Vudistav (Capsules) Instructions for Use

Marketing Authorization Holder

Ranbaxy Laboratories, Ltd. (India)

ATC Code

J05AF04 (Stavudine)

Active Substance

Stavudine (Rec.INN registered by WHO)

Dosage Forms

	Vudistav	Capsules 30 mg: 50, 56 or 60 pcs.
		Capsules 40 mg: 50, 56 or 60 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
60 pcs. – polyethylene bottles (1) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
60 pcs. – polyethylene bottles (1) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Stavudine is a synthetic nucleoside analogue of thymidine that inhibits HIV replication in cultured human cells and in cell lines in vitro. After entering the cell, Stavudine is converted by cellular enzymes into the active metabolite stavudine triphosphate, which inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate and disrupts HIV replication. Stavudine triphosphate also enhances chain termination of viral DNA due to the absence of 3′-hydroxyl groups in the molecule, which are necessary for DNA construction. In addition, stavudine triphosphate inhibits cellular DNA polymerases β and γ and significantly reduces mitochondrial DNA synthesis.

Study of the inhibitory activity of stavudine in combination with zidovudine in vitro showed that both drugs are phosphorylated by cellular thymidine kinase. Moreover, the conversion of zidovudine to its active form occurs faster, slowing down the activity of stavudine. Given this, combination therapy with these drugs is not recommended. According to in vitro studies, phosphorylation of stavudine is also slowed down in the presence of doxorubicin and ribavirin.

Pharmacokinetics

Adults. Stavudine is rapidly absorbed after oral administration. The absolute bioavailability is about 86.4%. After a single oral dose, C_max in plasma is observed in less than 1 hour. C_max values increase proportionally with increasing drug doses. No accumulation of stavudine was observed when administered every 6, 8, or 12 hours. The pharmacokinetics of stavudine in HIV patients without clinical manifestations, who took the drug after or during a high-fat meal or on an empty stomach, did not change significantly.

The apparent volume of distribution after a single dose averages 66 liters and is independent of dose. The drug is distributed equally between red and white blood cells. Binding to blood proteins is insignificant. After a single oral dose of 40 mg, the concentration in the cerebrospinal fluid (CSF) of healthy volunteers was 63 ng/ml (mean 44-71 ng/ml) over 4-5 hours. The CSF to plasma concentration ratio was about 40% (mean 31-45%).

The metabolism of stavudine in humans remains unstudied. After oral administration, the T_1/2 of the drug is 1.44 hours and is independent of dose.

Renal clearance is 40% of total clearance and is almost twice the clearance of endogenous creatinine, indicating active tubular secretion in the renal excretion of stavudine along with glomerular filtration.

Children. The absolute bioavailability of the drug in children averages 76.9%. The pharmacokinetics after a single dose are similar to those in adults and are independent of dose. Drug concentrations in CSF after single and multiple oral doses range from 16 to 125% relative to plasma concentration. No accumulation of stavudine is observed when taking a dose of 0.125-2 mg/kg every 12 hours. T_1/2 averages 1 hour. About 34.5% of the drug is excreted unchanged by the kidneys.

Elderly patients. Pharmacokinetics in patients over 65 years of age have not been studied.

Renal impairment. In case of impaired renal function, the clearance of stavudine decreases. Dose adjustment is recommended (see Dosage and Administration).

Hepatic impairment. The pharmacokinetics of the drug are similar in patients with impaired and normal liver function. No adjustment of the initial dose of the drug is required for patients with stable impaired liver function.

Indications

• Treatment of HIV infection (in combination with other nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors).

ICD codes

Dosage Regimen

Orally. The time of administration of the drug does not depend on the time of food intake. The dose of the drug depends on body weight.

Adults and children weighing at least 30 kg

Children with impaired renal function. There are no precise recommendations for dose adjustment of the drug in children. A dose reduction and/or an increase in the interval between doses of the drug is possible.

Adverse Reactions

When used in combination with other drugs with similar toxicity, the risk of side effects increases.

Peripheral neuropathy is a serious and dose-dependent side effect of the drug. The risk of developing this effect increases with simultaneous use with didanosine. Peripheral neuropathy is usually accompanied by bilateral symmetric numbness of the extremities: tingling and pain in the feet and less so in the hands. In clinical studies, the frequency of these reactions depended on the dose and/or stage of the disease. In the early stages of the disease, these phenomena are less frequent.

Pancreatitis of varying severity, including fatal outcome, can develop in a patient at different stages of treatment and does not depend on whether the drug is used as monotherapy or in combination with other drugs, or on the degree of immunosuppression. When the drug is used in combination with didanosine or other drugs that have a toxic effect on the pancreas, the risk of developing pancreatitis increases. Lactic acidosis. Severe steatosis with hepatomegaly, including fatal cases, have been observed with the use of nucleoside analogues as monotherapy or in combination with other antiviral drugs, including Stavudine. When stavudine is used in combination with didanosine, the risk of impaired liver function increases significantly. Nausea, vomiting, abdominal pain, rapid breathing or shortness of breath, or muscle weakness may indicate the development of lactic acidosis.

Other side effects thrombocytopenia, hepatitis, liver dysfunction, asthenia, headache, insomnia, dizziness, dry mouth, decreased appetite, diarrhea, pancreatitis, increased activity of “liver” transaminases, hyperbilirubinemia, neutropenia, allergic reactions (skin rash, fever), arthralgia, myalgia, chills.

Redistribution of adipose tissue

Cases of redistribution/accumulation of adipose tissue (lipodystrophy/lipoatrophy) have been observed in patients receiving antiretroviral therapy, manifested by central obesity, increased adipose tissue in the dorsocervical region, decreased adipose tissue in the extremities and face, breast enlargement, and “cushingoid face”. In randomized comparative clinical studies, it was found that in patients who had not previously received antiretroviral therapy, lipodystrophy/lipoatrophy is more common during treatment with stavudine than when other nucleoside analogues (tenofovir or abacavir) are prescribed.

Muscle weakness

In rare cases, muscle weakness develops during treatment with stavudine. Its symptoms may be similar to the clinical signs of Guillain-Barré syndrome (including respiratory failure). Symptoms may persist or worsen after discontinuation of therapy.

Osteonecrosis

Cases of osteonecrosis have been reported in patients taking Stavudine, especially with long-term treatment with antiretroviral drugs. Factors such as corticosteroid treatment, alcohol abuse, severe immunosuppression, and obesity play an important role in the etiology of osteonecrosis.

Children in clinical studies, the side effects of the drug in children and adult patients were similar. The development of peripheral neuropathy in children was observed less frequently than in adults. However, the symptoms of peripheral neuropathy were more difficult to detect in children.

Contraindications

• Hypersensitivity to stavudine and/or any of the excipients of the drug;
• Children weighing less than 30 kg;
• Chronic renal failure (CRF) with CC less than 50 ml/min;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

Alcoholism, chronic renal failure, hepatic failure, peripheral neuropathy, use in combination with didanosine, pancreatitis.

Use in Pregnancy and Lactation

Vudistav should be used during pregnancy only if there are strict indications and only in cases where the potential benefit of treatment for the mother outweighs the possible risk to the fetus. Animal studies have shown that Stavudine and/or its metabolites cross the placenta. It is not known whether the drug passes into breast milk. Breastfeeding should not be done during treatment with the drug.

Use in Hepatic Impairment

Caution should be exercised in patients with hepatic insufficiency.

Use in Renal Impairment

The drug is contraindicated in patients with chronic renal failure (CRF) with creatinine clearance less than 50 ml/min.

Pediatric Use

The use of the drug is contraindicated in children weighing less than 30 kg.

Special Precautions

The drug should be used with caution in patients at increased risk of developing peripheral neuropathy, with progressive HIV infection, with a history of peripheral neuropathy, as well as when used in combination with didanosine. Numbness, tingling, or pain in the extremities may indicate the development of peripheral neuropathy, which may disappear immediately after discontinuation of the drug. If these symptoms occur, treatment with the drug should be temporarily discontinued. Treatment with the drug can be resumed only after the symptoms have completely disappeared. It may be necessary to reduce the dose to half the recommended dose. The drug should be used with caution in patients at increased risk of developing pancreatitis, with progressive HIV infection, when prescribed simultaneously with didanosine. If symptoms of pancreatitis appear, treatment with the drug should be suspended. When re-prescribing the drug, simultaneous use of didanosine and hydroxyurea should be excluded. Regardless of whether the drug Vudistav is used as monotherapy or in combination with other drugs, biochemical parameters of liver function may increase. To detect the development of pancreatitis early, pancreatic function should be checked more frequently.

During therapy, constant medical monitoring of liver and kidney function is carried out. The severity of lipodystrophy in patients taking Stavudine decreases when they are switched to treatment with tenofovir or abacavir; however, the clinical manifestations of lipoatrophy do not decrease. In each specific case, the ratio of the risk of developing lipodystrophy/lipoatrophy and the benefit of treatment with stavudine-containing regimens should be taken into account; if the risk is high, the use of alternative treatment regimens should be considered. Careful monitoring of symptoms of lipodystrophy/lipoatrophy is necessary in all patients taking Stavudine.

Effect on ability to drive vehicles and mechanisms

Not studied.

Overdose

Peripheral neuropathy and impaired liver function.

Treatment symptomatic. Stavudine is removed by hemodialysis (removal rate is 120±18 ml/min). Peritoneal dialysis is not effective.

Drug Interactions

Vudistav is not recommended to be used simultaneously with the drug zidovudine. The conversion of stavudine to the active metabolite is reduced in the presence of zidovudine.

Concomitantly taken didanosine, lamivudine or nelfinavir do not affect the effectiveness of the drug Vudistav. The risk of side effects of the drug Vudistav increases with simultaneous use with didanosine.

Stavudine is almost not bound to blood proteins, which indicates a low likelihood of drug interactions involving the displacement mechanism from binding sites.

Concomitant use of drugs that cause peripheral neurological disorders (chloramphenicol, cisplatin, dapsone, ethambutol, ethionamide, hydralazine, isoniazid, lithium, metronidazole, nitrofurantoin, phenytoin, vincristine, zalcitabine) is not recommended.

Storage Conditions

Store in a dry place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.