Active substanceStavudineStavudine
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  • Vero-Stavudine
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    VEROPHARM SA     Russia
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  • Zerit®
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  • Zerit®
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  • Stavudine
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  • Stavudine
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  • Stavudine
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  • Stag
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    DIALOGPARMA, LLC     Russia
  • Dosage form: & nbspPowder for solution for oral administration
    Composition:1the vial containing the preparation contains:

    Active substance: Stavudine - 0.200 g; Excipients-. methyl parahydroxybenzoate 0.300 g, propyl parahydroxybenzoate 0.030 g, carmellose sodium 0.499 g, tdefoaming the defoamer in sucrose ** 0,499g, cherry flavored dry flavored (FMC # 20194) 0.798 g, sucrose 9.646 g

    In 1 ml of the prepared solution contains 1 mg of stavudine.

    * - Packing is done taking into account a 5% rebate, which is necessary to ensure the extraction of 200 ml of the drug. In this case, the amount of stavudine in the vial, taking into account the re-laying, is 210 mg, the mass of the contents, taking into account the -12.6 g.

    ** the composition of the defoamer trituration in sucrose: sucrose 0.494 g, simethicone emulsion (30%) 0.005 g.

    Description:

    Crystalline powder from almost white to light pink color with no visible foreign inclusions. When dissolved in water, a cloudy, colloidal solution is formed, from colorless to slightly pink.

    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 Zerit as part of combination therapy reduces 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.
    Mechanism of action
    Stavudine is an antiviral agent, a synthetic analogue of thymidine nucleoside, suppresses HIV replication in cultured human cells. After entering the cage stavudine under the action of cellular enzymes is converted into an active metabolite stavudine triphosphate, which suppresses the activity of reverse transcriptase of HIV 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, cellular DNA polymerase y is also susceptible to inhibition of stavudine triphosphate, while davudine levels of 4000 and 40 times (respectively) higher than davudine, leading to inhibition of reverse transcriptase, are required to inhibit cellular DNA polymerases of ayr.
    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.

    Pharmacokinetics:
    Absorption
    Stavudine is rapidly absorbed when taken orally. Absolute bioavailability is about 86.4%. Less than 1 hour after repeated administration in doses of 0.5 mg / kg, the maximum concentration of the drug (Cmax) in the blood plasma is about 810 ng / ml.The values ​​of Cmax increase in proportion to the increase in the dose of the drug. Notable cumulation of stavudine in its use every 6, 8 or 12 hours was not observed.
    The area under the concentration-time curve (AUC) of stavudine in HIV-infected patients with no symptoms of the disease did not differ depending on the fasting or after meals.
    Distribution
    The apparent volume of distribution after intravenous one-hour infusion of the drug is an average of 46 liters and does not depend on the dose. Binding to blood proteins is negligible. The drug is equally distributed between red blood cells and blood plasma. After a single dose of d4T inwards at a dose of 40 mg, its concentration in the cerebrospinal fluid (CSF) of healthy volunteers averaged 63 ng / ml (44-71 ng / ml) for 4-5 hours. The concentration of stavudine in CSF was on average 40% (31-45%) of its concentration in the blood plasma.
    Metabolism and excretion
    Metabolism plays a limited role in the clearance of stavudine. After taking 80 mg [14C] - stavudine, the main component of the total plasma radioactivity was unchanged stavudine, whereas metabolites accounted for a small part of the total radioactivity. In healthy volunteers, approximately 95% and 3% of radioactivity were determined in urine and feces, respectively.In urine, 73.7% of the radioactive unchanged stavudine was found, and in feces - 62%. The half-life of stavudine for single and multiple oral administration is 1.44-2.28 hours 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.
    Impaired renal function. There was a decrease in clearance of stavudine with a decrease in creatinine clearance. Dose correction is recommended in patients with impaired renal function.
    Violation of the function of the liver. Parameters of the pharmacokinetics of the drug in patients with impaired and normal liver function are similar. With a stable state of patients with impaired liver function, dose adjustment is not required.
    Elderly patients. 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 aged 5 weeks to 15 years is an average of 76.9%.When taking doses of 0.125 -2 mg / kg every 12 hours, pharmacokinetic parameters after taking the first dose and with repeated administration are not different, which indicates the absence of cumulation of stavudine. The volume of distribution after intravenous infusion of the drug is 0.73 l / kg. Concentrations of the drug in CSF are 16 - 125% of the concentration in the blood plasma. Apparent general clearance of the drug - 14 ml / min / kg, half-life on average 1 hour.

    Indications:
    Treatment of HIV infection in combination therapy.

    Contraindications:
    Hypersensitivity to any component of the drug.
    Children up to 3 months.
    Simultaneous use with hydroxycarbamide;
    Simultaneous use with zidovudine
    - Congenital intolerance fructose, deficiency of sugar / isomaltase, glucose-galactose malabsorption

    Carefully:
    Dysfunction of the liver, including chronic hepatitis in the active stage; peripheral neuropathy in history, pancreatitis in the anamnesis, combined use with doxorubicin and ribavarin, diabetes mellitus.

    Pregnancy and lactation:
    Adequate and well-controlled studies of the use of Zerit in pregnant women have not been conducted.Lactoacidosis has been reported in pregnant women receiving a combination of stavudine and didanosine with other antiretroviral drugs. Use Zerit as part of combination therapy with didanosine during pregnancy should be only in cases where the potential benefit of treatment for the mother exceeds the possible risk to the fetus. Patients receiving stavudine during pregnancy, should be carefully monitored in connection with the possible development of lactic acidosis / 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 side effects for the child and the risk of transmission from the mother to the infant, it is recommended to stop breastfeeding during treatment with the drug.

    Dosing and Administration:ATnutrition, regardless of food intake. Adults:

    The recommended dose of the drug is determined by the patient's body weight (see below).

    Weight

    bodies

    Doses

    > 60 kg

    40 mg (40 ml) every 12 hours

    <60 kg

    30 mg (30 ml) every 12 hours






    Dchildren:

    Recommended doses based on the weight of the child are shown in the table below.

    body mass

    dose

    <30 kg

    1 mg / kg every 12 hours

    > 30 kg <

    30 mg (30 ml) every 12

    60 kg

    hours

    > 60 kg

    40 mg (40 ml) every 12


    hours

    Application for renal dysfunction

    ATadults: dose adjustment is performed depending on the degree of impaired renal function (see table below).

    Clearance

    creatinine

    (ml / min)

    Dose according to body weight

    > 60 kg

    <60 kg

    > 50a

    40 mg (40 ml) every 12 hours

    30 mg (30 ml) every 12 hours3

    26-50

    20 mg (20 ml) every 12 hours

    15 mg (15 ml) every 12 hours

    <26b

    20 mg (20 ml) every 24 hours

    15 mg (15 ml) every 24 hours











    a Usual dose, dose adjustment not required

    6 For patients on hemodialysis: the daily dose of the drug is taken at the end of the hemodialysis session. On days when dialysis is not performed, the drug should be taken at the same hours as during the days of hemodialysis.

    Children:

    Due to stavudine mainly excreted by the kidneys, kidney dysfunction in children can have an effect on the clearance of stavudine. Clear recommendations for correcting the regimen of therapy in such cases are not available, but if necessary, consider reducing the dose or increasing 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, treatment with Zerit should be temporarily discontinued.

    Preparation of solution for oral administration

    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.

    DThe oz is measured by a measuring cap embedded in the package of the preparation. Shake the solution before each dose measurement.

    If you need to dispense the volume of the drug to less than 10 ml, use any suitable syringe.

    The prepared solution should be stored in a tightly closed vial, in a refrigerator (2-8 ° C), not more than 30 days.

    Side effects:

    Side effects, which are often noted when using various therapeutic regimens with the use of the drug Zerit: Peripheral neuropathy, lactic acidosis, pancreatitis, hepatitis, hepatic insufficiency, lipoatrophy / lipodystrophy.

    Peripheral Neuropathy /peripheral neurological

    symptoms: when applying the scheme stavudine + lamivudine + efavirenz the incidence of peripheral neurologic symptoms was 19%.

    Pancreatitis: pancreatitis, sometimes with lethal outcome, was observed in more than 1% of patients who received Zerit as part of a combination therapy.

    Lactic acidosis: cases of lactic acidosis, sometimes with a lethal outcome, were observed in nThe use of nucleoside analogues.

    Muscle weakness was noted in rare cases with the use of Zerit as a combination antirtrovirus therapy.

    Hepatitis or liver failure, sometimes with a fatal outcome, were observed with the use of Zerit and others nucleoside analogues.

    Lipoatrophy / lipodystrophy: cases lipoatrophy / lipodystrophy were observed with Zerit and other

    nucleoside analogues.

    Below is the incidence of adverse reactions with Zerit® in the form of combined therapy in accordance with the generally accepted

    classification: Very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); 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), andnoorexia;

    From the side of the locomotor system apparatus: 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 tissue:

    often - a rash, itching; infrequently urticaria.

    Organism as a whole: often fatigue; infrequently - asthenia, allergic reactions.

    Stavudine + lamivudine + indinavir:

    On the part of the digestive system: highly often - diarrhea, nausea, vomiting;

    From the nervous system: Often - peripheral neuropathy, paresthesia, peripheral neuritis, headache.

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

    Stavudine + didanosine + indinavir:

    On the part of the digestive system: highly often - diarrhea, nausea, vomiting;

    From the nervous system: Often - peripheral neuropathy, paresthesia, peripheral neuritis.

    From the skin and subcutaneous tissue:

    very often - a rash.

    The following are adverse reactions of any severity that were noted in clinical studies for various pdyshma therapy with stavudine with a frequency of at least 1%.

    Organism as a whole: asthenia, sweating;

    On the part of the digestive system: flatulence, dry mouth, increased appetite, gastritis, constipation;

    From the nervous system: confusion, emotional lability, nervous excitement, dizziness, euphoria, anxiety, stupor, decreased libido, impaired coordination, hallucinations;

    Metabolic disorders: hypertriglyceridemia, weight loss;

    From the musculoskeletal system: arthralgia, pain in the limbs;

    From the sense organs: perversion of the Taste.

    Lactic acidosis, pancreatitis, hepatitis and jaundice were noted in these studies in less than 1% of patients.

    Postmarketing data on the side effects reported with stavudine

    On the part of the blood system and hemopoiesis: frequency unknown - macrocytosis, anemia, neutropenia, thrombocytopenia;

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

    fromabout the endocrine system: frequency unknown - diabetes, hyperglycemia;

    From the side of the liver: frequency unknown - steatosis of the liver, hepatitis and liver failure;

    From the nervous system: frequency

    unknown - severe muscle weakness (most often with hyperlactatemia or lactic acidosis);

    Changes in laboratory parameters recorded when combining Zerit with other drugs:

    • Combination Therapy stavudine + lamivudine + indinavir: bilirubin >2.6 x VGN (upper limit of the norm) (7%); ACT > 5 x VGN (5%); ALT> 5 x VGN (6%); lipase> 2 x VGN (6%), GGT> 5 x VGN (2%); amylase> 2 x VGN (4%);

    • Combination Therapy stavudine + didanosine + indinavir: bilirubin> 2.6 x VGN (16%), ACT > 5 X VGN (7%), ALT> 5 x VHN (8%), lipase> 2 x VGN (5%), GGT> 5 x VHN (5%), amylase> 2 x VHN (8%). Changes in laboratory indicators recorded in patients receiving antiretroviral therapy for the first time:

    • Combination Therapy stavudine + lamivudine + Efavirenz: ACT > 5 x VGN

    (3%), ALT> 5 x VGN (3%), lipase> 2 x VHN (3%), neutropenia (ANC <750 / mm3) (5%), andneemia (hemoglobin <80 g / l) (less than 1%), thrombocytopenia (platelets <50,000 / mm3) (2%).

    Children: In clinical trials side effects of the drug in children (with birth to puberty period) and adult patients were similar.

    Development of peripheral neuropathy in children were observed less often than in adults, however, its symptoms are more complex in children are detectable.


    Overdose:

    Doses of the drug, 12 times greater than recommended daily dose do not cause in adults with acute toxicity symptoms.

    In case of chronic overdose peripheral neuropathy and abnormal liver function. Clearance Stavudine in hemodialysis is 120 ml / min, it is not known to what extent use of hemodialysis in Overdose helps to accelerate removing the drug from the body.

    It is not known whether stavudine at aid of peritoneal dialysis. When Overdosage requires the supervision of a doctor and, if necessary, symptomatic treatment.

    Interaction:
    Zerit is not recommended to be used concomitantly with the drug zidovudine, because the zidovudine can completely inhibit intracellular phosphorylation of stavudine. Caution should be exercised in the combined use of stavudine with doxorubicin andribavarin, since doxorubicin and ribavarin under in vitro conditions also inhibit stavudine phosphorylation.
    With combined Zerit therapy with didanosine, lamivudine or nelfinavir, pharmacokinetic interactions between stavudine and these drugs have not been observed.
    Stavudine does not inhibit the main isoforms of cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), so davudine interactions with drugs metabolized by these enzymes are 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 of drug interactions between stavudine and non-nucleoside reverse transcriptase inhibitors, such as efavirenz or nevirapine, were not carried out, however, due to the fact that stavudine metabolized by other metabolic pathways, clinically significant interactions of stavudine with these drugs are not expected.

    Special instructions:

    The drug should be used with caution in patients with elevated risk of development peripheral nerveneuropathies 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 peripheral neuropathy in the history, and also when used in combination with neurotoxic drugs, including didanosine. Cases of peripheral neuropathy, sometimes serious, 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 in a timely manner. 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 withdrawal of treatment signs of neuropathy do not disappear, but, on the contrary, temporarily amplified. Pancreatitis various degrees of severity, up to a lethal outcome, was registered in patients receiving combination therapy stavudine + didanosine or stavudine + didanosine + gidorkycarbamide. The risk of recurrence 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.

    When symptoms of pancreatitis appear, the combined treatment of stavudine with didanosine and other drugs that have 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 close medical supervision, the use of didanosine and hydroxycarbamide should be excluded.

    Lactoacidosis, severe form of steatosis with hepatomegaly, sometimes with a lethal outcome, as with the use of other nucleoside analogues, were rarely observed with stavudine. Risk factors are female sex, obesity and long-term use of nucleoside analogues.

    Lactic acidosis was fatalis registered in a pregnant woman with stavudine and didanosine in combination with other antiretroviral

    preparations.Zerit® should be used with extreme caution in patients with an increased risk of developing liver dysfunction. Signs of the development of symptomatic hyperlactatemia or lactic acidosis can be general fatigue, symptoms of the digestive system (nausea, vomiting, abdominal pain, sudden unexplained weight loss), respiratory system symptoms (rapid breathing, shortness of breath), muscle weakness with symptomatic hyperlactatemia or syndrome lactoacidosis, in rare cases was noted in the treatment of stavudine).

    When these symptoms appear, or if laboratory confirmation of lactic acidosis is obtained or expressed hepatotoxicity should be discontinued treatment with the drug.

    Impaired liver function: hepatitis and liver failure, sometimes fatal, were observed in patients who received stavudine.

    Hepatotoxicity and hepatic insufficiency, in some cases with a fatal outcome, were observed in patients taking antiretroviral drugs in combination with glt; / RTI & gt; Most lethal cases were noted in the appointment of combined therapy with hydroxycarbamide, didanosine and stavudine, therefore, the use of this scheme should be avoided. When applying the combination of antiretroviral drugs, as well as assigning Zerit® drug to patients with liver disease should ensure thorough monitoring of patients; if signs of worsening of liver function appear, consider abolishing or temporarily suspending treatment.

    When concomitant therapy of hepatitis B or C with the use of other drugs should carefully study the instructions for their use.

    Impaired renal function: 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, cases redistribution / accumulation of fatty tissue (lipodystrophy / lipoatrophy), which was manifested by obesity in the central type, an increase in the amount of fatty tissue in the dorsocervical zone ("buffalo hump"), a decrease infatty tissue of limbs and face, breast augmentation, "cushingoid face". In randomized comparative clinical trials, it was found that patients who had not previously had antiretroviral therapy, lipodystrophy / lipoatrophy are noted more often in the treatment of stavudine than with the appointment of 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 treatment with tenofovir or abacavir; however, the clinical manifestations of lipoatrophy do not decrease in this case. In each specific case, the risk ratio of lipodystrophy / lipoatrophy and the benefits of stavudine-containing regimens should be considered; At a high risk level, consideration should be given to the use of alternative treatment regimens. A thorough monitoring of the symptoms of lipodystrophy / lipoatrophy in all patients taking stavudine.

    Neurological disorders: In rare cases, when using combination antiretroviral therapy with stavudinemuscle weakness is called.In most of these cases, symptomatic hyperlactatemia or lactic acidosis was noted.

    Symptoms of muscle weakness may be masked by similar clinical signs of Guillain-Barre syndrome (including respiratory failure). If you have muscle weakness, treatment should be stopped.

    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. AT etiology of osteonecrosis, factors such as treatment corticosteroids, abuse alcohol, severe immunosuppression, obesity.

    Mitochondrial dysfunction. AT conditions in vitro and in vivo the ability of nucleotide and nucleoside analogs to cause damage has been revealed mitochondria of various degrees. There are reports of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues in utero or immediately after birth. The main manifestations mitochondrial dysfunction, often transient, were anemia, neutropenia, giperlactatemia and hyperlipazemia.There were also later manifestations of this disorder: hypertonicity

    musculature, convulsions, behavioral anomalies. Patients over 65 years of age. It should be carefully monitored for elderly patients when prescribing treatment with Zerit because they represent a group at increased risk of developing peripheral neuropathy; In addition, this age group has an average higher frequency of renal dysfunction, which should be taken into account when prescribing Zerit®.

    Immunodeficiency Syndrome was observed in patients receiving combination antiretroviral therapy, including Zerit®. Patients with severe immunodeficiency at the onset of combined antiretroviral therapy may develop an inflammatory response to low-level or residual resistant pathogens present in the body, which can significantly impair the general condition of the patient or exacerbate the symptoms of the disease. Examples include cytomegalovirus retinitis, generalized or focal Mycobacterial infection, as well as pneumonia caused by Pneumocystis jiroveci. It should be closely monitored withPatient status for the purpose of timely detection of any inflammatory diseases and their treatment.

    Diabetes. 1 ml of cooked solution for oral administration contains 50 m g sucrose. In an average daily dose (80 ml solution = 4 g sucrose) contains 0.33 bread units.

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

    Effect of the drug on the ability to manage car and dangerous machinery was studied. If the patient notes related with treatment symptoms such as dizziness and visual disturbances affecting its ability to concentration and reaction speed, it is recommended not to manage and potentially of hazardous activities requiring increased concentration and the speed of psychomotor reactions.

    Form release / dosage:
    Powder for solution for oral administration, 1 mg / ml
    To 12.6 g of powder into a 260 ml high-pressure polyethylene bottle (for obtaining 200 ml of oral solution), with a neck sealed with a foil with the BMS logo, sealed with a screwed polypropylene cover that can not be opened by children.The bottle cap is marked with two arrows and the inscriptions "Close tightly" and "While pushing down turn". One bottle in a set with a measuring cap and instructions for medical use in a cardboard box.

    Packaging:
    Powder for solution for oral administration, 1 mg / ml
    To 12.6 g of powder into a 260 ml high-pressure polyethylene bottle (for obtaining 200 ml of oral solution), with a neck sealed with a foil with the BMS logo, sealed with a screwed polypropylene cover that can not be opened by children. The bottle cap is marked with two arrows and the inscriptions "Close tightly" and "While pushing down turn". One bottle in a set with a measuring cap and instructions for medical use in a cardboard box.

    Storage conditions:
    Store at a temperature of 15 to 30 ° C.
    The prepared solution should be stored in the refrigerator (2-8 ° C) for no longer than 30 days. KEEP OUT OF THE REACH OF CHILDREN!


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

    Terms of leave from pharmacies:On prescription
    Registration number:П N015401 / 02
    Date of registration:30.04.2009
    The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA
    Manufacturer: & nbsp
    Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia
    Information update date: & nbsp19.08.2015
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