Actastav (Capsules) Instructions for Use

ATC Code

J05AF04 (Stavudine)

Active Substance

Stavudine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Stavudine (2′,3′-didehydro-3′-deoxythymidine) 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 viral DNA chain termination 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.

Pharmacokinetics

Adults.

Stavudine is rapidly absorbed after oral administration. The absolute bioavailability is approximately 86.4%. After a single oral dose, the C_max of the drug in plasma is observed in less than 1 hour. C_max values increase proportionally with increasing drug doses. No accumulation of stavudine is observed when administered every 6, 8, or 12 hours. Administration of the drug after or during meals does not have a significant effect on pharmacokinetics.

The apparent V_d after a single dose averages 66 L and is independent of dose. The drug is equally distributed 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 was 63 ng/ml (mean 44-71 ng/ml) over 4-5 hours. The ratio of cerebrospinal fluid concentration to plasma concentration is about 40% (mean 31-45%).

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 during the excretion of stavudine by the kidneys 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 the cerebrospinal fluid 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 by the kidneys unchanged.

In case of impaired renal function, the clearance of stavudine decreases. Dose adjustment is recommended.

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 HIV protease inhibitors).

ICD codes

Dosage Regimen

Capsules

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

Adults and children over 12 years old.

^ausual dose, no dose adjustment required.

^bpatients after a hemodialysis session are recommended to take the daily dose of the drug. On days when dialysis is not performed, the drug should be taken at the same time as on hemodialysis days.

Children with impaired renal function. There are no precise recommendations for adjusting the drug dose 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 severe 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 symmetrical 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 using the drug in combination with didanosine or other drugs that have a toxic effect on the pancreas, the risk of developing pancreatitis increases.

Lactic acidosis. Severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues as monotherapy or in combination with other antiviral drugs, including Stavudine. When using stavudine in combination with didanosine, the risk of impaired liver function increases significantly. Nausea, vomiting, abdominal pain, rapid breathing or shortness of breath, and 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.

In clinical studies, the side effects of the drug in children and adults 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 under 3 months of age.

With caution alcoholism, chronic renal failure (CrCl less than 50 ml/min), hepatic insufficiency, peripheral neuropathy, use in combination with didanosine, pancreatitis.

Use in Pregnancy and Lactation

Use during pregnancy is only possible if the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in chronic renal failure (creatinine clearance less than 50 ml/min).

Pediatric Use

The drug is contraindicated in children under 3 months.

There are no precise recommendations for adjusting the drug dose in children. A dose reduction and/or an increase in the interval between doses of the drug is possible.

Special Precautions

The drug should be used with caution in patients with an 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 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 with an 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 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.

Overdose

Symptoms peripheral neuropathy and impaired liver function.

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

Drug Interactions

Stavudine is not recommended to be used simultaneously with zidovudine. The conversion of stavudine to the active metabolite is reduced in the presence of zidovudine; the phosphorylation of stavudine is also slowed down in the presence of doxorubicin and ribavirin.

Concomitantly taken didanosine, lamivudine or nelfinavir do not affect the efficacy of the drug. The risk of side effects 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, light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date printed on the package.

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.