Composition, form of production and packaging
Capsules hard gelatinous, size 3, with a lid of dark red color and a case of bright yellow color; along the capsule marked "BMS 1964" and "15" in black; the contents of the capsules are white or white powder with a beige tint.
1 caps.
Stavudine 15 mg
Excipients: microcrystalline cellulose, sodium starch glycolate, anhydrous lactose, water lactose, magnesium stearate.
14 pcs. - blisters (4) - cardboard boxes.
Hard gelatin capsules, size 2, with lid and brown body; along the capsule marked "BMS 1965" and "20" in black; the contents of the capsules are white or white powder with a beige tint.
1 caps.
Stavudine 20 mg
Excipients: microcrystalline cellulose, sodium starch glycolate, water lactose, anhydrous lactose, magnesium stearate.
14 pcs. - blisters (4) - cardboard boxes.
Hard gelatin capsules, size 2, with a lid of dark orange color and a casing of light orange color, with black marking "BMS 1966" - on the lid and "30" on the body; the contents of capsules - powder from white to almost white, free from visible foreign impurities.
1 caps.
Stavudine 30 mg
Excipients: microcrystalline cellulose, anhydrous lactose, lactose monohydrate, sodium carboxymethyl starch, magnesium stearate.
The composition of the capsule shell: iron oxide red, iron oxide yellow, titanium dioxide, gelatin.
Ink composition: shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia, potassium hydroxide, iron oxide black, purified water.
14 pcs. - blisters (4) - cardboard boxes.
Capsules hard gelatinous, size 1, with lid and body dark orange color; with the black marking "BMS 1967" on the lid and "40" on the body; the content of capsules is a powder from white to almost white, free from visible foreign inclusions.
1 caps.
Stavudine 40 mg
Excipients: microcrystalline cellulose, anhydrous lactose, lactose monohydrate, sodium carboxymethyl starch, magnesium stearate.
The composition of the capsule shell: iron oxide red, iron oxide yellow, titanium dioxide, gelatin.
Ink composition: shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia, potassium hydroxide, iron oxide black, purified water.
14 pcs. - blisters (4) - cardboard boxes.
Powder for solution for oral administration from almost white to light pink color, crystalline, with no visible foreign inclusions; when dissolved in water, a cloudy, colloidal solution develops from colorless to slightly pink in color.
1 ml of finished r-ra
Stavudine 1 mg
Excipients: methylparahydroxybenzoate, propyl parahydroxybenzoate, sodium carmellose, trituration of defoamer in sucrose (sucrose, simethicone emulsion 30%), cherry pulverized dry flavor (FMC # 20194), sucrose.
The volume of the finished solution is 200 ml.
12.6 g - bottles of high-pressure polyethylene with a volume of 260 ml (1) complete with a measuring cap - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
An antiviral drug that is active against HIV.
The use of Zerit В® as a part of combination therapy leads to a decrease in the activity of the human immunodeficiency virus (HIV), preventing the replication of HIV RNA, which leads to an increase in the number of CD4 + cells. Viral suppression is longer for combination therapy with three drugs compared to combination therapy with two drugs.
Stavudine is a synthetic analogue of thymidine nucleoside, suppresses replication of HIV in cultured human cells. After entering the cell, 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 thymidine triphosphate. Due to the absence of 3'-hydroxyl groups in the molecule, which are necessary for the construction of DNA, stavudine triphosphate inhibits the synthesis of viral DNA. Along with reverse transcriptase, the cellular DNA polymerase? is also sensitive to inhibition of stavudine by triphosphate, while for inhibition of cellular DNA polymerases? and? the amounts of stavudine required, 4000 and 40 times (respectively) greater than the amount of d4T, leading to inhibition of reverse transcriptase.
The study of the inhibitory activity of stavudine in combination with zidovudine showed that both drugs are phosphorylated by cellular thymidine kinase. However, the conversion of zidovudine to the active form occurs faster than the conversion of stavudine to an active metabolite of stavudine triphosphate. In this regard, combined treatment with these drugs is not recommended.
Resistance and cross-resistance
The sensitivity to stavudine was studied on the culture of cells isolated from patients receiving stavudine. A decrease in sensitivity to stavudine after a prolonged course of treatment has been identified; several cases have been found, multiple resistance to nucleoside analogs. 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 the treatment with nucleoside analogs, stavudine is not recommended.
PHARMACOKINETICS
Suction
Stavudine is rapidly absorbed when taken orally. Absolute bioavailability is about 86.4%. Less than 1 hour after repeated administration of the drug at a dose of 0.5 mg / kg, Cmax in the blood plasma is about 810 ng / ml. The C max values ​​increase in proportion to the dose increase. A stavudine AUC in HIV patients without clinical manifestations did not differ depending on the intake on an empty stomach or after a meal.
Distribution
Cumulation of stavudine in its application every 6 hours, 8 hours or 12 hours was not observed.
The drug is equally distributed between red and white blood cells. Binding to blood proteins is negligible. After a single dose of stavudine at a dose of 40 mg, the concentration in the cerebrospinal fluid in healthy volunteers was 63 ng / ml (average 44-71 ng / ml) for 4-5 hours. The ratio of the concentration in the cerebrospinal fluid to the plasma concentration was about 40% (an average of 31-45%).
Metabolism and excretion
Metabolism plays a limited role in the clearance of stavudine. After a single or multiple davudine, 34 В± 5% and 40 В± 12% of unchanged stavudine were respectively detected in the urine. After taking 80 mg [ 14 C] - stavudine, the main component of the total plasma radioactivity was unchanged stavudine, while the metabolites accounted for a small part of the total radioactivity, respectively. In healthy volunteers, approximately 95% and 3% of radioactivity were detected in urine and feces. In urine, 73.7% of radioactive unchanged stavudine was found, and in feces - 62%. T 1/2 stavudine for single and multiple oral administration is 1.44-2.28 h and does not depend on the dose. Stdudine's renal clearance in unchanged form is approximately 272 ml / min, which corresponds to approximately 67% of apparent overall clearance. Kidney clearance is almost twice the clearance of endogenous creatinine, indicating active tubular secretion along with glomerular filtration.
Pharmacokinetics in special clinical cases
Pharmacokinetics in patients over the age of 65 years have not been studied.
With dysfunction of the kidneys, the clearance of stavudine decreases. Dose correction is recommended.
Pharmacokinetics of the drug has a similarity in patients with impaired and normal liver function. Patients with impaired liver function in a stable state are not required to adjust the initial dose of the drug.
Children
Suction
Absolute bioavailability of the drug in HIV-infected children aged 5 weeks to 15 years is an average of 76.9%. When taking doses of 0.125 -2 mg / kg every 12 h, the pharmacokinetic parameters after taking the first dose and with repeated administration are not different, which indicates the absence of cumulation of stavudine.Concentrations of the drug in the cerebrospinal fluid are 16-125% of the concentration in the blood plasma.
Distribution and deduction
T 1/2 is an average of 1 hour. The apparent overall clearance of the drug is 14 ml / min / kg.
INDICATIONS
- Treatment of HIV infection in combination therapy.
DOSING MODE
The drug is administered orally, regardless of food intake. If swallowing capsules is difficult, you should gently open the capsule and take the contents with a small amount of food. The dose of the drug depends on the body weight.
Adults
Body Weight Doses
? 60 kg 40 mg (or 40 ml r-ra d / ingestion) every 12 h
<60 kg 30 mg (or 30 ml r-ra d / ingestion) every 12 h
Children
Body Weight Doses
<30 kg 1 mg / kg every 12 hours
? 30 kg and <60 kg 30 mg (or 30 ml r-ra d / ingestion) every 12 hours
? 60 kg 40 mg (or 40 ml r-ra d / ingestion) every 12 h
Adults with impaired renal function are recommended to reduce the dose depending on the CK.
KK (ml / min) Dose depending on body weight
? 60 kg <60 kg
> 50 and 40 mg (or 40 ml of oral administration) every 12 hours 30 mg (or 30 ml of oral administration) every 12 hours
26-50 20 mg (or 20 ml of oral administration) every 12 hours 15 mg (or 15 ml of oral administration) every 12 hours
<25 b 20 mg (or 20 ml of oral administration) every 24 hours 15 mg (or 15 ml of oral administration) every 24 hours
a - the usual dose, dose adjustment is not required. Due to the fact that accurate dosage in the form of capsules with QC from 50 ml / min and below is not possible, these patients should be appointed Zerit В® powder for the preparation of a solution for oral administration.
b - patients after a hemodialysis session are advised to take a daily dose of the drug. On days when dialysis is not performed, the drug should be taken at the same hours as during the days of hemodialysis.
For children with impaired renal function, there are no precise recommendations for dose adjustment. It is possible to reduce the dose and / or increase the interval between doses of the drug.
With a stable condition of patients with hepatic insufficiency, dose adjustment is not required. With a rapid increase in aminotransferase activity during Zerit's treatment, therapy should be temporarily discontinued.
Rules for the preparation of oral solution
Add 202 ml of water to the contents of the vial and shake until completely dissolved. The prepared solution may slightly opalescent. The recovered volume of the solution in one bottle is 200 ml. The dose is measured by a measuring cap embedded in the package. Shake the solution before each dose measurement.
SIDE EFFECT
Side effects, which are often observed when using various therapeutic schemes with the use of Zerit В® : peripheral neuropathy, lactic acidosis, pancreatitis, hepatitis, hepatic insufficiency.
Peripheral neuropathy / peripheral neurological symptoms: with the use of the stavudine + lamivudine + efavirenz scheme, the incidence of peripheral neurologic symptoms was 19%.
Pancreatitis: pancreatitis, sometimes fatal, occurred in more than 1% of patients who received Zerit В® as part of a combination therapy.
Lactacidosis: cases of lactic acidosis, sometimes with a lethal outcome, were observed with the use of nucleoside analogues. Muscle weakness was rare in the use of Zerit В® as part of combination antiretroviral therapy.
Hepatitis or liver failure, sometimes with a lethal ZeritВ® drug and other nucleoside analogues.
Below is the incidence of adverse reactions with Zerit В® as a combination therapy 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 (<1/10 000).
Stavudine + lamivudine + efavirenz
From the endocrine system: infrequently - gynecomastia.
From 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: often - rash, itching; infrequently - hives.
On the part of the body as a whole: often - fatigue; infrequently - asthenia
Stavudine + lamivudine + indinavir
From the digestive system: very often - diarrhea, nausea, vomiting.
From the nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis, headache.
Stavudine + didanosine + indinavir
From the digestive system: very often - diarrhea, nausea, vomiting.
From the nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis.
From the skin: very often - a rash.
Postmarketing data on the side effects reported with stavudine.
On the part of the hematopoiesis system: the frequency is unknown - macrocytosis, anemia, neutropenia, thrombocytopenia.
Metabolic disorders: often - asymptomatic hyperlactatemia; frequency is unknown - lactic acidosis, lipoatrophy, lipodystrophy.
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 - pronounced muscle weakness (most often with hyperlactatemia or lactic acidosis).
Changes in laboratory parameters recorded when combining Zerit therapy with other drugs.
Combined therapy of stavudine + lamivudine + indinavir: bilirubin> 2.6 x VGN (7%); ACT> 5 x VGN (5%); ALT> 5 x VGN (6%); lipase> 2 x VGN (6%).
Combined therapy of stavudine + didanosine + indinavir: bilirubin> 2.6 Г— VGN (16%), ACT> 5 Г— VGN (7%), ALT> 5 Г— VLN (8%), lipase> 2 Г— VHN (5%).
Changes in laboratory indicators recorded in patients receiving antiretroviral therapy for the first time.
Combined therapy of stavudine + lamivudine + efavirenz: ACT> 5 x VGN (3%), ALT> 5 x VHN (3%), lipase> 2 x VHN (3%).
Children
In clinical trials, the side effects of the drug in children (from birth to puberty) and adult patients were similar. The development of peripheral neuropathy in children was less common than in adults, but its symptoms in children are more difficult to identify.
CONTRAINDICATIONS
- Children's age up to 3 months (for powder for solution for oral administration);
- chronic renal failure with KK less than 50 ml / min (for capsules);
- Children weighing less than 30 kg (for capsules);
- simultaneous application with hydroxycarbamide;
- simultaneous use with zidovudine;
- Congenital fructose intolerance, sugarase / isomaltase deficiency, glucose-galactose malabsorption;
- Hypersensitivity to the components of the drug.
With caution should prescribe the drug for violations of liver function, including chronic hepatitis in the active stage; with a history of peripheral neuropathy, history of pancreatitis, combined use with doxorubicin and ribavarin; at a diabetes (for a powder for a solution for reception inwards).
PREGNANCY AND LACTATION
Adequate and well-controlled studies of the use of Zerit in pregnant women have not been conducted. Lactacidosis has been reported in pregnant women receiving a combination of stavudine and didanosine with other antiretroviral drugs. Use Zerit В® as part of combination therapy with didanosine in pregnancy should be only in cases where the potential benefit of treatment for the mother exceeds the possible risk to the fetus. Patients taking stavudine during pregnancy should be closely monitored for possible development of lactic acidosis / steatosis of the liver.
There are no data on excretion of stavudine with 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, side effects in the child are recommended to stop breastfeeding during treatment with Zerit В® .
APPLICATION FOR FUNCTIONS OF THE LIVER
Adults with impaired renal function are recommended to reduce the dose depending on the CK.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be given to the drug for violations of liver function, including chronic hepatitis in the active stage.
APPLICATION FOR CHILDREN
Contraindicated in children under 3 months (for powder for the preparation of oral solution); in children weighing less than 30 kg (for capsules).
SPECIAL INSTRUCTIONS
Peripheral neuropathy
The drug 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 the drug, it is more often observed in patients with progressive HIV infection, with a history of peripheral neuropathy, and when used in combination with neurotoxic drugs, including didanosine. Cases of peripheral neuropathy, sometimes severe, have been 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 numbness, tingling, and tenderness in the hands and feet. If these symptoms appear, treatment should be stopped immediately. Usually, with the timely cessation of therapy, the symptoms of neuropathy disappear, in which case the treatment can be resumed.Sometimes after the abolition of treatment signs of neuropathy do not disappear, but, on the contrary, temporarily amplified.
Pancreatitis
The development of pancreatitis is usually associated with the progression of the disease or with the use of medications (to destination stavudine or simultaneously therewith), which can cause this side effect. The incidence of pancreatitis not dose-dependent; death was observed in rare cases. Increased risk of recurrence in patients with a history of pancreatitis: Pancreatitis when stavudine was observed in 5% of patients with a history of pancreatitis and 2% - with no history of pancreatitis.
Pancreatitis varying severity, or death, was reported in patients receiving combination therapy stavudine or didanosine + stavudine + didanosine + hydroxycarbamide. When symptoms of pancreatitis combined treatment with stavudine and didanosine, other drugs have toxic effects on the pancreas, to be discontinued. Resumption of stavudine therapy after a diagnosis of pancreatitis should be undertaken with extreme caution, patients should be under close medical supervision, and the use of didanosine and hydroxyurea should be deleted.
Lactic acidosis, severe hepatomegaly with steatosis
Lactic acidosis, severe steatosis with hepatomegaly, sometimes with fatal outcome, as the application of other nucleoside analogues, infrequently observed in the application of stavudine. Risk factors include female gender, obesity, and prolonged use of nucleoside analogues. Lactic acidosis with a fatal outcome was reported in pregnant women in the treatment of didanosine and stavudine in combination with other antiretroviral agents. Zerit В®It should be used with extreme caution in patients at increased risk for liver function abnormalities. Signs of symptomatic hyperlactatemia or lactic acidosis may be general fatigue, on the part of the digestive system symptoms (nausea, vomiting, abdominal pain, sudden unexplained weight loss), the symptoms of the respiratory system (tachypnea, dyspnea), muscle weakness, frequently associated with symptomatic hyperlactatemia or lactic acidosis syndrome, in rare cases, have been reported with stavudine. When the described symptoms or laboratory confirmation of receipt of lactic acidosis or pronounced hepatotoxicity should discontinue treatment with the drug.
Abnormal liver function
Hepatitis and hepatic failure, sometimes fatal, have been observed in patients receiving stavudine. Hepatotoxicity and hepatic failure, in some cases with fatal outcome, have been observed in patients receiving antiretroviral therapy in combination with hydroxyurea. Most of the deaths. observed with combination therapy of hydroxyurea, didanosine and stavudine, therefore, the application of this scheme should be avoided. When applying the combination of antiretroviral drugs, as well as assigning Zerit patients with liver diseases should ensure thorough monitoring of patients; when the signs of worsening liver function should consider abolishing the treatment.
Renal impairment
Clearance stavudine decreases with a decrease in creatinine clearance; however stavudine dose for patients with impaired renal function (creatinine clearance? 50 ml / min) should be corrected.
Redistribution of fatty tissue
In patients receiving antiretroviral therapy, there have been cases of redistribution / accumulation of body fat (lipodystrophy / lipoatrophy), which was manifested obesity on the central type, increasing the amount of fat in dorsotservikalnoy zone, reducing the amount of fat of the limbs and face, breast augmentation, "Kushingoid face" . In a randomized, comparative clinical studies revealed that patients not previously treated with antiretroviral therapy, lipodystrophy / lipoatrophy observed more frequently with stavudine than in the appointment of other nucleoside analogues (tenofovir or abacavir). These effects are cumulative, increasing as the duration of use of stavudine. The severity of lipodystrophy in patients treated with stavudine,decreases when translating them for treatment tenofovir or abacavir;but the clinical manifestations of lipoatrophy do not decrease. In each case, to consider the ratio of risk of lipodystrophy / lipoatrophy and benefit from treatment-containing stavudine circuits; At a high risk level, consideration should be given to the use of alternative treatment regimens. A careful monitoring of the symptoms of lipodystrophy / lipoatrophy in all patients taking stavudine is required.
Muscle Weakness
In rare cases, muscle weakness develops in the stavudine. Its symptoms may be similar to the clinical signs of Guillain-Barre 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 prolonged treatment with antiretroviral drugs. The etiology of osteonecrosis of the important role played by factors such as treatment with corticosteroids, alcohol abuse, severe immunosuppression, obesity.
Mitochondrial dysfunction
in conditions in vitro and in vivo ability to identify nucleotide and nucleoside analogues cause mitochondrial damage of varying degrees. There are reports of mitochondrial dysfunction in HIV-negative children exposed to the influence of nucleoside analogues in utero or shortly after birth. The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, and hyperlactatemia giperlipazemiya. There have also been more recent manifestations of disorders: muscle hypertonicity, seizures, abnormal behavior.
Patients older than 65 years
Elderly patients should be carefully monitored when assigning them to treatment Zerit, as they are at increased risk of developing peripheral neuropathy; In addition, this age group is on average higher incidence of renal dysfunction, which should be considered in the appointment of Zerit.
Immune reconstitution syndrome
have been reported in patients receiving combination antiretroviral therapy including Zerit. You should carefully monitor the condition of patients for timely detection of any inflammatory diseases and their treatment.
Diabetes mellitus
should be noted that 1 ml of the prepared solution for oral administration contains 50 mg of sucrose. The average daily dose (= 80 ml of a solution of 4 g sucrose) contained 0.33 XE.
Impact on the ability to drive vehicles and manage mechanisms
Effect on ability to drive and use dangerous machinery has not been studied. If the patient notes related to the treatment of symptoms, such as dizziness and visual disturbances, affecting its ability to concentration and reaction speed, it is recommended to give up driving and the performance of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Dose 12 times higher than the recommended daily dose in adults do not cause symptoms of acute toxicity. In chronic overdose may occur peripheral neuropathy and impaired liver function. Clearance in hemodialysis stavudine is 120 ml / min, it is not known to what extent the use of dialysis in overdose to accelerate excretion of the drug from the body. In overdose physician must monitor and, if necessary symptomatic treatment.
DRUG INTERACTION
Zerit В® not recommended for use together with zidovudine, zidovudine as can completely inhibit the intracellular phosphorylation of stavudine.
Care must be taken in the combined use of stavudine with doxorubicin and ribavirin, as doxorubicin and ribavirin under conditions in vitro also inhibit the phosphorylation of stavudine.
In combination therapy with Zerit didanosine, lamivudine or nelfinavir pharmacokinetic interaction between stavudine and these preparations were not observed.
Stavudine does not inhibit the major isoforms of cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), so stavudine interaction with drugs metabolized by these enzymes using unlikely.
Stavudine does not bind to blood proteins, which indicates a low probability of pharmacokinetic interactions with drugs that bind to plasma proteins.
Special studies drug interaction stavudine and non-nucleoside reverse transcriptase inhibitors such as nevirapine or efavirenz, is not carried out, but due to the fact that stavudine metabolised by other pathways, stavudine clinically significant interaction with these agents is expected.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List B. The drug should be kept out of reach of children at a temperature of from 15 В° to 30 В° C. Shelf life - 2 years.
The prepared solution should be stored in tightly closed bottle in a refrigerator between 2 В° to 8 В° C, no more than 30 days.
