Zerit (Stavudine)

ZERIT™

Bristol-Myers Squibb

Stavudine

Antiretroviral

Action And Clinical Pharmacology: Stavudine is a synthetic thymidine nucleoside analogue active against the Human Immunodeficiency Virus (HIV).

In vitro studies demonstrate that stavudine is converted to the triphosphate by cellular kinases. The 5′-triphosphate is the active form of the drug. In cell culture studies with 2 different cell lines, stavudine triphosphate had an intracellular half-life of 3.5 hours. Stavudine triphosphate has been shown to be a potent competitive inhibitor of HIV reverse transcriptase (ki=0.0083 to 0.032 M). In addition, both stavudine triphosphate and the natural substrate, thymidine triphosphate, are used by HIV reverse transcriptase in vitro for incorporation into the nascent DNA chain. Stavudine lacks the 3′-hydroxyl group necessary for DNA elongation and once incorporated into DNA, functions as a DNA chain terminator in vitro. Both the inhibition of binding of thymidine triphosphate to reverse transcriptase and DNA chain termination may be partially responsible for inhibition of HIV replication in vitro. In addition to the inhibitory effect on HIV reverse transcriptase, stavudine triphosphate exhibits some inhibitory effect on DNA polymerase beta and gamma, and markedly reduces the syntheses of mitochondrial DNA.

Clinically, stavudine has been studied in various combinations with other drugs, including didanosine, lamivudine (3TC), ritonavir, nelfinavir, saquinavir, indinavir, and hydroxyurea. However, zidovudine in combination with stavudine is not recommended (see Precautions/Drug Interactions). Both drugs are phosphorylated by the same enzyme (thymidine kinase), which may preferentially phosphorylate zidovudine, thereby preventing the phosphorylation of stavudine to its active triphosphate form.

Based on in vitro testing, the activation of stavudine has also been shown to be inhibited by other drugs. Among the several drugs tested, the only ones that may interfere with stavudine phosphorylation at relevant concentrations are doxorubicin and ribavirin, but not other drugs used in the therapy of HIV infection which are similarly phosphorylated. The clinical significance of this is unknown.

Indications And Clinical Uses: For the treatment of HIV-infected adults who have received prolonged prior zidovudine therapy.

Contra-Indications: Patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

Manufacturers’ Warnings In Clinical States: Peripheral Neuropathy: The major clinical toxicity of stavudine is peripheral neuropathy. This occurred in 15 to 24% of patients in the controlled clinical trials. Patients should be monitored for the development of a neuropathy that is usually characterized by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy usually resolves when therapy is withdrawn, on occasion after a period of worsening. If symptoms resolve completely, resumption of treatment may be considered at a reduced dose (see Dosage).

Patients with a history of peripheral neuropathy are at increased risk for the development of neuropathy. If stavudine must be administered in this clinical setting, careful monitoring is essential.

Lactic Acidosis: As with other nucleoside analogues, occurrences of lactic acidosis, which may be fatal, and usually associated with severe hepatic steatosis have been reported in patients receiving stavudine. It is not known whether these events are causally related to nucleoside analogues; this condition has also been reported as a disease-related event. In the event of rapidly elevating aminotransferase or lactic acid levels, consideration should be given to discontinuation of all nucleoside analogue therapy.

Precautions: General: Patients receiving stavudine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore, should remain under close clinical observation by physicians experienced in the treatment of patients with HIV disease and associated complications.

Renal Insufficiency: In HIV-infected patients with renal impairment, renal clearance and apparent oral clearance of stavudine was decreased. The terminal elimination half-life (t 1/2) was prolonged up to 8 hours. Cmax and Tmax were not significantly affected by reduced renal function. Based on these preliminary observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance (see Dosage).

Hepatic Insufficiency: Hepatitis or liver failure, which was fatal in some cases, have been reported. In patients with pre-existing liver dysfunction, discontinuation of all nucleoside analogues should be considered when worsening liver disease occurs.

Pregnancy: 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.

Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) 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 or impaired fertility. A slight postimplantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. 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. 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. Stavudine has been shown to cross the human placenta in an ex vivo term model.

Lactation : Studies in which lactating rats were administered a single dose (5 or 100 mg/kg) of stavudine demonstrated that stavudine is readily excreted into breast milk.

It is not known whether stavudine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential of adverse reactions from stavudine in nursing infants, mothers should be instructed to discontinue nursing if they are receiving stavudine.

Children: The safety and effectiveness of stavudine have been established in pediatric patients supported by evidence from adequate and well-controlled studies of stavudine in adults with additional data concerning safety and pharmacokinetics in pediatric patients.

Patients should be monitored for clinically significant elevations of hepatic transaminases. If these evaluations develop on treatment, stavudine therapy should be interrupted. If the hepatic transaminase values return to pretherapy levels, resumption of treatment may be considered using a dosage schedule of 1 mg/kg/day, not to exceed the recommended adult dose of 20 mg twice daily.

One open-label, phase I trial enrolled 38 subjects aged 5 weeks to 15 years; 9 had received no prior antiretroviral therapy and 29 had received zidovudine for a median duration of 104 weeks. Patients in this trial received stavudine in initial doses ranging from 0.125 to 4.0 mg/kg/day with an average dose of 1.7 mg/kg/day for a median duration of 84 weeks (range 8 to 140 weeks). A second open-label trial, initiated to provide stavudine for children who had failed or were intolerant of alternative antiretroviral therapy, enrolled 51 subjects aged 8 months to 18 years who had received prolonged zidovudine and didanosine. These patients were treated with stavudine at a dose of 2 mg/kg/day, for a median duration of 33 weeks (range 2 days to 82 weeks).

Diabetes Mellitus: The constituted powder for oral solution contains 50 mg sucrose per mL of constituted solution.

Lactose Intolerance: Zerit capsules contain lactose (120 and 240 mg depending on capsule strength). This amount is probably insufficient to induce specific symptoms of intolerance.

Laboratory Tests: Complete blood counts and clinical laboratory tests should be performed prior to initiating stavudine therapy and at appropriate intervals thereafter.

Moderate elevations of mean corpuscular volume may be observed in patients taking stavudine and may provide an indication of treatment compliance.

Drug Interactions: A clinical trial in HIV-infected patients (n=10) has demonstrated that there were no clinically significant interactions between stavudine (40 mg) and didanosine (100 mg) when the agents were administered simultaneously every 12 hours for 4 days. The pharmacokinetic profile of each drug was unchanged when given as a single agent or following first-dose and steady-state conditions when given in combination. Neither stavudine nor didanosine affected the pharmacokinetics of the other. Based on results of studies of radiolabeled stavudine in nonhuman primates, there is no expectation that drugs affecting hepatic metabolism would have any effect on the disposition of stavudine in humans.

Since zidovudine may inhibit the intracellular phosphorylation of stavudine, it is not recommended to use zidovudine in combination with stavudine.

Information to be provided to the Patient: Patients receiving stavudine should be advised that:

The long-term effects of stavudine are unknown at this time.

Stavudine therapy has not been shown to reduce the risk of HIV transmission.

They may continue to develop opportunistic infections and other complications of HIV infection, and therefore, should remain under the care of a physician experienced in treating HIV-associated diseases.

They must report symptoms including tingling, burning, pain or numbness in the hands or feet to their physicians and follow their physician’s instructions regarding the prescribed dose in order to reduce the risk of peripheral neuropathy.

Adverse Reactions: Adverse event data presented below are based on 2 major clinical trials in adults. One trial was a controlled, comparative double-blind study (stavudine compared with zidovudine) in patients with less advanced HIV infection (median CD4 cell count of 250 cells/mm. In this trial, 412 patients were treated with stavudine for a median duration of 79 weeks; patients ³ 60 kg received 40 mg b.i.d.

Clinical Events: Many of the serious clinical adverse events reported from patients receiving stavudine in clinical trials were consistent with the course of HIV infection. Concurrent therapy with other medications was permitted in these trials. Therefore, it is difficult to distinguish which events were related to stavudine, the disease itself, or other therapies.

Peripheral Neuropathy: The major clinical toxicity of stavudine is dose-related peripheral neuropathy. Patients with a history of peripheral neuropathy are at increased risk for developing this complication during therapy with stavudine. Stavudine-related peripheral neuropathy may resolve if therapy is promptly withdrawn. In some cases, symptoms may worsen temporarily following discontinuation of therapy. Resumption of treatment with stavudine may be considered at a reduced dosage if symptoms resolve satisfactorily (see Dosage).

Pancreatitis: Pancreatitis was generally attributed to advanced disease or to prior or concurrent treatment with medications known to be associated with pancreatitis. The occurrences were not dose-related, and were occasionally fatal. Patients with a history of pancreatitis appear to be at increased risk for recurrence.

Lactic Acidosis: As with other nucleoside analogues, occurrences of lactic acidosis, which were fatal in some cases and usually associated with severe hepatic steatosis, have been reported postmarketing (see Warnings).

Hepatic Dysfunction: Hepatitis or liver failure, which was fatal in some cases, have been reported postmarketing (see Precautions).

Laboratory Abnormalities: The laboratory abnormalities reported in these clinical trials included those shown in Table II.

Children: Adverse events and clinical laboratory abnormalities were generally similar to those seen in adults, and generally related to underlying disease. Drug-related peripheral neuropathy has not been reported in pediatric patients who have received stavudine monotherapy in controlled clinical trials.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known antidote for stavudine overdosage. Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Patients may benefit from administration of activated charcoal. Stavudine can be removed by hemodialysis, the mean±SD hemodialysis clearance of stavudine is 120±18 mL/minute. It is not known whether stavudine is eliminated by peritoneal dialysis.

Dosage And Administration: Adults: The interval between oral doses should be 12 hours. Stavudine may be taken with or without food. The recommended starting doses are based on body weight, as outlined in Table III.

Based on available clinical data, either of the doses within each weight category in Table III could be recommended. The choice of the higher or lower dose should be based on clinical judgment reflecting the balance of potential efficacy versus possible toxicity (see Adverse Effects).

Children: The interval between doses of stavudine oral solution should be 12 hours and doses may be taken without regard to meals. The recommended starting dose for pediatric patients is 2 mg/kg/day, not to exceed the recommended adult dose of 40 mg twice daily. Oral solution and capsule formulations of stavudine have been shown to be bioequivalent.

There is no clinical experience with stavudine in children under the age of 3 months.

Children: There is insufficient data to recommend a dosage adjustment for children with renal impairment.

Hepatic Impairment: Dosing adjustment is not necessary in subjects with stable hepatic impairment. In the event of rapidly elevating aminotransferase levels, consideration should be given to discontinuation of all nucleoside analogue therapy.

Peripheral Neuropathy: Clinical symptoms of peripheral neuropathy should prompt interruption of stavudine treatment and evaluation of the patient. These symptoms may be difficult to detect in children. If symptoms resolve completely, based on experience in adults, resumption of treatment may be considered at a reduced dose. Clinically significant elevations of hepatic transaminases should be managed in the same fashion.

Children: Patients should be monitored for clinically significant elevations of hepatic transaminases. If these elevations develop on treatment, stavudine therapy should be interrupted. If the hepatic transaminase values return to pretherapy levels, resumption of treatment may be considered using a dosage schedule of 1 mg/kg/day, not to exceed the recommended adult dose of 20 mg twice daily.

Method of Preparation: Oral Solution: 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 (2 to 8°C). Discard any unused portion after 30 days. The solution may also be stored at room temperature for up to 3 days.

Availability And Storage: Capsules: 15 mg: Each light yellow and dark red capsule, imprinted with “BMS 1964” and “15”, contains: stavudine 15 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60. Packages of 100 individually foil-wrapped capsules. Unit dose blister strips of 14, packages of 4. Store at room temperature (15 to 30°C) and protect from excessive moisture. Keep bottles tightly closed.

20 mg: Each light brown capsule, imprinted with “BMS 1965” and “20”, contains: stavudine 20 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60. Packages of 100 individually foil-wrapped capsules. Unit dose blister strips of 14, packages of 4. Store at room temperature (15 to 30°C) and protect from excessive moisture. Keep bottles tightly closed.

30 mg: Each light orange and dark orange capsule, imprinted with “BMS 1966” and “30”, contains: stavudine 30 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60. Packages of 100 individually foil-wrapped capsules. Unit dose blister strips of 14, packages of 4. Store at room temperature (15 to 30°C) and protect from excessive moisture. Keep bottles tightly closed.

40 mg: Each dark orange capsule, imprinted with “BMS 1967” and “40” contains: stavudine 40 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60. Packages of 100 individually foil-wrapped capsules. Unit dose blister strips of 14, packages of 4. Store at room temperature (15 to 30°C) and protect from excessive moisture. Keep bottles tightly closed.

Powder for Oral Solution: Each mL of fruit-flavored solution contains: stavudine 1 mg (after reconstitution with water per label instructions). Nonmedicinal ingredients: antifoaming agents (glyceryl monostearate, polyethylene glycol monostearate, simethicone, sorbic acid and water), flavoring agents, methylparaben, propylparaben, sodium carboxymethylcellulose and sucrose. Dye-free. HDPE bottles with child-resistant closures of 200 mL. Powder for oral solution should be protected from excessive moisture and stored in tightly closed containers at room temperature (15 to 30°C). After constitution, store tightly closed containers in a refrigerator (2 to 8°C). Discard any unused portion after 30 days. The solution may also be stored at room temperature for up to 3 days.

ZERIT™ Bristol-Myers Squibb Stavudine Antiretroviral

Connected Diseases :

HIV, AIDS

General Illness Information Common Name: HIV, AIDS Medical Term: HIV, Human Immunodeficiency Virus Infection Description: A chronic infection with a variable course (about 10 years…