemodialysis [see DOSAGE AND ADMINISTRATION and CLINICAL