ZERIT® is the brand name for stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the Human Immunodeficiency Virus (HIV).

ZERIT (stavudine) Capsules are supplied for oral administration in strengths of 15, 20, 30, and 40 mg of stavudine. Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and iron oxides.

ZERIT (stavudine) for Oral Solution is supplied as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL stavudine solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:

Stavudine is a white to off-white crystalline solid with the molecular formula C ₁₀ H ₁₂ N ₂ O ₄ and a molecular weight of 224.2. The solubility of stavudine at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23°C is 0.144.

MICROBIOLOGY

Mechanism of Action:   Stavudine, a nucleoside analogue of thymidine, inhibits the replication of HIV in human cells in vitro . Stavudine is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV reverse transcriptase both by competing with the natural substrate deoxythymidine triphosphate (K _i =0.0083 to 0.032 µM), and by its incorporation into viral DNA causing a termination of DNA chain elongation because stavudine lacks the essential 3'-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA.

In Vitro HIV Susceptibility:   The in vitro antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit viral replication by 50% (ED ₅₀ ) ranged from 0.009 to 4 mM against laboratory and clinical isolates of HIV-1. Stavudine had additive and synergistic activity in combination with didanosine and zalcitabine, respectively, in vitro . Stavudine combined with zidovudine had additive or antagonistic activity in vitro depending upon the molar ratios of the agents tested. The relationship between in vitro susceptibility of HIV to stavudine and the inhibition of HIV replication in humans has not been established.

Drug Resistance:   HIV isolates with reduced susceptibility to stavudine have been selected in vitro and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV isolates from stavudine-treated patients revealed, in 3 of 20 paired isolates, a 4- to 12-fold decrease in susceptibility to stavudine in vitro . The genetic basis for these susceptibility changes has not been identified. The clinical relevance of changes in stavudine suceptibility has not been established.

Cross-resistance:   Five of 11 stavudine post-treatment isolates developed moderate resistance to zidovudine (9- to 176-fold) and 3 of those 11 isolates developed moderate resistance to didanosine (7- to 29-fold). The clinical relevance of these findings is unknown.

in Adults:   The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Table 1). 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.

Absorption --Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution.

Distribution --Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Stavudine distributes equally between red blood cells and plasma.

Metabolism --The metabolic fate of stavudine has not been elucidated in humans.

Excretion --Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Special Populations:

Pediatric --For pharmacokinetic properties of stavudine in pediatric patients, see Table 1.

Renal Insufficiency --Data from two studies indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). C _max and T _max were not significantly altered by renal insufficiency. The mean ± SD hemodialysis clearance value of stavudine was 120 ± 18 mL/min (n=12); the mean ± SD percentage of the stavudine dose recovered in the dailysate, timed to occur between 2-6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that ZERIT (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION section).

Hepatic Insufficiency --Stavudine pharmacokinetics were not altered in 5 non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40 mg dose.

Geriatric --Stavudine pharmacokinetics have not been studied in patients >65 years of age.

Gender --A population pharmacokinetic analysis of stavudine concentrations collected during a controlled clinical study in HIV-infected patients showed no clinically important differences between males (n=291) and females (n=27).

Race --A population pharmacokinetic analysis of stavudine concentrations collected during a controlled clinical study in HIV-infected patients (233 Caucasian, 39 African American, 41 Hispanic, 1 Asian, and 4 Other). The results of this analysis showed no clinically important differences associated with race.

Drug Interactions --Drug interaction studies have demonstrated that there are no clinically significant interactions between stavudine and the following: didanosine, lamivudine, or nelfinavir.

Zidovudine may competitively inhibit the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT is not recommended.

ZERIT, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection (see CLINICAL STUDIES ).

CLINICAL STUDIES

Combination Therapy:   The combination use of ZERIT is based on the results of clinical studies in HIV-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing ZERIT (40 mg BID) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude or inhibition of HIV RNA levels and increases in CD4 cell counts through 48 weeks.

Monotherapy:   The efficacy of ZERIT was demonstrated in a randomized, double-blind study (Al455-019, conducted 1992-1994) comparing ZERIT with zidovudine in 822 patients with a spectrum of HIV-related symptoms. The outcome in terms of progression of HIV disease and death was similar for both drugs.

CONTRAINDICATIONS

ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

1. 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. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering ZERIT to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ZERIT should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
2. Peripheral Neuropathy: Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving ZERIT (stavudine) therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see ADVERSE REACTIONS ).

PRECAUTIONS

Information for Patients:   Patients should be informed that an important toxicity of ZERIT is peripheral neuropathy. Patients should be 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. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of ZERIT may be required if toxicity develops.

Caregivers of young children receiving ZERIT therapy should be instructed regarding detection and reporting of peripheral neuropathy.

Patients should be informed that when ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. These patients should be followed closely.

Patients should be informed that ZERIT is not a cure for HIV infection, and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using ZERIT. They should be advised that ZERIT therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of ZERIT are unknown at this time.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

Drug Interactions:   Zidovudine may competitively inhibit the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT is not recommended. (See CLINICAL PHARMACOLOGY .)

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 C _max ) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

Pregnancy Pregnancy "Category C".  Reproduction studies have been performed in rats and rabbits with exposures (based on C _max ) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, stavudine should be used during pregnancy only if clearly needed.

Antiretrovial Pregnancy Registry:   To monitor maternal-fetal outcomes of pregnant women exposed to stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers:   Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Mothers should be instructed to discontinue nursing if they are receiving stavudine. This instruction is consistent with the Centers for Disease Control recommendation that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection.

Pediatric Use:   Use of stavudine in pediatric patients is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients.

Adverse events that were reported to occur in 105 pediatric patients receiving ZERIT 2 mg/kg/day for a median of 6.4 months in study ACTG 240 were generally similar to those reported in adults.

Stavudine pharmacokinetics have been evaluated in 25 HIV-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after I.V. or oral administration of single doses and BID regimens (see CLINICAL PHARMACOLOGY , Table 1).

ADVERSE REACTIONS

Adults:   ZERIT therapy has been associated with peripheral neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with neurotoxic drug therapy, including didanosine, in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy.

Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the dose (see DOSAGE AND ADMINISTRATION ). If neuropathy recurs after resumption of ZERIT, permanent discontinuation of ZERIT should be considered.

When ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. Patients treated with ZERIT in combination with didanosine may be at increased risk for adverse events such as pancreatitis, peripheral neuropathy, and liver function abnormalities. (See and PRECAUTIONS ).

Selected clinical adverse events that occurred in adult patients receiving ZERIT (stavudine) in a controlled monotherapy trial (Study AI455-019) are provided in Table 3.

Pancreatitis was observed in three of the 412 adult patients who received ZERIT in a controlled monotherapy study.

Selected clinical adverse events that occurred in antiretroviral naive adult patients receiving ZERIT from two controlled combination studies are provided in Table 4.

Pancreatitis resulting in death was observed in one patient who received ZERIT plus didanosine plus indinavir in the START 2 study.

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 5.

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 6 and 7.

Observed During Clinical Practice:   The following events have been identified during post-approval use of ZERIT (stavudine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events 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, and chills/fever.

Digestive Disorders anorexia

Hematologic Disorders --anemia, leukopenia, and thrombocytopenia.

Liver --lactic acidosis and hepatic steatosis (see ), hepatitis and liver failure.

Musculoskeletal myalgia

Nervous insomnia

Pediatric Patients:   Adverse reactions and serious laboratory abnormalities in pediatric patients were similar in type and frequency to those seen in adult patients.

OVERDOSAGE

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.

DOSAGE AND ADMINISTRATION

The interval between doses of ZERIT should be 12 hours. ZERIT may be taken without regard to meals.

Adults:   The recommended dose based on body weight is as follows:

40 mg twice daily for patients >/=60 kg.

30 mg twice daily for patients <60 kg.

Pediatrics   The recommended dose for pediatric patients weighing less than 30 kg is 1 mg/kg/dose, given every 12 hours. Pediatric patients weighing 30 kg or greater should receive the recommended adult dosage.

Dosage Adjustment:   Patients should be monitored for the development of peripheral neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. These symptoms may be difficult to detect in young children (see ). If these symptoms develop during treatment, stavudine therapy should be interrupted. Symptoms may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the recommended dose.

20 mg twice daily for patients >/=60 kg.

15 mg twice daily for patients <60 kg.

If neuropathy recurs after resumption of ZERIT, permanent discontinuation of ZERIT should be considered.

Renal Impairment --ZERIT may be administered to adult patients with impaired renal function with adjustment in dose as shown in Table 8.

Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of ZERIT in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.

Hemodialysis Patients --The recommended dose is 20 mg every 24 hours (>/=60 kg) or 15 mg every 24 hours (<60 kg), administered after the completion of hemodialysis and at the same time of day on non-dialysis days.

Method of Preparation:
ZERIT (stavudine) for Oral Solution

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:

1. Add 202 mL of purified water to the container.
2. 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.
3. 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, 36° to 46°F (2° to 8°C). Discard any unused portion after 30 days.

HOW SUPPLIED

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

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 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.

US Patent No.: 4,978,655

Storage:   ZERIT Capsules should be stored in tightly closed containers at controlled room temperature, 59° to 86°F (15° to 30°C).

ZERIT (stavudine) for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at controlled room temperature, 59° to 86°F (15° to 30°C). After constitution, store tightly closed containers of ZERIT for Oral Solution in a refrigerator, 36° to 46°F (2° to 8°C). Discard any unused portion after 30 days.

BRISTOL-MYERS SQUIBB

IMMUNOLOGY

Bristol-Myers Squibb Company

Princeton, NJ 08543

U.S.A.

F9-B001-8-99                     1017718A4

                              Revised August 1999

PRODUCT PHOTO(S):