Stavudine - instructions for use, dose, side effects, contraindications

Lactose - 138.0 mg / 138.0 mg; corn starch - 132.0 mg / 130.0 mg; carboxymethyl starch sodium (primogel) - 26.0 mg / 26.0 mg; sodium lauryl sulfate - 1.4 mg / 1.4 mg; silicon dioxide colloid (aerosil brand A-300) - 7.0 mg / 7.0 mg; magnesium stearate - 3.4 mg / 3.4 mg; talc - 2.2 mg / 2.2 mg.

The composition of hard gelatin capsules:

For the dosage of 30 mg:

titanium dioxide - from 1.65% to 2.0%, dye sunset yellow E 110 - 0.47%, gelatin - up to 100%.

For a dosage of 40 mg:

titanium dioxide - from 1% to 2%, azorubin E 122 -0.19%, dye quinoline yellow E 104 - 0.37%, gelatin - up to 100%.

Description:

For the dosage of 30 mg:

hard gelatin capsules № 0 capsule body white, cap capsule orange.

For a dosage of 40 mg:

hard gelatin capsules No. 0 capsule body white, cap capsule red.

The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:antiviral (HIV) agent

ATX: & nbsp

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

J.05.A.F.04 Stavudine

Pharmacodynamics:

The use of stavudine in combination antiretroviral therapy leads to an increase in the number of CD + lymphocytes and a decrease in the concentration of HIV RNA in the blood plasma. Viral suppression is longer with combination therapy with three antiretroviral drugs compared to combination therapy with two drugs.

Mechanism of action

Stavudine is an antiviral. Synthetic analogue of thymidine nucleoside, suppresses replication of HIV in cultured human cells and in cell lines in vitro. After entering the cage stavudine under the action of cellular enzymes is converted into an active metabolite of stavudine triphosphate, which suppresses the activity of HIV reverse transcriptase due to competition with the natural substrate of dioxytimidine triphosphate and disrupts the replication of HIV.Due to the absence of 3'-hydroxyl groups in the molecule necessary for DNA construction, stavudine triphosphate inhibits the synthesis of viral DNA. Along with the reverse transcriptase, the cellular DNA polymerase y is also sensitive to the inhibition of stavudine by triphosphate, while the amount of stavudine required to inhibit cellular DNA polymerases a and β is 4,000 and 40 times, respectively, exceeding the amount of stavudine resulting in inhibition of reverse transcriptase The study of the inhibitory activity of stavudine in combination with zidovudine in vitro has shown that both drugs are phosphorylated by cellular thymidine kinase, but the conversion of zidovudine to the active form occurs rapidly her than the conversion of stavudine to stavudine triphosphate .. Given this, combined treatment with stavudine and zidovudine is not recommended.

Resistance and cross-resistance

The sensitivity to stavudine was studied on the culture of cells isolated from patients receiving stavudine therapy. A decrease in sensitivity to stavudine after a prolonged course of treatment has been identified; several cases of multiple resistance to nucleoside analogues have been found.There have also been cases of cross-resistance to reverse transcriptase inhibitors. So, long-term treatment with stavudine can induce or maintain resistance to zidovudine.

In the presence of mutations of the HIV-1 gene (especially M41L and T215Y) as a result of treatment with nucleoside analogs, stavudine is not recommended.

Pharmacokinetics:

Adults

Stavudine is rapidly absorbed when taken orally. Absolute bioavailability is about 86.4%. After a single dose, the maximum concentration of the drug in the blood plasma (Cmax) is observed in less than 1 hour. The Cmax values increase in proportion to the increase in drug doses. Cumulation of stavudine in its application every 6, 8 or 12 hours was not observed.

The pharmacokinetics of stavudine in patients with HIV without clinical manifestations taking the drug after or during a meal with a high fat content or fasting did not noticeably change.

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

Stabudine metabolism in the human body remains unexplored. After oral administration, the half-life of the drug is 1.44 hours and is dose independent.

After oral administration, the half-life of the drug is 1.44 hours and is dose independent. Kidney clearance is 40% of the total clearance and almost twice the clearance of endogenous creatinine, which indicates active tubular secretion when d4T is released through the kidneys along with glomerular filtration. Children

Absolute bioavailability of stavudine in children is an average of 76.9%. Pharmacokinetics after a single dose of the drug is similar to that in adults and does not depend on the dose. After a single and multiple intake of the drug concentration in the CSF are from 16 to 125% with respect to the concentration in the blood plasma.Cumulation of stavudine in doses of 0.125 to 2 mg / kg every 12 hours is not observed. Half-life is an average of 1 hour. About 34.5% of the drug is excreted through the kidneys unchanged.

Elderly patients

Pharmacokinetics in patients older than 65 years has not been studied.

Impaired renal function

If the kidney function is impaired, the stavudine clearance is reduced. A dose adjustment is recommended (see Dosage and Administration).

Impaired liver function

Disturbance of liver function does not significantly affect the pharmacokinetics of stavudine. Patients with a dysfunction of the liver do not need a dose adjustment.

Indications:

Treatment of HIV infection in adults and children older than 3 years and with a body weight of more than 30 kg in combination antiretroviral therapy.

Contraindications:

Hypersensitivity to stavudine or any other component of the drug. Children under 3 years of age and weighing less than 30 kg.

Simultaneous use with zidovudine.

Simultaneous use with hydroxycarbamide.

Impaired renal function with creatinine clearance less than 50 ml / min.

It is not recommended to take patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome, since the preparation contains lactose.

Carefully:

Alcoholism, chronic renal failure (with a creatinine clearance of more than 50 ml / min), impaired liver function, incl. hepatitis in the active stage, peripheral neuropathy, pancreatitis, simultaneous administration with didanosine, diabetes mellitus, combined use with ribavirin, doxorubicin.

Pregnancy and lactation:Use stavudine during pregnancy should only be in the presence of strict indications and only in those cases when the potential benefit of treatment outweighs the possible risk. Studies in animals have shown that stavudine and / or its metabolites pass through the placenta. It is not known whether stavudine with breast milk. It is not recommended to breast-feed HIV-infected mothers receiving stavudine therapy

Dosing and Administration:

Inside. The time of taking the drug does not depend on the time of eating. The dose of the drug depends on the body weight.

Body mass Doses

> 60 kg 40 mg every 12 hours

> 30 kg <60 kg 30 mg every 12 hours

If swallowing capsules is difficult, you should gently open the capsule and take the contents with a small amount of food.

Adults with impaired renal function

When the creatinine clearance is more than 50 ml / min, no dose adjustment is required.

For patients weighing less than 60 kg, the drug is given in a dose of 30 mg every 12 hours; with a body weight of 60 kg and more - in a dose of 40 mg every 12 hours.

Children with impaired renal function

Precise recommendations for adjusting the dose of the drug in children are absent. It is possible to reduce the dose and / or increase the interval between doses of the drug.

Application for violations of liver function

With a stable condition of patients with hepatic insufficiency, dose adjustment is not required. With a rapid increase in aminotransferase activity, zidovudine treatment should be temporarily discontinued.

Side effects:

Side effects, which are often observed when using various therapeutic regimens including stavudine: peripheral neuropathy, lactic acidosis, pancreatitis, hepatitis, hepatic failure,

lipoatrophy / lipodystrophy.

Peripheral neuropathy / peripheral neurologic symptoms

When applying the scheme stavudine + lamivudine + efavirenz frequency of peripheral

neurologic symptoms was 19%.

Pancreatitis

Pancreatitis, sometimes fatal, was noted in more than 1% of patients who received stavudine in combination antiretroviral therapy.

Lactic acidosis

Cases of lactic acidosis, sometimes with a fatal outcome, were observed with the use of nucleoside analogues.

Muscular weakness was observed in rare cases with stavudine in combination antiretroviral therapy.

Hepatitis or liver failure, sometimes fatal, have been observed with stavudine and other nucleoside analogues. Lipoatrophy / lipodystrophy

The cases of lipoatrophy / lipodystrophy were noted with the use of stavudine and other nucleoside analogues.

Below is the frequency of adverse reactions with stavudine in accordance with generally accepted classification: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10,000, <1/1000), very rarely (<1/10000).

Staudin + 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 side of the musculoskeletal system: infrequently, arthralgia, myalgia.

From the nervous system: often - depression, peripheral neuropathy, paresthesia, peripheral neuritis, dizziness, "unusual" dreams, headache, insomnia, drowsiness, "unusual" thoughts, anxiety, emotional lability.

From the skin and subcutaneous fat: often - a rash, itching; infrequently - hives.

The body as a whole: often - fatigue, infrequently - asthenia, allergic reactions.

Staudin + lamivudine + indinavir

On the part of the digestive system: very often - diarrhea, nausea, vomiting, flatulence, dryness of the oral mucosa, increased appetite, gastritis, constipation.

From the side of the nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis, headache.

From the skin and subcutaneous fat: very often - a rash.

Staudin + 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 fat: very often - a rash.

Post-pancharketing data on the side effects registered with the administration of stavudine

On the part of the blood system and hematopoiesis: the frequency is unknown - macrocytosis, anemia, neutropenia, thrombocytopenia.

Metabolic disorders: often - asymptomatic hyperlactatemia; frequency unknown - lactic acidosis, lipoatrophy, lipodystrophy.

On the part of the endocrine system: the frequency is unknown - diabetes, hyperglycemia.

On the part of the liver and bile ducts, the frequency is unknown - fatty liver disease (steatosis), 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 recorded with combined therapy of stavudine with other drugs

Combined therapy stanovu din + lamivudine + indinavir:

bilirubin> 2.6 x VGN (upper limit of normal) (7%); aspartate aminotransferase> 5 x VGN (5%); alanine aminotransferase> 5 x VGN (6%); lipase> 2 × VGN (6%), gamma-glutamyl transpeptidase> 5 × VGN (2%); amylase> 2 x VGN (4%).

Combination Therapy stavudine + didanosine + indinavir: bilirubin> 2.6 x VGN (16%); aspartate aminotransferase> 5 x VGN (7%); alanine aminotransferase> 5 x VGN (8%); lipase> 2 × VGN (5%), gamma-glutamyl transpeptidase> 5 × VGN (5%); amylase> 2 x VGN (8%).

Changes in laboratory indicators recorded in patients receiving antiretroviral therapy for the first time

Combination Therapy stavudine + lamivudine + efavirenz: aspartate aminotransferase> 5 x VGN (3%); alanine aminotransferase> 5 x VGN (3%); lipase> 2 x VGN (3%), neutropenia (ANC <750 / mm3) (5%), anemia (hemoglobin <80%) (less than 1%), thrombocytopenia (platelets <50,000 / mm)

(2%).

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 less common than in adults. However, the symptoms of peripheral neuropathy in children are more difficult to identify.

Overdose:

Symptoms: Peripheral neuropathy and impaired liver function.

Treatment: symptomatic. Stavudine is removed during hemodialysis (the rate of excretion is 120 ± 18 ml / min). Peritoneal dialysis is not effective.

Interaction:

Stavudine is not recommended to be used concurrently with zidovudine, since

zidovudine can completely inhibit intracellular phosphorylation

stavudine.

Caution should be exercised while using stavudine with doxorubicin and ribavirin, since doxorubicin and ribavirin in in vitro conditions also inhibit stavudine phosphorylation.

Simultaneously accepted didanosine, lamivudine or nelfinavir do not affect the effectiveness of stavudine. The risk of side effects of stavudine increases with simultaneous use with didanosine.

Stavudine almost does not bind to blood plasma proteins, which indicates a low probability of drug interactions involving the mechanism of displacement from the binding sites.

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

It is not recommended to apply simultaneously stavudine and hydroxycarbamide in connection with an increased risk of toxic effects (pancreatitis, peripheral neuropathy, hepatotoxicity).

Special instructions:

Peripheral Neuropathy

Stavudine should be used with caution in patients with an increased risk of developing peripheral neuropathy and peripheral neuropathy in the anamnesis.

Peripheral neuropathy is a serious, dose-dependent side effect of stavudine therapy, observed in patients with progressive HIV infection, with a history of peripheral neuropathy, and with simultaneous use with neurotoxic drugs, including didanosine. Cases of peripheral neuropathy, sometimes severe, were observed in HIV-infected patients who received hydroxycarbamide in combination with antiretroviral drugs, including didanosine and / or stavudine. Patients should be carefully monitored to detect such signs of peripheral neuropathy as a feeling of numbness of the limbs, tingling and pain in the soles of the feet and hands. If these symptoms appear, stop stavudine immediately. Usually, with the timely cessation of therapy, the symptoms of peripheral neuropathy disappear, in which case the treatment can be resumed. Sometimes after the abolition of stavudine therapy, the symptoms of neuropathy do not disappear, but, on the contrary, temporarily intensify.

Pancreatitis

The development of pancreatitis is usually associated with the progression of the disease or with the use of drugs (prior to the appointment of davudine or simultaneously with it), which can cause this side effect.The frequency of pancreatitis does not depend on the dose. In rare cases, there was a lethal outcome. The risk of developing this complication was increased in patients with pancreatitis in history: pancreatitis in stavudine was observed in 5% of patients with pancreatitis in the history and 2% - without pancreatitis in the anamnesis.

Pancreatitis of varying severity, up to a lethal outcome, was registered in patients receiving combinations of drugs: stavudine + didanosine or stavudine + didanosine + hydroxycarbamide. When symptoms of pancreatitis appear, the combined treatment of stavudine with didanosine and other drugs that exert a toxic effect on the pancreas should be discontinued. Resumption of stavudine therapy after confirmation of the diagnosis of pancreatitis should be carried out with extreme caution, patients should be under careful medical supervision, the use of didanosine and hydroxycarbamide should be excluded.

Lactoacidosis, a severe form of steatosis with hepatomegaly, sometimes with a fatal outcome, as with other nucleoside analogues, was rarely noted in the treatment of stavudine.Risk factors are female sex, obesity and long-term use of nucleoside analogues. Lactic acidosis with a fatal outcome was registered in a pregnant woman with stavudine and didanosine in combination with other antiretroviral drugs. Stavudine should be used with extreme caution in patients with an increased risk of developing violations of the liver. Signs of development of symptomatic hyperlactatemia or lactic acidosis can be general weakness, sudden unexplained weight loss, symptoms on the part of the digestive system (nausea, vomiting, pain in the abdominal area), symptoms from the respiratory system (rapid breathing or shortness of breath), muscle weakness. In case of clinical or laboratory signs of lactic acidosis or liver dysfunction, stavudine should be discontinued.

Dysfunction of the liver: hepatitis and liver failure, sometimes with a fatal outcome, were observed in patients who received stavudine. Hepatotoxicity and hepatic insufficiency, in some cases with a fatal outcome, were observed in patients receiving antiretroviral drugs in combination with hydroxycarbamide.Most lethal cases were noted with combined therapy with hydroxycarbamide, didanosine and stavudine, therefore, the use of this scheme should be avoided. When using a combination of antiretroviral drugs, as well as when administering stavudine, patients with liver disease should be closely monitored for such patients; If signs of impaired liver function appear, consideration should be given to the possibility of reversing therapy.

Dysfunction of the kidneys: clearance of stavudine decreases with a decrease in creatinine clearance, so the dose of the drug in patients with impaired renal function (with a clearance of creatinine <50 ml / min) should be corrected.

Redistribution of subcutaneous fat

In some patients receiving combined antiretroviral therapy, there were cases of redistribution / accumulation of subcutaneous fat (lipodystrophy / lipoatrophy), which manifested itself as obesity of the central type, an increase in fatty tissue in the dorso-cervical region ("buffalo buffalo"), a decrease in the amount of adipose tissue in the region face and limbs, hypertrophy mammary glands and "cushingoid appearance." AT

randomized comparative clinical trials revealed that lipodystrophy / lipoatrophy is more common in patients with stavudine in patients who have not previously received antiretroviral therapy than with other nucleoside analogues (tenofovir or abacavir). These phenomena are cumulative, intensifying with the duration of stavudine. The severity of lipodystrophy in patients taking stavudine, decreases when transferring them to therapy with tenofovir or abacavir, however, the clinical manifestations of lipoatrophy do not decrease. In each case, the risk ratio of lipodystrophy / lipoatrophy and the benefits of stavudine-containing regimens should be considered. If the risk of developing lipodystrophy / lipoatrophy is high, consideration should be given to the use of alternative treatment regimens. A thorough monitoring of the symptoms of lipodystrophy / lipoatrophy in all patients receiving stavudine.

Muscle weakness

In rare cases, the treatment with stavudine develops muscle weakness. Its symptoms may be similar to the clinical signs of Guillain-Barre syndrome (including respiratoryfailure). Symptoms may persist or worsen after the abolition of stavudine 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 corticosteroid treatment, alcohol abuse, severe immunosuppression, obesity.

Mitochondrial dysfunction

In vitro and in vivo conditions, the ability of nucleotide and nucleoside analogues to cause damage to mitochondria of various degrees was revealed. There are reports of mitochondrial dysfunction in HIV-negative children who have been exposed to nucleoside analogues in utero or immediately after birth. The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, hyperlactatemia and increased lipase activity in blood plasma. There were also later manifestations of this violation: hypertonicity

musculature, convulsions, behavioral anomalies.

Patients over 65 years of age

It should be carefully monitored for elderly patients with stavudine, since they represent a group at increased risk of developing peripheral neuropathy.In addition, this age group has, on average, a higher incidence of renal dysfunction, which should be considered when administering stavudine.

The immune reconstitution syndrome was noted in patients receiving combined antiretroviral therapy, including the administration of stavudine. Care should be taken to monitor the patient's condition in order to detect inflammatory diseases and treat them in a timely manner. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

Patients infected with both HIV and hepatitis C virus

Hepatic insufficiency (sometimes fatal) cases have been reported in patients infected with HIV-1 with concomitant hepatitis C who are receiving antiretroviral drugs and interferon alfa with ribavirin or without ribavirin. With simultaneous use of stavudine and interferon alfa with ribavirin or without ribavirin, care should be taken and careful clinical monitoringfor signs of toxicity, especially liver failure, neutropenia and anemia. If clinical manifestations of toxicity progress, dosage should be reduced or canceled interferon alfa, ribavirin or both.

Effect on the ability to drive transp. cf. and fur:

Special studies to study the effect of the drug on the ability to drive a car and dangerous mechanisms have not been carried out. However, based on the pharmacological properties of stavudine, it can be assumed that it does not affect the ability to concentrate.

However, given the profile of side effects (dizziness, visual impairment), one should refrain from performing these activities.

Form release / dosage:

Capsules of 30 mg, 40 mg.

Primary packaging of medicinal product.

10 capsules per contour cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

By 28, 56, 60 or 100 capsules in a polymer jar with a lid tightened with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

Secondary packaging of medicinal product.

For 6 contour squares, together with the instruction for use, they are placed in a pack of cardboard for the consumer packaging of the subgroup chrome or chrome - ersatz or other similar quality. The packets are placed in a shipping container.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare of subgroups chrome or chrome-ersatz or other similar quality.

Packaging:

Primary packaging of medicinal product.

10 capsules per contour cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

Secondary packaging of medicinal product.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare of subgroups chrome or chrome-ersatz or other similar quality.

Storage conditions:

Store in the original packaging of the manufacturer at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002394

Date of registration:07.03.2014

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspFARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Information update date: & nbsp19.08.2015

Illustrated instructions

Instructions

Stavudine (Stavudin)