Composition, form of production and packaging
The solution for oral administration is clear, light yellow in color, with the smell of strawberry.
5 ml
zidovudine 50 mg
[PRING] dextrose hydrogenated syrup 3.2 g, glycerol 500 mg, citric acid anhydrous 17.5 mg, sodium benzoate 10 mg, sodium saccharinate 10 mg, strawberry flavor 37.5 Ојl, flavor white sugar 12.5 Ојl, water purified to 5 ml.
200 ml - bottles of yellow glass (1) complete with plastic adapter and syringe dosing - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Mechanism of action
Zidovudine is an antiviral drug, a thymidine analogue, highly active against retroviruses, including the human immunodeficiency virus (HIV).
Zidovudine undergoes phosphorylation in both infected and intact cells with the formation of monophosphate by means of cellular thymidine kinase. Subsequent phosphorylation of zidovudine monophosphate to zidovudine diphosphate, and then to zidovudine triphosphate is catalyzed by cellular thymidylate kinase and nonspecific kinases, respectively.
Zidovudine triphosphate acts as an inhibitor and substrate for viral reverse transcriptase. The formation of proviral DNA is blocked by the incorporation of zidovudine triphosphate into its chain, which leads to chain termination. The competition of zidovudine triphosphate for reverse transcriptase of HIV is approximately 100 times stronger than for the cellular? -polymerase of human DNA.
Zidovudine acts additively or synergistically with a large number of antiretroviral drugs, such as lamivudine, didanosine, ОІ-interferon, suppressing HIV replication in cell culture.
The development of resistance to thymidine analogues (zidovudine is one of them) occurs as a result of gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. The viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations at positions 41 and 215 or accumulation of at least 4 of 6 mutations. These mutations do not cause cross-resistance to other nucleoside analogs, which allows further inhibitors of reverse transcriptase to be used in the treatment of HIV infection.
Two kinds of mutations lead to the development of multiple drug resistance.
In one case, mutations occur at 62, 75, 77, 116, and 151 positions of HIV reverse transcriptase, and in the second case, it is a T69S mutation with the insertion of 6 pairs of nitrogen bases in this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, and also to other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit the therapeutic possibilities for HIV infection.
A decrease in the sensitivity to zidovudine in vitro of HIV isolates was observed with long-term treatment of HIV infection with zidovudine.
At present, the relationship between sensitivity to zidovudine in vitro and the clinical effect of therapy has not been studied.
In vitro studies of zidovudine in combination with lamivudine have shown that zidovudine-resistant isolates of the virus become susceptible to zidovudine while simultaneously acquiring resistance to lamivudine. Clinical studies have demonstrated the fact that the use of zidovudine in combination with lamivudine delayed the emergence of zidovudine-resistant strains of the virus in patients who had not previously received antiretroviral therapy.
PHARMACOKINETICS
Suction
Zidovudine is well absorbed after oral administration, the bioavailability is 60-70%. The mean values ​​of the maximum concentration in the equilibrium state (C ss max) and the minimum concentration in the equilibrium state (C ss min ) in the plasma with the administration of 5 mg / kg zidovudine every 4 hours were 7.1 and 0.4 μmol respectively (or 1.9 and 0.1 μg / ml) .
Bioequivalence
It was shown that, according to the area under the pharmacokinetic curve "concentration-time" (AUC), the zidovudine solution for oral administration is bioequivalent to zidovudine capsules.
Distribution
Binding to plasma proteins is relatively low, amounts to 34-38%.
Zidovudine penetrates into the cerebrospinal fluid, placenta, amniotic fluid, fetal blood, sperm and breast milk.
Metabolism
Zidovudine 5'-glucuronide is the main end metabolite of zidovudine, is determined in plasma and urine and is approximately 50-80% of the dose of the drug that is excreted by the kidneys.
Excretion
The renal clearance of zidovudine is much higher than QC, which indicates the predominant excretion of zidovudine by tubular secretion.
Pharmacokinetics in special clinical cases
In children older than 5-6 months, pharmacokinetic parameters are similar to those in adults. Zidovudine is well absorbed from the intestine, bioavailability is 60-74% with an average of 65%. After taking zidovudine in doses of 120 mg / m 2 and 180 mg / m 2 as a solution for ingestion, C ss max was 4.45 ОјM (1.19 Ојg / ml) and 7.7 ОјM (2.06 Ојg / ml), respectively. Pharmacokinetic data suggest that zidovudine glucuronization in newborns and infants is reduced, leading to increased bioavailability.A decrease in clearance and a longer T 1/2 are recorded in infants younger than 14 days, then the pharmacokinetic parameters become similar to those of adults.
The pharmacokinetics of zidovudine in patients older than 65 years has not been studied.
In patients with severe renal insufficiency, C max zidovudine in plasma is increased by 50% compared to that in patients without renal dysfunction. Systemic exposure to zidovudine (AUC) increases by 100%, T 1/2 does not change significantly. In case of renal dysfunction, a significant cumulation of the main metabolite of 5'-glucuronide of zidovudine is observed, however, no signs of toxic effect are detected. Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while the excretion of 5'-glucuronide zidovudine is enhanced.
With hepatic insufficiency, zidovudine cumulation may be observed due to a decrease in glucuronization, which requires correction of the dose of the drug.
Pharmacokinetic parameters of zidovudine in pregnant women do not change, there are no signs of cumulation of zidovudine.
The concentration of zidovudine in the plasma in children at birth is the same as that of their mothers during childbirth.
INDICATIONS
- Treatment of HIV infection in combination therapy;
- treatment of HIV infection in pregnant women to reduce the frequency of transplacental transmission of HIV from the mother to the fetus.
DOSING MODE
The drug Retrovir solution is intended for oral administration.
Adults and adolescents with a body weight of at least 30 kg recommended dose is 500 or 600 mg per day, divided into two doses, as part of a combination therapy.A dose of 1000 mg / day, divided into several doses, was used in clinical trials. The effectiveness of doses in the range below 1000 mg / day for the treatment or prevention of HIV-associated neurological dysfunction is unknown.
Children with a body weight of at least 9 kg, but less than 30 kg , the recommended dose is 18 mg / kg / day, divided into two doses, as part of combination therapy. The effectiveness of doses in the range below 720 mg / m 2 / day (about 18 mg / kg 2 times / day) for the treatment of HIV-associated neurological dysfunction is unknown. The maximum daily dose should not exceed 600 mg (300 mg 2 times / day).
Children with a body weight of at least 4 kg, but less than 9 kg, the recommended dose is 24 mg / kg / day, divided into two doses, as part of a combination therapy.
The pharmacokinetics of zidovudine in patients over the age of 65 years has not been studied. However, given the age-related decline in kidney function and the possible changes in peripheral blood parameters, such patients should be especially careful when prescribing Retrovir and perform appropriate monitoring before and during treatment.
In severe disorders of kidney function, the recommended dose of Retrovir is 300-400 mg / day. Depending on the response from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not have a significant effect on the excretion of zidovudine, but the excretion of 5'-glucuronide of zidovudine is accelerated. For patients with end-stage renal failure who are on hemodialysis or peritoneal dialysis , the recommended dose of Retrovir is 100 mg every 6-8 hours.
Data obtained in patients with cirrhosis of the liver indicate that patients with hepatic insufficiency may experience cumulation of zidovudine due to a decrease in glucuronization, which may require dose adjustment. If monitoring of zidovudine concentrations in plasma is not possible, the physician should pay special attention to the clinical signs of drug intolerance and, if necessary, adjust the dose and / or increase the interval between doses of the drug.
Adequate correction of the dosing regimen - dose reduction or withdrawal of the drug Retrovir - may be required in patients with adverse reactions from the hematopoiesis system (in the case of a hemoglobin concentration reduction of 75-90 g / l (4.65-5.59 mmol / L) or the number of leukocytes to 0.75-1.0 x 10 9 / L).
To prevent the transmission of HIV from the mother to the fetus , the effectiveness of the following 2 preventive measures for pregnant women was demonstrated:
- For pregnant women, starting from the 14th week of pregnancy, it is recommended to prescribe the drug Retrovir inwards before the birth at a dose of 500 mg / day (100 mg 5 times / day). During labor, Retrovir is administered IV until the umbilical cord is compressed.
- Pregnant women, starting from the 36th week of pregnancy, are recommended to prescribe Retrovir in a dose of 600 mg / day (300 mg / day) inside before the birth, then every 3 hours for 300 mg of Retrovir preparation inside from the beginning of labor until delivery.
The newborn shows the appointment of Retrovir in a dose of 2 mg / kg body weight every 6 hours, starting from the first 12 hours after birth and continuing until the age of 6 weeks. Newborns who can not take the Retrovir solution inside should have a retrovir in / in.
Instructions for using a dispensing syringe
The attached dispensing syringe and adapter are designed for accurate dosing of the drug Retrovir, solution for oral administration.
1. Remove the lid from the vial.
2. Insert the supplied adapter into the neck of the vial, holding the vial
3. Insert the dosing syringe into the adapter hole.
4. Turn the vial over.
5. Pull the plunger of the dispensing syringe, measure the exact amount of the first dose from the full dose given to you.
6. Turn the bottle upside down, remove the syringe from the adapter.
7. Carefully place the syringe in the mouth, on the cheek, swallow the drug, slowly pressing the plunger of the syringe. Do not press the plunger too much, the solution can get to the back of the pharynx and cause choking.
8. Repeat the procedures 3-7 until the complete dose is obtained.
9. Do not leave the syringe in the vial, after use, rinse the dosing syringe and adapter thoroughly with clean water.
10. Close the vial tightly.
SIDE EFFECT
The profile of adverse events with zidovudine is similar in adults and children.
The undesirable phenomena presented below are listed depending on the anatomical and physiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1 000 and <1/100), rarely (? 1/10 000 and <1/1 000), very rarely(<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.
From the hemopoiesis and lymphatic system: often - anemia (which may require blood transfusion), neutropenia and leukopenia. Anemia often occurs when taking high doses of the drug (1200-1500 mg / day) and in patients in the late stages of HIV infection, in particular, when the concentration of CD4-lymphocytes is less than 100 cells / Ојl. As a result, a dose reduction or discontinuation of therapy may be required. The incidence of neutropenia was higher in patients who had low neutrophil counts, hemoglobin and serum levels of vitamin B12 before treatment; infrequently - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.
From the side of metabolism and nutrition : often - hyperlactatemia; rarely - lactic acid, anorexia. Redistribution and / or accumulation of subcutaneous fat (the development of this phenomenon depends on many factors, including the combination of antiretroviral drugs).
From the central and peripheral nervous system: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions.
From the psychic sphere: rarely - anxiety, depression.
From the cardiovascular system: rarely - cardiomyopathy.
From the respiratory system, chest and mediastinum : infrequently - shortness of breath; rarely - a cough.
From the digestive tract: very often - nausea; often - vomiting, abdominal pain, diarrhea; infrequently - flatulence; rarely - pigmentation of the oral mucosa, a taste disorder, dyspepsia.
From the liver, biliary tract and pancreas: often - increased levels of bilirubin and liver enzyme activity; rarely - liver damage, such as severe hepatomegaly with steatosis; pancreatitis.
From the skin and subcutaneous fat: rarely - rash, itchy skin; rarely - pigmentation of nails and skin, urticaria, increased sweating.
From the osteomuscular system: often - myalgia; infrequently - myopathy.
From the urinary system: rarely - frequent urination.
From the endocrine system: rarely - gynecomastia.
General and local reactions: often - malaise; infrequently - fever, generalized pain syndrome, asthenia; rarely - chills, chest pain, flu-like syndrome.
Undesirable reactions that occur when using Retrovir to prevent the transmission of HIV from the mother to the fetus
Pregnant women tolerate Retrovir well at recommended doses. Children have a decrease in hemoglobin, which, however, does not require blood transfusions. Anemia disappears 6 weeks after the completion of Retrovir therapy.
CONTRAINDICATIONS
- hypersensitivity to zidovudine or any other component of the drug;
- neutropenia (the number of neutrophils is less than 0.75 x 10 9 / l);
- reduction of hemoglobin (less than 75 g / l or 4.65 mmol / l).
With caution: patients of advanced age; when oppression of bone marrow hematopoiesis; with anemia; with severe hepatic insufficiency.
PREGNANCY AND LACTATION
Zidovudine penetrates the placenta. The drug Retrovir can be used earlier than 14 weeks of pregnancy only if the potential benefit to the mother exceeds the risk to the fetus.
The use of Retrovir after 14 weeks of pregnancy and its subsequent administration in neonates leads to a decrease in the frequency of vertical transmission of HIV.
The long-term consequences of the use of Retrovir in children who received it in the prenatal or neonatal periods are unknown. It is impossible to completely exclude the possibility of carcinogenic effects. Pregnant women should be informed about this.
Pregnant women who use Retrovir during pregnancy to prevent vertical transmission of HIV should be informed of the risk of fetal infection, despite ongoing therapy.
Because zidovudine and HIV penetrate into breast milk, women should not breast-feed while taking Retrovir.
There is no evidence of the effect of Retrovir on women's fertile function. In men, taking Retrovir does not affect the sperm composition, morphology and motility of spermatozoa.
APPLICATION FOR FUNCTIONS OF THE LIVER
In severe disorders of kidney function, the recommended dose of Retrovir is 300-400 mg / day. Depending on the response from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not have a significant effect on the excretion of zidovudine, but the excretion of 5'-glucuronide of zidovudine is accelerated. For patients with terminal stage of renal failure who are on hemodialysis or peritoneal dialysis , the recommended dose of Retrovir В® is 100 mg every 6-8 hours.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Data obtained in patients with cirrhosis of the liver indicate that patients with hepatic insufficiency may experience cumulation of zidovudine due to a decrease in glucuronization, which may require dose adjustment. If monitoring of zidovudine concentrations in plasma is not possible, the physician should pay special attention to the clinical signs of drug intolerance and, if necessary, adjust the dose and / or increase the interval between doses of the drug.
APPLICATION FOR CHILDREN
The application is possible according to the dosing regimen.
APPLICATION IN ELDERLY PATIENTS
With caution: patients of advanced age;
SPECIAL INSTRUCTIONS
Treatment with Retrovir should be performed by a physician with experience in the treatment of HIV-infected patients. After opening the vial, it should not be stored for more than 28 days at a temperature not exceeding 30 В° C.
Patients should be informed about the danger of the simultaneous use of the drug Retrovir with OTC drugs and that use of the drug Retrovir does not prevent the transmission of HIV through sexual contact or contaminated blood. Appropriate security measures.
Emergency prevention probable infection with
According to international guidelines (Center for Disease Control and Prevention, USA, June 1998), and the probability of contact with HIV-infected material (blood, other fluids) is an urgent need for 1-2 hours after infection assign combination therapy preparations and Retrovir Epivir. In the case of a high risk of exposure to the treatment regimen must be enabled preparation from the group of protease inhibitors. Prophylactic treatment is recommended for 4 weeks. Despite the rapid initiation of treatment with antiretroviral drugs, we can not exclude the development of seroconversion.
Symptoms that side reactions take for Retrovir drug therapy may be a manifestation of the underlying disease or response to treatment with other drugs used to treat HIV infection. The relationship between the developed symptoms and the effect of the drug Retrovir is often very difficult to establish, especially in the developed clinical picture of HIV infection. In such cases, may decrease the dose of the drug or its cancellation.
Retrovir is not a cure for HIV infection and patients remain at risk of opportunistic infections and malignancies, which is associated with immunosuppression. Retrovir reduces the risk of developing opportunistic infections. Data on the risk of developing lymphomas during treatment with the drug is limited.
Adverse reactions from the hematopoietic system
Anemia (usually occurs within 6 weeks from the start of the use of Retrovir drug, but sometimes it can develop earlier), neutropenia (usually develops within 4 weeks of starting treatment with Retrovir, but sometimes occurs earlier), leucopenia may occur in the later stages of HIV infection in patients receiving Retrovir, especially at high doses (1200-1500 mg / day), and having reduced hematopoiesis bone marrow before treatment.
During a drug Retrovir patients developed clinical picture of HIV infection should monitor hematologic parameters at least once every 2 weeks during the first 3 months of treatment and then monthly. In the early stages of HIV infection (at nondepleted reserves medullary hematopoiesis) adverse reactions on the part of the hematopoietic system are rare, so the common blood tests may be performed less often, depending on the overall condition of the patient (once in 1-3 months).
If the hemoglobin content is reduced to 75-90 g / L (4.65-5.59 mmol / L) or the number of neutrophils is reduced to 0.75-1.0 Г— 10 9/ L, a daily dose of Retrovir preparation should be reduced to restore blood counts or Retrovir canceled for 2-4 weeks prior to recovery of blood parameters. Generally, the blood picture normalized after 2 weeks, after which the drug Retrovir reduced dose may be reappointed. Despite the reduction in the dose of the drug Retrovir, blood transfusion may be required in severe anemia.
Radiation therapy enhances myelosuppressive effect of zidovudine.
Lactic acidosis and severe hepatomegaly with steatosis
These complications can be fatal as in monotherapy Retrovir and when applying Retrovir drug in combination therapy. Clinical signs of these complications may be weakness, anorexia, sudden unexplained weight loss, from the gastrointestinal tract symptoms, respiratory symptoms (dyspnea and tachypnea).
Caution must be exercised when administering the drug to patients, especially with risk factors for liver disease. The risk of developing these complications increases in women. Retrovir drug should cancel in all cases the appearance of clinical or laboratory signs of lactic acidosis or hepatotoxicity, which may include hepatomegaly with steatosis even in the absence of increasing transaminase activity.
Subcutaneous fat Redistribution
Redistribution and / or accumulation of subcutaneous fat, including central type obesity, increased fat layer on the back of the neck ( "buffalo hump"), reducing the subcutaneous fat layer on the face and limbs, breast enlargement, increase of serum lipids and glucose in the blood It was noted in the complex, and separately in some patients receiving combination antiretroviral therapy.
Until the present time, all drugs in the class of protease inhibitors and nucleoside reverse transcriptase inhibitors are associated with one or more specific undesired phenomenon associated with a common syndrome is often called lipodystrophy. However, the data indicate the existence of differences in the risk of developing this syndrome among specific members of therapeutic classes.
In addition, the lipodystrophy syndrome has a multifactorial etiology, for example, such factors as the stage of HIV infection, older age and duration of antiretroviral therapy, play an important role may potentiate.
Long-term consequences of this phenomenon are currently unknown.
Clinical examination should include physical examination to assess the presence of redistribution of subcutaneous fat. It should be encouraged to study concentrations of serum lipids and blood glucose. Lipid disorders should be treated in accordance with clinical indications.
Immune reconstitution syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy may increase the inflammatory process in the background asymptomatic or residual opportunistic infections that can cause serious deterioration or worsening of symptoms. Typically, such reactions have been described in the first weeks or months of initiation of antiretroviral therapy. The most significant examples - cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and Pneumocystis (P. carinii). Any inflammatory symptoms should be immediately identified and begin treatment if necessary.
Co-infection with HIV and hepatitis C
It has been reported about the rise of ribavirin-induced anemia in HIV-infected patients receiving concomitant therapy with zidovudine, but the exact mechanism is unknown. Therefore it is not recommended to combine the use of ribavirin and zidovudine. It is necessary to change the antiretroviral regimen, using a scheme not containing zidovudine, particularly in patients with AZT-induced anemia in history.
Impact on the ability to drive vehicles and manage mechanisms
Retrovir influence of the drug on the ability to drive or explore mechanisms. However, an adverse effect on these abilities is unlikely, based on the pharmacokinetics of the drug. However, when deciding on the possibility to drive a car or moving machinery, it should be borne in mind the patient's condition and the possibility of adverse reactions (dizziness, drowsiness, lethargy, convulsions).
OVERDOSE
Symptoms may be fatigue, headache, vomiting; very rarely - changes in the blood parameters. There is one report of an overdose of an unknown quantity of zidovudine when AZT concentration in the blood exceeded 16 times the normal therapeutic concentration, however, with clinical, biochemical or haematological signs were absent.
Treatment: symptomatic therapy and supportive therapy. Hemodialysis and peritoneal dialysis are not highly efficient for the removal of AZT from the body, but enhance its metabolite excretion - 5'-glucuronide of AZT.
DRUG INTERACTION
Zidovudine mainly excreted as inactive metabolite constituting the glucuronide conjugate, produced in the liver. Preparations having similar clearance path can potentially inhibit the metabolism of AZT.
Zidovudine is used in combination therapy with other nucleoside reverse transcriptase inhibitors, and drugs of other groups (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
The list of interactions listed below should not be considered exhaustive, but it includes a group of drugs that require careful use together with zidovudine.
atovaquone:Zidovudine has no effect on the pharmacokinetic parameters of atovaquone. Atovaquone retards transformation AZT glucuronide derivative (AUC zidovudine in the equilibrium state is increased by 33% and the maximum concentration of glucuronide reduced by 19%). Zidovudine unlikely change the safety profile at doses of 500 or 600 mg / day with concomitant use of atovaquone for three weeks for the treatment of Pneumocystis carinii pneumonia. If necessary a longer combined use of these drugs is recommended careful monitoring of the clinical state of the patient.
Clarithromycin: reduces the absorption of zidovudine. The interval between doses of clarithromycin and zidovudine must be at least 2 hours.
Lamivudine: observed a moderate increase in C maxzidovudine (up to 28%) while the use of lamivudine, but overall exposure (AUC) is not changed. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin: while use of the drug phenytoin Retrovir reduced concentration of the latter in the blood plasma, it is necessary to control the concentration of phenytoin in blood plasma when using this combination.
Probenecid: reducing glucuronidation and increases the average T 1/2 and AUC of zidovudine. Renal excretion of AZT glucuronide and reduced in the presence of probenecid.
Rifampicin: combination drug Retrovir rifampicin reduces the AUC for zidovudine 48% В± 34%, but the clinical significance of this change is not known.
Stavudine: zidovudine may inhibit the intracellular phosphorylation of stavudine. Thus, it is not recommended to use both stavudine with zidovudine.
Others: acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinosine can disrupt the metabolism of zidovudine by competitively inhibiting glucuronidation or direct suppression microsomal metabolism in the liver. By the possibility of using these drugs in combination with a preparation Retrovir, especially for long-term therapy, must be viewed with caution.
Combination drug Retrovir, especially in emergency therapy with potentially nephrotoxic and myelotoxic agents (e.g., pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse drug reactions Retrovir . It should be monitored for renal function and blood count, lower doses of the drugs, if necessary.
Since in some patients, even though the drug Retrovir therapy may develop opportunistic infections, it is necessary to consider the appointment of prophylactic antimicrobial therapy. Such prevention comprises the co-trimoxazole, pentamidine aerosol, pyrimethamine and acyclovir. Limited data from clinical studies showed no significant increase in the risk of adverse reactions when used together Retrovir medication with these drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored at temperatures not above 30 В° C, the reach of children. Shelf life - 2 years. Do not use after the expiration date printed on the package.
