Composition, form of production and packaging
The tablets covered with a film membrane of white or almost white color, round, biconcave.
1 tab.
zidovudine 100 mg
Excipients: sodium carboxymethyl starch 5 mg, pregelatinized starch 5 mg, silicon dioxide colloid 0.4 mg, magnesium stearate 0.6 mg, microcrystalline cellulose 86 mg.
Film coating composition: ready water-soluble film membrane 3 mg (hypromellose 25%, copolyvidone 22.5%, polyethylene glycol 6000 9.5%, glyceryl caprylcaprate 3%, polydextrose 15%, titanium dioxide 25%).
10 pieces. - Cellular outline packaging (aluminum / PVC) (1) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (2) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (3) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (5) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (6) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (10) - cardboard packs.
20 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
50 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
60 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
100 pieces. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
200 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
500 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
Tablets covered with a film coat of white or almost white color, capsular, biconvex, with a risk on one side.
1 tab.
zidovudine 300 mg
Excipients: sodium carboxymethyl starch 15 mg, pregelatinized starch 15 mg, colloidal dioxide silicon dioxide 1.2 mg, magnesium stearate 1.8 mg, microcrystalline cellulose 258 mg.
Composition of the film shell: ready water-soluble film membrane 9 mg (hypromellose 25%, copolyvidone 22.5%, polyethylene glycol 6000 9.5%, glyceryl caprilocaprate 3%, polydextrose 15%, titanium dioxide 25%).
10 pieces. - Cellular outline packaging (aluminum / PVC) (1) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (2) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (3) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (5) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (6) - cardboard packs.
10 pieces. - Cellular outline packaging (aluminum / PVC) (10) - cardboard packs.
20 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
50 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
60 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
100 pieces. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
200 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
500 pcs. - polymer cans with a ring of the first opening - boxes cardboard (for hospitals).
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Synthetic analogue of nucleosides. Within the cell, zidovudine is sequentially phosphorylated to the active metabolite, zidovudine-5'-triphosphate. Zidovudine triphosphate inhibits reverse transcriptase of HIV by interrupting the synthesis of the virus DNA after incorporation into the nucleotide chain. Zidovudine-triphosphate weakly inhibits cellular DNA-polmerase alpha and gamma.
In combination with other antiviral drugs increases the number of CD4 + cells.
PHARMACOKINETICS
Adults
Pharmacokinetics for oral administration is dose-independent in the dose range from 2 mg / kg every 8 hours to 10 mg / kg every 4 hours.
Absorption - fast, reception with fatty food reduces the degree and speed of absorption. Bioavailability in adults is 54-74%. Time to reach the maximum concentration in the blood (TC max ) after ingestion is 0.5-1.5 hours. The volume of distribution is 1.0-2.2 l / kg. The connection with plasma proteins is less than 38%.
Penetrates into most tissues and body fluids. It is found in cerebrospinal fluid at a concentration of 15-64% of that in plasma. Metabolised in the liver. The main metabolite of zidovudine is glucuronide. the area under the "concentration-time" curve (AUC) of which is 3 times greater than the AZUC of AZT. The average half-life (T 1/2 ) of the cells is 3.3 h; from serum of blood in adults-about 1 hour (0.8-1.2 hours). After ingestion, 14% of zidovudine and 74% of its metabolite are found in the urine.
Patients with impaired renal function
In patients with severe renal failure, the maximum concentration of zidovudine in plasma is increased by 50% compared to that in patients without impaired renal function. The system exposure of the drug (defined as the area under the concentration-time curve) is increased by 100%; the half-life does not change significantly. With renal failure, there is a significant cumulation of the main metabolite of zidovudine - glucuronide, with no signs of toxic effects. Hemodialysis and peritoneal dialysis do not affect the elimination of zidovudine, while the removal of glucuronide is enhanced.
Patients with impaired hepatic function
With hepatic insufficiency, cumulation of zidovudine may be observed due to a decrease in glucuronization, which requires correction of the dose of the drug.
Elderly patients
The pharmacokinetics of zidovudine has not been studied in patients older than 65 years.
Pharmacokinetics in children
In children older than 5-6 months, pharmacokinetic parameters are similar to those in adults.
Pregnancy
Pharmacokinetics in pregnant women is similar to that of non-pregnant women. 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 caused by HIV-1 (as part of combined aitiretroviral therapy);
- prevention of perinatal transmission of HIV from an infected mother to a child, as zidovudine reduces the risk of intrauterine infection of the fetus.
DOSING MODE
Inside, regardless of food intake.
For adults , the drug is administered at a dose of 600 mg per day in several divided doses. Children with a body weight of more than 30 kg - 300 mg 2 times a day or 200 mg 3 times a day. When calculating the surface area of ​​the body appoint 160 or 240 mg / m 2 3 or 2 times a day, respectively (daily dose of 480 mg / m 2 ).
If the hemoglobin content is reduced to 75-90 g / l and / or the neutrophil count is reduced to 0.75-1.0 Г— 10 9 / L, a dose reduction or Zidovudip therapy can be required before hematopoiesis is restored. When anemia occurs, drug cancellation does not always reduce the need for blood transfusion. For more rapid recovery of bone marrow function, epoetin alfa can be prescribed at recommended doses.
Elderly patients
The pharmacokinetics of zidovudine in patients over the age of 65 years has not been studied. However, given the age-related decline in renal function and possible changes in peripheral blood parameters, such patients should be especially careful when using zidovudine and perform appropriate monitoring before and during treatment with the drug.
Renal insufficiency
In severe renal failure, the recommended daily dose is 300-400 mg. Depending on the response from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis have no significant effect on the elimination of zidovudine, but accelerate the excretion of its metabolite - glucuronide. For patients with end-stage renal failure who are on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6-8 hours.
Liver failure
In patients with hepatic insufficiency cumulation of zidovudine may be observed due to a reduction in glucuronization, which may require correction of the dose of the drug. 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.
Prevention of mother-to-child transmission of HIV
Effective 2 schemes of prevention:
1. Pregnant women, starting from 14 weeks of pregnancy, are recommended to prescribe zidovudine inside before the birth at a dose of 500 mg per day (100 mg 5 times a day).
2. Pregnant women, starting at 36 weeks of gestation, are recommended to administer zidovudine inside at a dose of 600 mg per day (300 mg 2 times per day) before the onset of labor, and then at a dose of 300 mg every 3 hours until delivery.
SIDE EFFECT
Undesirable reactions that occur with zidovudine treatment are the same in children and adults.
The following gradations were used to estimate the incidence of undesired reactions: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000), very rarely (<1/10000).
From the hemopoiesis: often - anemia (which may require blood transfusion), neutropenia, leukopenia, infrequently - thrombocytopenia, pancytopenia with bone marrow hypoplasia, rarely - erythrocyte aplasia, very rarely - aplastic anemia.
From the digestive tract: very often - nausea, often - vomiting, pain in the upper abdomen, diarrhea, infrequent - flatulence, rarely - dyspepsia, taste distortion, pigmentation of the oral mucosa, pancreatitis, anorexia.
From the hepatobiliary system: often - hyperbilirubinemia, increased activity of hepatic enzymes, rarely expressed hepatomegaly with steatosis.
From the nervous system : very often - headache, often - dizziness, rarely - paresthesia, insomnia, drowsiness, decreased mental performance, convulsions, anxiety, depression.
From the respiratory system: infrequently - shortness of breath, rarely - cough.
From the cardiovascular system: cardiomyopathy.
From the urinary system: rarely - frequent urination.
On the part of the endocrine system and metabolism: often - hyperlactatemia, rarely - lactate-acidosis, gynecomastia.
From the musculoskeletal system: often - myalgia, infrequently - myopathy.
On the part of the skin: infrequent - skin rash, skin itch, rarely - pigmentation of nails and skin, increased sweating, urticaria.
Other: often - malaise, infrequently - fever, asthenia, generalized pain syndrome, rarely - flu-like syndrome. Chills, chest pain, redistribution / accumulation of subcutaneous fat.
Adverse reactions that occur when zidovudine is used to prevent the transmission of HIV from mother to fetus.
Pregnant women tolerate zidovudine well at recommended doses. Children have a decrease in hemoglobin, which, however, does not require blood transfusions. Anemia disappears 6 weeks after the end of zidovudine therapy.
CONTRAINDICATIONS
- hypersensitivity to zidovudine or any other component of the drug;
- neutropenia / leukopenia (the number of neutrophils is below 0.75 Г— 10 9 / l); anemia (hemoglobin below 75 g / l);
- simultaneous reception with stavudine, doxorubicin, other drugs that reduce the antiviral activity of zidovudine;
- Children's age (with a body weight of less than 30 kg).
Carefully
Oppression of bone marrow hematopoiesis, deficiency of cyanocobalamin or folic acid, hepatic insufficiency, elderly age, obesity, hepatomegaly. hepatitis or any risk factors for liver disease, neutropenia / leukopenia (neutrophil count 0.75-1.0 Г— 10 9 / L): anemia (hemoglobin 75-90 g / l).
PREGNANCY AND LACTATION
Zidovudine penetrates the placenta. The drug can be used during pregnancy before 14 weeks only if the potential benefit to the mother exceeds the possible risk to the fetus. The use of zidovudine after 14 weeks of pregnancy and its subsequent use in neonates leads to a decrease in the frequency of HIV transmission from mother to the fetus. The long-term effects of zidovudine in children who received it in the intrauterine or neonatal periods are not known. It is impossible to completely exclude the possibility of carcinogenic effects.
If zidovudine is used during lactation, breastfeeding should be stopped.
APPLICATION FOR FUNCTIONS OF THE LIVER
In severe renal failure, the recommended daily dose is 300-400 mg. Depending on the response from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis have no significant effect on the elimination of zidovudine, but accelerate the excretion of its metabolite - glucuronide. For patients with end-stage renal failure who are on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6-8 hours.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with hepatic insufficiency cumulation of zidovudine may be observed due to a reduction in glucuronization, which may require correction of the dose of the drug. 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.
APPLICATION FOR CHILDREN
The drug is contraindicated for children with a body weight of less than 30 kg.
APPLICATION IN ELDERLY PATIENTS
The pharmacokinetics of zidovudine in patients over the age of 65 years has not been studied. However, given the age-related decline in renal function and possible changes in peripheral blood parameters, such patients should be especially careful when using zidovudine and perform appropriate monitoring before and during treatment with the drug.
SPECIAL INSTRUCTIONS
Patients should be informed of the danger of concomitant use of zidovudine with OTC drugs and that the use of zidovudine does not prevent the risk of HIV transmission to other people during sexual intercourse or blood transfusion. Therefore, patients should take appropriate precautions.
Emergency prevention in case of possible HIV infection
According to international recommendations, if a person infected with HIV is likely to be infected through the blood (for example, through an injection needle), an emergency combination of zidovudine and lamivudine should be prescribed within 1-2 hours of the time of infection. In the case of a high risk of infection, a drug from the protease inhibitor group should be included in the regimen of antiretroviral therapy. Preventive treatment is recommended for 4 weeks. Despite the rapid onset of treatment with antiretroviral drugs, seroconversion can not be ruled out.
Symptoms that are taken for adverse reactions to zidovudine may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between evolved symptoms and the effects of zidovudine is often very difficult to establish, especially when the clinical picture of HIV infection is deployed. In such cases, it is possible to reduce the dose of the drug or to abolish it.
Zidovudine does not cure HIV infection, and patients remain at risk of developing a detailed picture of the disease with suppression of immunity and the emergence of opportunistic infections and malignant tumors. In HIV infection, zidovudine reduces the risk of developing opportunistic infections, but does not reduce the risk of developing lymphomas.
Undesirable reactions from the organs of hematopoiesis
Anemia (usually observed 6 weeks after the initiation of zidovudine therapy, but sometimes it may develop earlier), neutropenia (usually occurs 4 weeks after the initiation of zidovudine therapy, but sometimes occurs earlier), leukopenia can occur in patients with a developed clinical picture of HIV infection receiving zidovudine. especially in high doses (1200-1500 mg / day), with a reduced reserve of bone marrow before the start of therapy. When taking zidovudine in patients with a developed clinical picture of HIV infection, blood tests should be monitored at least once every 2 weeks during the first 3 months of therapy, and then monthly. In the early stage of HIV infection (when bone marrow hemopoiesis is still within the normal range), adverse reactions from the blood develop rarely, so blood tests are performed less often - depending on the patient's general condition once every 1-3 months.
If the hemoglobin content is reduced to 75-90 g / l and / or the number of neutrophils is reduced to 0.75-1.0 Г— 10 9 / l, the daily dose of the drug should be reduced, or zidovudine is canceled for 2-4 weeks before the recovery of blood. Usually, the blood picture is normalized after 2 weeks, after which zidovudine in a reduced dose can be re-assigned. When anemia occurs, drug cancellation does not always reduce the need for blood transfusion.
Radiation therapy enhances the myelosuppressive effect of zidovudine.
Lactic Acidosis and severe hepatomegaly with steatosis
These complications can have a fatal outcome, both with zidovudine monotherapy and with zidovudine in combination antiretroviral therapy. The risk of these complications is higher in female patients. Signs of development of these complications can be general weakness, sudden unexplained weight loss, anorexia, symptoms of the digestive system (nausea, vomiting, pain in the abdominal area), symptoms from the respiratory system (rapid breathing or shortness of breath). In case of clinical or laboratory signs of lactic acidosis or toxic liver damage, zidovudine should be discontinued.
Redistribution of subcutaneous fat
In some patients, combination antiretroviral therapy may be associated with redistribution / accumulation of subcutaneous fat, including reducing the amount of fat in the face and extremities, an increase in visceral fat, an increase in mammary glands and fat deposition on the back of the neck and back ( "buffalo hump"), as well as an increase in lipid concentration in serum and the concentration of glucose in the blood.
Although one or more of the above adverse reactions associated with a common syndrome, which is often called lipodystrophy can cause weight drugs in the classes of protease inhibitors and nucleoside reverse transcriptase inhibitors, accumulated data suggest that there are differences between individual representatives of these classes of drugs in the ability to induce the undesirable reactions.
In addition, the lipodystrophy syndrome is a multifactorial etiology; eg, stage of HIV infection, older age and duration of antiretroviral therapy are important, possibly potentiating role in the development of this complication. Long-term consequences of these adverse reactions is not currently installed. Clinical examination should include inspection for signs of fat redistribution. It should also monitor the concentration of lipids and glucose in the blood serum. Lipid metabolism must be adjusted according to clinical indications.
myopathy
It should be borne in mind that the development of myopathy symptoms (myalgia, weakness, increased activity of CK) in HIV-infected patients may be due to the underlying disease. In the application of AZT at doses of 500 mg or 600 mg per day of myopathy associated with the administration of the drug, it is rarely observed. In the case of myopathy caused by AZT, the drug should be discontinued.
Immune reconstitution syndrome
In HIV-infected patients with severe immune deficiency at the time of the beginning aitiretrovirusnoy therapy may increase the inflammatory process in the background asymptomatic or low-grade opportunistic infection that can cause serious deterioration or worsening of symptoms. Typically, such reactions have been observed within the first weeks or months after the start of therapy aitiretrovirusnoy. The most significant examples - cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and Pneumocystis pneumonia. Any inflammatory symptoms should be immediately identified and begin treatment on time. Autoimmune diseases (such as Graves disease, nolimiozit and Guillain-Barre syndrome) observed on a background of immune reconstitution, however, the time of primary manifestations varied,and the disease could occur many months after initiation of therapy and have an atypical course.
Patients infected with both HIV and hepatitis C virus (HCV)
in vitro studies have shown that ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs, including zidovudine. While clear evidence of a pharmacokinetic and pharmacodynamic interaction ribavirin and zidovudine in patients with co-infection (HIV-1 / HCV) has been detected.
It reported a worsening of ribavirin-induced anemia in HIV-infected patients receiving concomitant therapy with zidovudine. The mechanism of this effect is currently unknown. Therefore, the simultaneous use of ribavirin and zidovudine is not recommended. Replace circuit antiretroviral therapy alternative containing no AZT, especially with a history with anemia associated with zidovudine.
It reported cases of hepatic impairment (sometimes fatal) in patients infected with HIV-1 with concomitant hepatitis C receiving combination antiretroviral therapy for HIV-1 and interferon alpha with ribavirin or without ribavirin. With simultaneous use of zidovudine and interferon alpha with ribavirin or ribavirin should be performed without careful monitoring of patients for signs of toxicity, particularly liver failure, anemia and neutropenia. With increasing clinical manifestations of toxicity, particularly liver failure (> 6 points on the Child-Pugh) dose should be reduced or canceled interferon alpha, ribavirin, or both drugs. In the case of myelosuppression should consider interruption or discontinuation of zidovudine.
Effects on ability to drive vehicles and mechanisms
In the period of treatment must be careful when driving and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions. At occurrence of such undesirable effects like dizziness, drowsiness, lethargy, convulsions, you should refrain from carrying out these activities.
OVERDOSE
Symptoms: fatigue, headache, vomiting, impaired hematological parameters.
Treatment: symptomatic. Hemodialysis and peritoneal dialysis are not effective for the removal of zidovudine from the body, but accelerate the excretion of its metabolite - glucuronide.
DRUG INTERACTION
AZT is used as part of combination antiretroviral therapy, together with other nucleoside reverse transcriptase inhibitors, and other groups of drugs (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). The list of interactions listed below should not be considered exhaustive, but they are typical for products that require careful application together with zidovudine.
Lamivudine: observed a moderate increase in maximum blood concentration (28%) for the appointment of zidovudine together with lamivudine, however, the total exposure (AUC) is not disturbed. Zidovudine has no effect on the pharmacokinetics of lamivudine.
phenytoin:zidovudine reduces the concentration of phenytoin in the blood, which requires monitoring the concentration of phenytoin in the blood, while his appointment with zidovudine.
Probenecid: reducing glucuronidation and increases the average half-life and AUC of zidovudine. Renal excretion of AZT glucuronide and reduced in the presence of probenicid.
Atovaquone: Zidovudine has no effect on the pharmacokinetic parameters of atovaquone. AZT slows atovaquone glucuronidation (AUC zidovudine in the equilibrium state is increased by 33%, the maximum concentration of glucuronide reduced by 19%). It is unlikely change the safety profile of AZT, administered in doses of 500 or 600 mg per day, while the use of atovaquone for three weeks.
If necessary a longer simultaneous 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 drugs must be at least 2 hours.
Valproic acid, fluconazole, methadone: reduce zidovudine clearance, thereby increasing its systemic exposure.
Ribavirin: nucleoside analogue ribavirin antagonizes AZT. Avoid the simultaneous use of zidovudine and ribavirin.
Rifampicin: combination of zidovudine with rifampicin reduces the AUC for zidovudine 48% В± 34%, however, the clinical significance of this change is not known.
stavudine:Zidovudine can inhibit the intracellular phosphorylation of stavudine. Stavudine should not be used concurrently with zidovudine.
other:drugs such as paracetamol, acetylsalicylic acid, codeine, methadone, morphine, 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 zidovudine, especially for long-term therapy, must be viewed with caution. The combination of zidovudine, particularly 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 reactions to zidovudine.You need to monitor renal function and blood counts and dose reduction, if required.
