Stavudine (Zerit)

The recommended adult dosage is based on body weight as follows:

• For patients weighing less than 60 kg: 30 mg every 12 hours.
• For patients weighing at least 60 kg: 40 mg every 12 hours.

• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
• For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
• For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per mL of solution, as follows:

• Add 202 mL of purified water to the container.
• Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL stavudine solution. The solution may appear slightly hazy.
• Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

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 (4) and Use in Specific Populations (8.1)].

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 Warnings and Precautions (5.3 )] 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 (4) and Drug Interactions ( 7)].

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 therapy.

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 (7)].

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 (4)]. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring.

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 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience in Adults

Selected adverse reactions that occurred in adult patients receiving ZERIT in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Pancreatitis was observed in 3 of the 412 adult patients who received ZERIT in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving ZERIT from two controlled combination studies are provided in Table 3.

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

Clinical Trials Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients [see Use in Specific Populations (8.4)].

The following adverse reactions have been identified during postmarketing use of ZERIT. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to ZERIT, or a combination of these factors.

Body as a Whole: abdominal pain, allergic reaction, chills/fever.Digestive Disorders: anorexia.Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4)].Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1 ) ], hepatitis and liver failure.Metabolic Disorders: lipoatrophy [see Warnings and Precautions (5.5)], diabetes mellitus and hyperglycemia.Musculoskeletal: myalgia.Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1, 5.3)].

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.

Risk Summary

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 (5.1 )]. The combination of ZERIT and didanosine is contraindicated [see Contraindications (4) ].

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 (C_max) times, respectively, the exposures in humans at the recommended human dose (RHD) of ZERIT (see Data).

Clinical Considerations

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 (5.1)].

Data

Human Data

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.

Animal Data

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 C_max 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.

Risk Summary

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 (2.2 ) and Adverse Reactions (6.1)].

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 (12.3, 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 peripheral neuropathy.

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 Administration (2.3)].

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 (2.3) and Clinical Pharmacology (12.3)].

Stavudine is an antiretroviral drug [see Microbiology (12.4)].

The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours.

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.

Capsules

ZERIT^® (stavudine) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures:

Oral Solution

ZERIT^® (stavudine) for oral solution is a dye-free, fruit-flavored powder that provides 1 mg of stavudine per mL of solution upon constitution with water. Directions for solution preparation are included on the product label and in the Dosage and Administration (2) section of this insert. ZERIT for oral solution (NDC No. 0003-1968-01) is available in child-resistant containers that provide 200 mL of solution after constitution with water.

Storage

ZERIT Capsules should be stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted (see USP Controlled Room Temperature).

ZERIT for oral solution should be protected from excessive moisture and stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted (see USP Controlled Room Temperature). After constitution, store tightly closed containers of ZERIT for oral solution in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

Lactic Acidosis

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 (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Hepatic Toxicity

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 (4)]. Avoid coadministration of ZERIT with hydroxyurea [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Peripheral Neuropathy

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 and Precautions (5.3)].

Pancreatitis

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 (4)]. 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 and Precautions (5.4)].

Lipoatrophy

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 (5.5)].