Зерит®

General characteristics. Structure:

Active ingredient: 15 mg, 20 mg, 30 mg or 40 mg of a stavudin.

Excipients: cellulose microcrystallic, sodium starch glycollate, lactose water and anhydrous, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Pharmokodinamika is more long at a combination therapy three Use of drug of Zerit as a part of a combination therapy leads to increase in number CD4 of positive cells that is caused by decrease of the activity of the human immunodeficiency virus (HIV) and reduction of concentration of HIV of RNA. Virus suppression drugs in comparison with a combination therapy two medicines.

Action mechanism. Stavudin - antiviral means, a synthetic analog of a nukleozyd of thymidine, suppresses replication of HIV in the cultivated cells of the person. After hit in a cell ставудин under the influence of cellular enzymes turns into an active metabolite ставудинтрифосфат which suppresses activity of the HIV return transcriptase due to the competition to natural substrate thymidinetriphosphate. Thanks to absence in a molecule of the Z-hydroxylic groups necessary for creation of DNA, a stavudin triphosphate inhibits synthesis of virus DNA. Along with the return transcriptase, a cellular DNA polymerase scale is also sensitive to inhibition stavudintrifosfaty while for inhibition of cellular DNA polymerases an alpha and Betta the quantities of a stavudin, in 4000 and 40 times (respectively) exceeding quantity of the stavudin leading to inhibition of the return transcriptase are required.

Studying of the inhibiting activity of a stavudin in a combination with a zidovudine showed that both drugs are phosphorylated by a cellular thymidinekinase. However, transformation of a zidovudine into an active form happens quicker, than transformation of a stavudin into an active metabolite ставудинтрифосфат. In this regard the combined treatment by these drugs is not recommended.

Resistance and cross resistance. Sensitivity to a stavudin was studied on culture of the cells allocated at the patients receiving ставудин. Decrease in sensitivity to a stavudin after a long course of treatment is revealed; at the same time several cases of multiple resistance to analogs of nucleosides are revealed. Also cases of cross resistance to inhibitors of the return transcriptase were observed. So, prolonged treatment stavudiny can induce or maintain resistance to a zidovudine. In the presence of VICh-1 gene mutations (especially M41L and T215Y) as a result of treatment by analogs of nucleosides purpose of a stavudin is not recommended.

Pharmacokinetics. Adults. Stavudin is quickly soaked up at intake. Absolute bioavailability makes about 86,4%. After the dose which is once accepted внтурь the maximum concentration of drug in a blood plasma is observed less, than in 1 hour. Values About the shah increase in proportion to increase in doses of drug. Cumulation of a stavudin at its use was not observed each 6, 8 or 12 hours.

The pharmacokinetics of a stavudin at sick HIV without the clinical manifestations accepting drug after or during meal with the high content of fat or on an empty stomach considerably did not change.

The seeming distribution volume after a single dose of drug averages 66 liters and does not depend on a dose. Drug is equally distributed between red and white blood cells. Linkng with blood proteins is insignificant. After a single peroral dose of 40 mg concentration in cerebrospinal fluid (SMZh) of healthy volunteers made 63 ng/ml (an average of 44-71 ng/ml) for 4-5 hours. SMZh attitude towards concentration in a blood plasma made about 40% (an average of 31-45%).

Metabolism of a stavudin in a human body remains not studied. After intake the elimination half-life of drug makes 1,44 hours and does not depend on a dose. The renal clearance makes 40% of the general clearance and exceeds clearance of endogenous creatinine almost twice that indicates active canalicular secretion at removal of a stavudin through kidneys along with glomerular filtering.

Children. Absolute bioavailability of drug at children averages 76,9%. The pharmacokinetics after a single dose of drug is similar to pharmacokinetics of adults and does not depend on a dose. Concentration of drug in SMZh after single and multiple dose inside make from 16 to 125% in relation to concentration in a blood plasma. Cumulation of a stavudin at reception of a dose of 0,125 - 2 mg/kg is not observed each 12 hours. The elimination half-life averages 1 hour. About 34,5% of drug are removed through kidneys in not changed look.

Elderly patients. The pharmacokinetics at patients is more senior than 65 years was not studied.

Renal failure. At an impaired renal function the clearance of a stavudin decreases. Correction of a dose is recommended (see the Route of administration and doses).

Abnormal liver function. The pharmacokinetics of drug has similarity at patients to the broken and normal function of a liver. With the broken function of a liver in a stable condition of correction of an initial dose of drug it is not required to patients.

Indications to use:

Treatment of HIV of infectious diseases (in a combination with other nukleozidny and nenukleozidny inhibitors of the return transcriptase and inhibitors of HIV protease).

Route of administration and doses:

Inside. Time of administration of drug does not depend on meal time. The dose of drug depends on body weight.

Adults and children are more senior than 12 years.

Body weight ≥ 60 kg: To 40 mg there are each 12 hours

Body weight <60 kg: To 30 mg there are each 12 hours

Children are more senior than 3 months.

Body weight <30 kg: To 1 mg/kg there are each 12 hours

Body weight is ≥30 kg <60 kg: To 30 mg there are each 12 hours

Body weight is ≥60 kg: To 40 mg there are each 12 hours

If the proglatyvaniye of capsules is complicated, it is necessary to open accurately the capsule and to accept contents with a small amount of food.

The dose decline depending on clearance of creatinine is recommended to adults with an impaired renal function:

 a - the usual dose, corrections of a dose is not required 
b - patients after the session of a hemodialysis are recommended to accept a daily dose of drug.

In days when dialysis is not carried out, drug should be accepted in the same hours, as in days of carrying out a hemodialysis.

To children with an impaired renal function. Exact recommendations about correction of a dose of drug at children are absent. The dose decline and/or increase in an interval between administrations of drug is possible.

Preparation of solution for intake. To stir up contents in a bottle. To add 202 ml of water to a bottle and to stir up before full dissolution. The prepared solution can opalestsirovat slightly. The dose is measured the enclosed measured kopachok. Before the use to shake up. It is necessary to store the prepared solution densely closed in the refrigerator at (2-8 °C) no more than 30 days. After a period of validity unused solution of drug is thrown out.

Features of use:

Pregnancy and lactation. It is necessary to apply Zerit during pregnancy only in the presence of strict indications and only when the potential advantage of treatment outweighs possible risk. Researches on animals showed that ставудин and/or its metabolites pass through a placenta. It is unknown whether passes drug into breast milk. During treatment by drug it is not necessary to nurse.

Drug should be used with care at patients with the increased risk of development of peripheral neuropathy and peripheral neuropathy in the anamnesis.

Peripheral neuropathy is serious, dozozavisimy side effect of use of drug, more often it is observed at patients with the progressing HIV infection, with peripheral neuropathy in the anamnesis, and also at use in a combination with neurotoxic drugs, including диданозин. Cases of peripheral neuropathy, sometimes serious, were noted at HIV-positive patients,

receiving a hydroxycarbamide in a combination with anti-retrovirus drugs, including диданозин and/or ставудин. It is necessary to conduct careful observation of patients for the purpose of early detection of such symptoms of peripheral neuropathy as numbness, a pricking and morbidity in hands and feet. At emergence of these symptoms treatment should be stopped immediately. Usually at the timely termination of therapy symptoms of neuropathy disappear, in this case treatment can be resumed. Sometimes after treatment cancellation symptoms of neuropathy do not disappear, and, on the contrary, temporarily amplify. Pancreatitis of varying severity, up to a lethal outcome, was registered at the patients receiving therapy by a combination ставудин + диданозин or ставудин + диданозин + a hydroxycarbamide. The risk of a recurrence is increased at patients with pancreatitis in the anamnesis: pancreatitis at treatment stavudiny was noted at 5% of patients with pancreatitis in the anamnesis and at 2% - without pancreatitis in the anamnesis.

At emergence of symptoms of pancreatitis the combined treatment of a stavudin with didanoziny and other drugs having toxic effect on a pancreas has to be stopped. Therapy resuming the stavudiny ambassador of confirmation of the diagnosis of pancreatitis should be carried out with extra care, patients have to be under careful medical observation, use and a didanozin and a hydroxycarbamide should be excluded. Lactoacidosis, a severe form of a steatosis with a hepatomegalia, sometimes with a lethal outcome, as well as at use of other nukleozidny analogs, were infrequently noted at use of a stavudin. Risk factors are the female, obesity and long use of nukleozidny analogs.

Lactoacidosis with a lethal outcome was registered at the pregnant woman at treatment stavudiny and didanoziny in a combination with other anti-retrovirus drugs. The drug Zerit® should be used with extra care at patients with the increased risk of development of abnormal liver functions. The general fatigue, symptoms from the alimentary system (nausea, vomiting, an abdominal cavity pain, sudden inexplicable decrease in body weight), symptoms from respiratory system (hurried breathing, an asthma), muscular weakness can be signs of development of a symptomatic giperlaktatemiya or lactoacidosis (it is more often connected with a symptomatic giperlaktatemiya or a syndrome of lactoacidosis, it was in rare instances noted at treatment stavudiny).

At emergence of the described symptoms or receiving laboratory confirmation of lactoacidosis or the expressed hepatotoxic it is necessary to stop treatment by drug.

Abnormal liver function Hepatitis and a liver failure, sometimes with a lethal outcome, were observed at the patients receiving ставудин. A hepatotoxic and a liver failure, in some cases with a lethal outcome, were observed at the patients accepting anti-retrovirus drugs in combination with a hydroxycarbamide. The majority of lethal cases was noted at purpose of a combination therapy by a hydroxycarbamide, didanoziny and stavudiny therefore use of this scheme should be avoided. At use of a combination of anti-retrovirus drugs, and also at purpose of the drug Zerit® patients with diseases of a liver should provide careful observation of patients; at emergence of signs of deterioration in function of a liver it is necessary to consider a question of cancellation or temporary suspension of treatment.

At the accompanying therapy of hepatitis B or use of a stavudin. Expressiveness of a lipodystrophy at the patients accepting ставудин decreases at their transfer into treatment tenofoviry or abakaviry; however, clinical manifestations of a lipoatrophia at the same time do not decrease. In each case it is necessary to consider a ratio of risk of development of a lipodystrophy/lipoatrophia and advantage of treatment by the stavudin-containing schemes; at a high risk it is necessary to consider a question of use of alternative schemes of treatment. Careful monitoring of symptoms of a lipodystrophy/lipoatrophia at all patients accepting ставудин is necessary.

Neurologic disturbances. In rare instances when using of the combined anti-retrovirus therapy using a stavudin muscular weakness develops. In the majority of similar cases the symptomatic giperlaktatemiya or lactoacidosis were noted.

Symptoms of muscular weakness can mask similar clinical signs of a syndrome of Giyen - Barret (including respiratory insufficiency). At emergence of muscular weakness treatment should be stopped.

Symptoms can remain or worsen after the therapy termination. Osteonecrosis. Cases of an osteonecrosis were noted at the patients accepting ставудин, especially at prolonged treatment by anti-retrovirus drugs. In an osteonecrosis etiology an important role is played by such factors as treatment by corticosteroids, an alcohol abuse, the expressed immunosuppression, obesity.

Mitochondrial dysfunction. In the conditions of in vitro and in vivo ability of nucleotide and nukleozidny analogs to cause damage of mitochondrions of various degree is revealed. The HIV-negative children submitted influence nukleozidny analogovvnutriutrobno or right after the birth have messages on mitochondrial dysfunction. The main displays of mitochondrial dysfunction, anemia, a neutropenia, a giperlaktatemiya and a hyperlipasemia were often passing. Later manifestations of this disturbance were noted to a tayuka: gipertonusmuskulatura, spasms, anomalies of behavior. Patients are more senior 65 years It is necessary to watch carefully elderly patients at purpose of treatment by it the drug Zerit® as they represent group of the increased risk of development of peripheral neuropathy; besides, at this age group the frequency of renal failures is on average higher that should be considered at purpose of drug of Zerit.

Immunity recovery syndrome. it was noted at the patients receiving the combined anti-retrovirus therapy including the drug Zerit®. At patients with a heavy immunodeficiency at the beginning of the combined anti-retrovirus therapy inflammatory reaction on the low-active or residual resistant pathogenic microorganisms who are present at an organism can develop that can worsen considerably the general condition of the patient or strengthen disease symptoms. It is possible to give a Cytomegaloviral retinitis, a generalized or focal mikobakterialny infection, and also the pneumonia caused by Pneumocystis jiroveci as examples. It is necessary to control carefully a condition of patients for the purpose of early detection of any inflammatory diseases and their treatment.

The cases of autoimmune diseases (for example, Greyvs's disease) arising at immunity recovery were noted, however time of the beginning of development of such diseases varied at different patients and could come in many months after the beginning of therapy.

Diabetes mellitus. 1 ml of the prepared solution for intake contains 50 mg of sucrose. The average daily dose (80 ml of solution = 4 g of sucrose) contains 0,33 grain units.

Influence on ability to manage vehicles and mechanisms. Influence of drug on ability to drive the car and dangerous mechanisms was not studied. If the patient notes the symptoms connected with treatment, such as the dizziness and vision disorders influencing its ability to concentration and speed of reaction it is recommended to refuse driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Side effects which are often noted when using various therapeutic schemes using drug of Zerit: Peripheral neuropathy, lactoacidosis, pancreatitis, hepatitis, liver failure.

Peripheral neuropathy / peripheral neurologic symptoms: at use of the scheme ставудин + ламивудин + эфавиренз the frequency of peripheral neurologic symptoms made 19%. Pancreatitis: pancreatitis, sometimes with a lethal outcome, was noted at more than 1% of the patients receiving Zerit as a part of a combination therapy.

Lactoacidosis: lactoacidosis cases, sometimes with a lethal outcome, were noted at use of nukleozidny analogs. Muscular weakness was noted in rare instances at use of drug of Zerit as a part of the combined anti-retrovirus therapy.

Hepatitis or liver failure, sometimes with a lethal outcome, were noted at use of drug of Zerit and other nukleozidny analogs. Frequency of side reactions at use of drug of Zerit in the form of a combination therapy according to the standard classification is included below: Very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000).

Stavudin + ламивудин + эфавиренз.

From endocrine system: infrequently - a gynecomastia.

From digestive organs: often - diarrhea, abdominal pains, nausea, dyspepsia; infrequently - pancreatitis, vomiting, hepatitis, jaundice.

Metabolic disturbances: often - a lipoatrophia, a lipodystrophy; infrequently - lactoacidosis (sometimes with muscular weakness), anorexia.

From a musculoskeletal system: infrequently - an arthralgia, a mialgiya.

From a nervous system: often - a depression, peripheral neuropathy, paresthesia, peripheral neuritis, dizziness, pathological dreams, a headache, sleeplessness, drowsiness, pathological thoughts, uneasiness, emotional lability.

From skin and hypodermic cellulose: often - rash, an itch; infrequently - a small tortoiseshell. Organism in general: often - fatigue; infrequently - an adynamy.

Stavudin + ламивудин + индинавир.

From digestive organs: very often - diarrhea, nausea, vomiting.

From a nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis, a headache.

Stavudin + диданозин + индинавир.

From digestive organs: very often - diarrhea, nausea, vomiting.

From a nervous system: very often - peripheral neuropathy, paresthesia, peripheral neuritis.

From skin and hypodermic cellulose: very often - rash.

Post-marketing data on the side effects registered at use of a stavudin.

From system of blood and bodies of a hemopoiesis: frequency is unknown - a macrocytosis, anemia, a neutropenia, thrombocytopenia.

Metabolic disturbances: often - the symptomless giperlaktatemiya, frequency is unknown - lactoacidosis, a lipoatrophia, a lipodystrophy.

From endocrine system: frequency is unknown - a diabetes mellitus, a hyperglycemia.

From a liver: frequency is unknown - a liver steatosis, hepatitis and a liver failure.

From a nervous system: frequency is unknown - the expressed muscular weakness (most often at a giperlaktatemiya or lactoacidosis).

The changes of laboratory indicators registered at a combination of therapy by Zerit with other drugs:
- Combination therapy ставудин + ламивудин + индинавир: bilirubin> 2.6 x UBN (upper bound of norm) (7%); ACT> 5 x VGN (5%); ALT> 5 x VGN (6%); lipase> 2 x VGN (6%).
- Combination therapy ставудин + диданозин + индинавир: bilirubin> 2.6
x VGN (16%), ACT> 5 x VGN (7%), ALT> 5 x VGN (8%), lipase> 2 x VGN (5%).

The changes of laboratory indicators registered at the patients receiving antiretrovisny therapy for the first time:
- Combination therapy ставудин + ламивудин + эфавиренз: ACT> 5 x VGN (3%), ALT> 5 x VGN (3%), lipase> 2 x VGN (3%).

Children: In clinical trials children (from the moment of the birth and till the pubertal period) and adult patients had similar side effects of drug. Development of peripheral neuropathy in children was observed less than at adults, however its symptoms at children give in to identification more difficult.

Interaction with other medicines:

Zerit does not rekomenudtsya to apply a zidovudine along with drug. Transformation of a stavudin into an active metabolite decreases in the presence of a zidovudine.

At the same time accepted диданозин, ламивудин or нелфинавир do not influence efficiency of drug of Zerit. The risk of development of side effects of drug of Zerit increases at simultaneous use with didanoziny.

Stavudin almost does not contact blood proteins that indicates small probability of medicinal interactions with participation of the mechanism of replacement from places of binding.

The accompanying administration of drugs, causing peripheral neurologic frustration is not recommended (chloramphenicol, Cisplatinum, dapsone, Ethambutolum, Etioniamidum, гидралазин, an isoniazid, lithium, metronidazole, nitrofurantoin, Phenytoinum, Vincristinum, залцитабин).

Contraindications:

Hypersensitivity to a stavudin and/or any of drug excipients, children's age up to 3 months.

With care: alcoholism, a chronic renal failure (clearance of creatinine less 50ml/mines), a liver failure, peripheral neuropathy, use in a combination with didanoziny, pancreatitis.

Overdose:

Peripheral neuropathy and abnormal liver function.

Treatment: symptomatic. Stavudin leaves at a hemodialysis (speed of removal makes 120+18ml/mines). Peritonialny dialysis is not effective.

Storage conditions:

In the place protected from light, at a temperature not above 30 °C. A period of validity - 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules on 15, 20, 30 or 40 mg. On 14 capsules in the blister. In a cardboard box 4 blisters with the application instruction. Packaging: on 14 capsules in the blister. In a cardboard box 4 blisters with the application instruction.