Stavudine (Stavudin)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceStavudineStavudine
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    • Dosage form: & nbspcapsules
    Composition:
    1 capsule
    active substance: stavudine 30 mg or 40 mg;
    auxiliary substances: lactose monohydrate, crospovidone, microcrystalline cellulose, magnesium stearate;
    excipients for hard gelatin capsules No. 3 (for a dosage of 30 mg): gelatin, titanium dioxide, methyl parahydroxybenzoate, propyl parahydroxybenzoate;
    auxiliary substances for capsules of hard gelatinous No. 1 (for dosage of 40 mg): gelatin, titanium dioxide, blue patented dye, methyl parahydroxybenzoate, propyl parahydroxybenzoate.

    Description:
    Capsules number 3 with a body and a lid of white color (for a dosage of 30 mg); Capsule number 1 with a body and a lid of blue color (for a dosage of 40 mg). The contents of capsules are white or white powder with a yellowish tinge.

    Pharmacotherapeutic group:antiviral (HIV) agent
    ATX: & nbsp

    J.05.A.F   Nucleosides - reverse transcriptase inhibitors

    J.05.A.F.04   Stavudine

    Pharmacodynamics:
    Stavudine is an antiviral agent, a synthetic analogue of thymidine nucleoside.
    Suppress HIV replication in cultured human cells and in cell li-
    i
    in vitro. It is phosphorylated by cellular enzymes to its active form - stavudine triphosphate, which suppresses HIV reverse transcriptase activity by competition with the natural substrate with deoxythymidine triphosphate and disrupts HIV replication. Stavudine triphosphate also enhances the termination of viral DNA chains due to the lack of 3'-hydroxyl groups in the molecule required for DNA construction, inhibits cellular DNA polymerase γ, and decreases the synthesis of mitochondrial DNA.
    The use of stavudine in combination therapy leads to an increase in the number of SP4 + lymphocytes, which is caused by a decrease in the activity of human immunodeficiency virus (HIV), a decrease in the concentration of HIV RNA.

    Pharmacokinetics:
    Adults. Absorption at ingestion - fast and complete. The time to reach the maximum concentration (TCmax) after repeated administration in doses of 0.5 mg / kg is observed in less than 1 hour, the C max values ​​increase in proportion to the increase in doses of the preparation and is about 810 ng / ml. Bioavailability is 78-86%.The values ​​of Stax increase in proportion to the increase in the dose of the drug. Stavudine cumulation at its application every 6, 8 or 12 h is not observed. The use of the drug after or before meals does not have a significant effect on the pharmacokinetics - the areas under the concentration-time curve (AUC) of stavudine in HIV-infected patients without symptoms did not differ from the time of ingestion. A small part is associated with plasma proteins, about half - with the shaped elements of the blood. Apparent volume of distribution after a single intake is about 66 liters. It penetrates the blood-brain barrier and is defined in the cerebrospinal fluid (CSF). After a single dose of stavudine, at a dose of 40 mg, its concentration in the CSF of healthy volunteers averaged 63 ng / ml (45-70 ng / ml) for 4-5 hours. The concentration of d4T in CSF averaged 40% (31-45 %) of the concentration in the blood plasma. After a single or multiple davudine administration, 34 ± 5% and 40 ± 12% of unchanged stavudine, respectively, were detected in the urine. Inside the cell, it is phosphorylated to stavudine triphosphate, an active substrate for HIV reverse transcriptase.
    LSR-006943 / 10-210710
    The half-life (Ti / 2) in adults is 1.44 hours and is dose independent. Renal clearance is about 40% of the total clearance and almost 2 times higher than the endogenous creatinine clearance, which indicates active tubular-secretion when d4T is excreted through the kidney along with glomerular filtration. There was a decrease in clearance of stavudine with a decrease in creatinine clearance. Dose correction is recommended in patients with impaired renal function. If the liver function is disturbed, the pharmacokinetics is similar to that in healthy patients (dosage adjustment is not required). The pharmacokinetics of the drug in patients older than 65 years has not been studied.
    Children. Absolute bioavailability of the drug in HIV-infected children averages about 77%. Pharmacokinetics after a single dose of the drug is similar to the pharmacokinetics in adults and does not depend on the dose. Pharmacokinetics after a single administration of the drug is similar to pharmacokinetics in repeated administration, which indicates the absence of cumulation of stavudine. Concentration of the drug in CSF after a single and multiple oral intake is from 16 to 125% of the concentration in the blood plasma. Cumulation of stavudine with a dose of 0.125-2 mg / kg every 12 hours is not observed. T1 / 2 is an average of 1 hour.About 35% of the drug is excreted through the kidneys unchanged. The apparent overall clearance of the drug is 14 ml / min / kg. With dysfunction of the kidneys, the clearance of stavudine decreases; correction of the dosing regimen is recommended.

    Indications:
    HIV infection (as part of combination therapy).

    Contraindications:
    Hypersensitivity to stavudine and / or any of the components of the drug, children with a body weight of less than 30 kg, chronic renal failure (CRF) with creatinine clearance less than 50 ml / min, concomitant use with hydroxycarbamide, zidovudine.
    Due to the presence of lactose in the composition: lactase deficiency, lactose intolerance, glucose-galactase malabsorption.

    Carefully:
    Alcoholism; CRF (KK more than 50 ml / min); violation of liver function, including liver failure, chronic active hepatitis in the active stages; peripheral neuropathy, incl. in the anamnesis; pancreatitis; simultaneous reception with doxorubicin and ribavirin.

    Pregnancy and lactation:
    Adequate and well-controlled studies of stavudine in pregnant women have not been conducted. Reported cases of lactic acidosis in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents.
    The use of the drug in combination therapy during pregnancy is possible only if there are strict indications and only if the intended benefit for the mother exceeds the potential risk to the fetus. Patients receiving stavudine during pregnancy, should be under close supervision in connection with the possible development of lactic acidosis and steatosis of the liver.
    There are no data on the penetration of stavudine into breast milk. In connection with the inability to exclude the risk of transmission of infection and the possibility of developing side effects of the drug in the child during treatment with the drug, during lactation breastfeeding should be discontinued.

    Dosing and Administration:
    Inside, regardless of food intake. The dose of the drug depends on the body weight. If swallowing capsules is difficult, you should gently open the capsule and take its contents with a small amount of food.
    Adults and children with a body weight> 60 kg - 40 mg every 12 hours, adults and children weighing not less than 30 kg and not more than 60 kg - 30 mg every 12 hours.
    The course of treatment is long.
    In adult patients with CRF with CK more than 50 ml / min and with a body weight> 60 kg - 40 mg 2 times a day with an interval of 12 hours; At JS more than 50 ml / min and body weight less than 60 kg - 30 mg 2 times a day with an interval of 12 h, i.е.the usual dose, correction of it is not required. Exact recommendations for children with impaired renal function are absent. For children with chronic renal failure, stavudine in the form of a solution for oral administration.

    Side effects:
    Side effects, which are often observed with the use of various therapeutic regimens, including stavudine: peripheral neuropathy *, lactic acidosis, pancreatitis, hepatitis, hepatic insufficiency.
    The following are the side effects of stavudine in combination therapy, distributed in frequency: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000).
    Stavudine +lamivudine+ Efavirenz:
    From the endocrine system: infrequently - gynecomastia.
    On the part of the digestive system: often - diarrhea, abdominal pain, nausea, dyspepsia; infrequently - pancreatitis, vomiting, hepatitis, jaundice.
    Metabolic disorders: often - lipoatrophy, lipodystrophy; infrequently - lactic acidosis (sometimes with muscle weakness), anorexia.
    From the musculoskeletal system: infrequently - arthralgia, myalgia.
    From the nervous system: often - depression, peripheral neuropathy,paresthesia, peripheral neuritis, dizziness, pathological dreams, headache, insomnia, drowsiness, pathological thoughts, anxiety, emotional lability.
    From the skin and subcutaneous tissue: often - rash, itching; infrequently - hives.
    The body as a whole: often - fatigue; infrequently, asthenia. Stavudinelamivudine+ indinavir:
    On the part of the digestive system: very often - diarrhea, nausea, vomiting.
    From the side of the nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis, headache.
    Stavudine +didanosine+ indinavir:
    On the part of the digestive system: very often - diarrhea, nausea, vomiting.
    From the side of the nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis.
    From the skin and subcutaneous tissue: very often - a rash. Postmarketing data for stavudine
    On the part of the blood system and hemopoiesis: the frequency is unknown - anemia, neutropenia, thrombocytopenia.
    Metabolic disorders: often - asymptomatic hyperlactatemia; frequency is unknown - lactic acidosis.
    On the part of the endocrine system: the frequency is unknown - diabetes, hyperglycemia.
    From the liver: the frequency is unknown - steatosis of the liver, hepatitis and liver failure.
    From the side of the nervous system: the frequency is unknown - a pronounced muscle weakness (most often with hyperlactatemia or lactic acidosis).
    Changes in laboratory parameters with combined therapy with other drugs:
    Stavudine +lamivudine+ indinavir:
    Increased bilirubin concentration> 2.6 x VGN (upper limit of normal) (7%); an increase in activity of aspartate aminotransferase (ACT)> 5 × HHV (5%), alanine-minotransferase (ALT)> 5 × HHV (6%), lipase> 2 × HNG (6%). Stavudinedidanosine+ indinavir:
    An increase in bilirubin concentration> 2.6 × VGN (16%), ACT activity> 5 × HHV (7%), ALT activity> 5 × HHV (8%), lipase activity> 2 × HHV (5%).
    Changes in laboratory indicators in patients receiving antiretroviral therapy for the first time:
    Stavudine +lamivudine+ efavirenz: increased activity of ACT> 5 x VGN (3%), ALT> 5 x VNG (3%), lipase> 2 x UGH (3%).
    ♦ The development of peripheral neuropathy in children was less common than in adults, but its symptoms are more difficult to detect in children.

    Overdose:
    Doses of the drug, 12 times the recommended daily dose, do not cause acute symptoms in adults.In chronic overdosage, peripheral neuropathy and impaired liver function can be noted. The clearance of stavudine in hemodialysis is 120 ml / min; the effectiveness of hemodialysis is unknown. In case of an overdose, it is necessary to observe the doctor and, if necessary, symptomatic treatment.

    Interaction:
    The study of the inhibitory activity of stavudine in combination with zidovudine showed that both drugs are phosphorylated by cellular thymidine kinase. The transformation of zidovudine into the active form occurs faster than the conversion of stavudine to the active metabolite stavudine triphosphate. In combination with zidovudine decreased antiviral effect, t. in the presence of zidovudine, the conversion of stavudine into an active metabolite decreases. In this regard, combined treatment with these drugs is not recommended.
    Phosphorylation of stavudine also slows down in the presence of doxorubicin and ribavirin.
    Stavudine practically does not bind to blood proteins, so it does not displace other drugs (LS) from the binding sites with the protein.
    Didanosine, lamivudine, nelfinavir do not affect the antiviral activity of stavudine.
    With simultaneous use with didanosine, the risk of side effects increases.
    Stavudine does not inhibit the main isoenzymes of cytochrome P450 (CYP3A4, CYP2D6, CYP2D9, CYP1A2, CYP2C19), so davudine interactions with drugs metabolized by these enzymes are unlikely.
    It is not recommended concomitant use of drugs that cause peripheral neurological disorders (chloramphenicol, cisplatin, dapsone, didanosine, ethambu-tol, ethionamide, hydralazine, isoniazid, lithium preparations, metronidazole, nitrofurantoin, phenytoin, vincristine, zalcitabine).

    Special instructions:
    The drug should be used with caution in patients with an increased risk of peripheral neuropathy and peripheral neuropathy in history, with progressive HIV infection. The risk of developing this effect increases with simultaneous use with didanosine. Feeling of numbness, tingling, or pain in the extremities can indicate the development of peripheral neuropathy. These symptoms may disappear immediately after discontinuation of the drug. If these symptoms occur, you should temporarily stop treatment with the drug.Resumption of treatment with the drug can only be after complete disappearance of symptoms. You may need to adjust the dose of the drug. In addition to the dose of the drug, the frequency of these phenomena depends and / or the stage of the disease (in the early stages are recorded less frequently). Sometimes after the withdrawal of treatment signs of neuropathy do not disappear, but, on the contrary, temporarily amplified.
    The drug should be used with caution in patients with an increased risk of pancreatitis. The risk of recurrence is elevated in patients with pancreatitis in the anamnesis. Pancreatitis of varying severity, including cases with a fatal outcome, can develop at different stages of treatment, regardless of the degree of immunosuppression. When symptoms of pancreatitis appear, drug treatment should be discontinued. For the purpose of early detection of the development of pancreatitis, it is often necessary to check the function of the pancreas.
    When using the drug, biochemical indicators of liver function may worsen. Lactate acidosis and severe liver steatosis with hepatomegaly, including fatal cases, are noted when nucleoside analogues are used in combination with other antiretroviral drugs.With the use of stavudine in combination with didanosine, the risk of liver dysfunction significantly increases. Often manifested in women. A special group of risk is represented by pregnant women. Redistribution of adipose tissue - atrophy of subcutaneous fat in the face (around the eyes, temples), limbs and buttocks, excess visceral fat, also on the neck and occiput, in muscles and liver, the increase in mammary glands is observed in the first months of therapy.
    The immune reactivation syndrome is manifested by the exacerbation of sluggish infections and activation of the opportunistic flora and is also observed at the initial stage of treatment.
    Children: in clinical trials, 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:
    Muscular weakness: in rare cases, dyshine muscle weakness develops with stavudine. Its symptoms may be similar to the clinical symptoms of Guillain-Barre syndrome (including respiratory failure). Symptoms may persist or worsen after discontinuation of therapy.
    Osteonecrosis: cases of osteonecrosis were noted in patients taking stavudine, especially with prolonged treatment with antiretroviral drugs. An important role in the etiology of osteonecrosis is played by factors such as previous treatment with glucocorticosteroids, alcohol abuse, severe immunosuppression, obesity.
    Mitochondrial dysfunction: In vitro and in vivo studies, the ability of nucleotide and nucleoside analogues to cause damage to mitochondria of different degrees is revealed. There are reports of mitochondrial dysfunction in HIV-negative children who underwent the treatment of nucleoside analogues in utero or immediately after birth. The main manifestations of mitochondrial dysfunction were anemia, neutropenia, hyperlactatemia and increased lipase activity in blood plasma. There were also later manifestations of this disorder: hypertonicity of skeletal muscles, convulsions, behavioral anomalies.

    Effect on the ability to drive transp. cf. and fur:
    The effect of the drug on the ability to drive and work with machinery has not been studied. If, on the background of treatment, the patient observes symptoms such as dizziness and visual disturbances that affect his ability to concentrate and the speed of the reaction,it is recommended to abandon the management of a car and to carry out potentially dangerous activities requiring an increased concentration of attention and speed of psychomotor reactions.

    Form release / dosage:

    Capsules 30 mg, 40 mg.

    By 7, 8, 10, 14, 28 capsules in the contour cell pack of film polyvinylchloride and aluminum foil printed lacquered.

    By 56.112 or 224 capsules in a polymer or glass jar.

    According to 1, 2, 3, 4, 5, 6, 7, 8 contour mesh packs or 1 bank together with instructions for use are placed in a pack of cardboard.

    Packaging:

    By 7, 8, 10, 14, 28 capsules in the contour cell pack of film polyvinylchloride and aluminum foil printed lacquered.

    By 56.112 or 224 capsules in a polymer or glass jar.

    According to 1, 2, 3, 4, 5, 6, 7, 8 contour mesh packs or 1 bank together with instructions for use are placed in a pack of cardboard.

    Storage conditions:
    In a dry, protected from light place at a temperature of no higher than 25 ° C.
    Keep out of the reach of children.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-006943/10
    Date of registration:21/07/2010
    The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCRussia
    Information update date: & nbsp19.08.2015
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