Azimitem (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AF01 (Zidovudine)

Active Substance

Zidovudine (Rec.INN registered by WHO)

Dosage Forms

	Azimitem	Film-coated tablets, 100 mg: 10, 20, 30, 50, 60 or 100 pcs.
		Film-coated tablets, 300 mg: 10, 20, 30, 50, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex.

	1 tab.
Zidovudine	100 mg

Excipients: sodium carboxymethyl starch 5 mg, pregelatinized starch 5 mg, colloidal silicon dioxide 0.4 mg, magnesium stearate 0.6 mg, microcrystalline cellulose 86 mg.

Film coating composition: ready-to-use water-soluble film coating 3 mg (hypromellose 25%, copovidone 22.5%, polyethylene glycol 6000 9.5%, glyceryl caprylocaprate 3%, polydextrose 15%, titanium dioxide 25%).

10 pcs. – contour cell packaging (aluminum/PVC) (1) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (2) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (3) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (5) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (6) – cardboard packs.
10 pcs. – contour cell packaging (aluminum/PVC) (10) – cardboard packs.
20 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).
50 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).
60 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).
100 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).
200 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).
500 pcs. – polymer jars with first opening ring – cardboard boxes (for hospitals).

Film-coated tablets white or almost white, capsule-shaped, biconvex, with a score on one side.

	1 tab.
Zidovudine	300 mg

Excipients: sodium carboxymethyl starch 15 mg, pregelatinized starch 15 mg, colloidal silicon dioxide 1.2 mg, magnesium stearate 1.8 mg, microcrystalline cellulose 258 mg.

Film coating composition: ready-to-use water-soluble film coating 9 mg (hypromellose 25%, copovidone 22.5%, polyethylene glycol 6000 9.5%, glyceryl caprylocaprate 3%, polydextrose 15%, titanium dioxide 25%).

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleoside and nucleotide reverse transcriptase inhibitors

Pharmacological Action

Synthetic nucleoside analogue. Inside the cell, Zidovudine is sequentially phosphorylated to the active metabolite, Zidovudine-5′-triphosphate. Zidovudine triphosphate inhibits HIV reverse transcriptase by interrupting viral DNA synthesis after incorporation into the nucleotide chain. Zidovudine triphosphate weakly inhibits cellular DNA polymerases alpha and gamma.

In combination with other antiviral drugs, it increases the number of CD4+ cells.

Pharmacokinetics

Adults

Pharmacokinetics after oral administration is dose-independent in the dose range from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.

Absorption is rapid; administration with fatty food reduces the extent and rate of absorption. Bioavailability in adults is 54-74%. Time to reach maximum blood concentration (T_max) after oral administration is 0.5-1.5 hours. Volume of distribution is 1.0-2.2 L/kg. Plasma protein binding is less than 38%.

It penetrates into most body tissues and fluids. It is detected in the cerebrospinal fluid at a concentration of 15-64% of that in plasma. It is metabolized in the liver. The main metabolite of zidovudine is the glucuronide. The area under the concentration-time curve (AUC) of the glucuronide is 3 times greater than the AUC of zidovudine. The mean half-life (T_1/2) from cells is 3.3 hours; from serum in adults is about 1 hour (0.8-1.2 hours). After oral administration, 14% of zidovudine and 74% of its metabolite are found in the urine.

Patients with impaired renal function

In patients with severe renal impairment, the maximum plasma concentration of zidovudine is increased by 50% compared to patients without renal impairment. Systemic exposure to the drug (defined as the area under the concentration-time curve) is increased by 100%; the half-life does not change significantly. In renal failure, significant accumulation of the main metabolite of zidovudine, the glucuronide, is observed, with no signs of toxic effects. Hemodialysis and peritoneal dialysis do not affect the elimination of zidovudine, while the elimination of the glucuronide is enhanced.

Patients with impaired liver function

In hepatic insufficiency, accumulation of zidovudine may occur due to reduced glucuronidation, which requires dose adjustment of the drug.

Elderly patients

The pharmacokinetics of zidovudine has not been studied in patients over 65 years of age.

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 in non-pregnant women. The plasma concentration of zidovudine in children at birth is the same as in their mothers during childbirth.

Indications

Treatment of HIV infection caused by HIV-1 (as part of combined antiretroviral therapy);
Prevention of perinatal transmission of HIV from an infected mother to her child, as Zidovudine reduces the risk of intrauterine infection of the fetus.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
B24	Human immunodeficiency virus [HIV] disease, unspecified
O98.7	Human immunodeficiency virus [HIV] disease complicating pregnancy, childbirth and the puerperium

ICD-11 code	Indication
1C62.1	HIV disease, clinical stage 2, without mention of tuberculosis or malaria
JB63.7	Human immunodeficiency virus complicating pregnancy, childbirth, or the puerperium

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Orally, regardless of meals.

Adult patients are prescribed the drug at a dose of 600 mg per day in several doses. Children weighing more than 30 kg – 300 mg 2 times a day or 200 mg 3 times a day. When calculated based on body surface area, 160 or 240 mg/m² is prescribed 3 or 2 times a day, respectively (daily dose 480 mg/m²).

If hemoglobin decreases to 75-90 g/L and/or the neutrophil count decreases to 0.75-1.0×10⁹/L, a dose reduction or discontinuation of zidovudine therapy may be required until hematopoiesis is restored. If anemia occurs, discontinuing the drug does not always reduce the need for blood transfusion. For faster recovery of bone marrow function, epoetin alfa may be prescribed at recommended doses.

Elderly patients

The pharmacokinetics of zidovudine in patients over 65 years of age has not been studied. However, given the age-related decline in renal function and possible changes in peripheral blood parameters, special caution should be exercised when using zidovudine in such patients and appropriate monitoring should be carried out before and during treatment with the drug.

Renal impairment

In severe renal impairment, the recommended daily dose is 300-400 mg. Depending on the response of peripheral blood and clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not significantly affect the elimination of zidovudine but accelerate the excretion of its metabolite, the glucuronide. For patients with end-stage renal disease on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6-8 hours.

Hepatic impairment

In patients with hepatic impairment, accumulation of zidovudine may occur due to reduced glucuronidation, which may require dose adjustment of the drug. If monitoring of zidovudine plasma concentration is not possible, the physician should pay special attention to clinical signs of drug intolerance and, if necessary, adjust the dose and/or increase the interval between doses.

Prevention of HIV transmission from mother to fetus

Two prevention regimens are effective

Pregnant women, starting from 14 weeks of pregnancy, are recommended to take Zidovudine orally until the onset of labor at a dose of 500 mg per day (100 mg 5 times a day).
Pregnant women, starting from 36 weeks of pregnancy, are recommended to take Zidovudine orally at a dose of 600 mg per day (300 mg 2 times a day) until the onset of labor, and then at a dose of 300 mg every 3 hours until delivery.

Adverse Reactions

Adverse reactions occurring during treatment with zidovudine are the same in children and adults.

The following gradations were used to assess the frequency of adverse reactions: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000).

From the hematopoietic organs common – anemia (which may require blood transfusions), neutropenia, leukopenia, uncommon – thrombocytopenia, pancytopenia with bone marrow hypoplasia, rare – pure red cell aplasia, very rare – aplastic anemia.

From the gastrointestinal tract very common – nausea, common – vomiting, pain in the upper abdomen, diarrhea, uncommon – flatulence, rare – dyspepsia, taste perversion, pigmentation of the oral mucosa, pancreatitis, anorexia.

From the hepatobiliary system common – hyperbilirubinemia, increased activity of liver enzymes, rare – pronounced hepatomegaly with steatosis.

From the nervous system: very common – headache, common – dizziness, rare – paresthesia, insomnia, drowsiness, decreased mental performance, seizures, anxiety, depression.

From the respiratory system uncommon – dyspnea, rare – cough.

From the cardiovascular system cardiomyopathy.

From the urinary system rare – frequent urination.

From the endocrine system and metabolism common – hyperlactatemia, rare – lactic acidosis, gynecomastia.

From the musculoskeletal system common – myalgia, uncommon – myopathy.

From the skin uncommon – skin rash, skin itching, rare – pigmentation of nails and skin, increased sweating, urticaria.

Other common – malaise, uncommon – fever, asthenia, generalized pain syndrome, rare – flu-like syndrome. Chills, chest pain, redistribution/accumulation of subcutaneous fat.

Side effects occurring with the use of zidovudine for the prevention of HIV transmission from mother to fetus.

Pregnant women tolerate Zidovudine well at recommended doses. In children, a decrease in hemoglobin content is observed, which, however, does not require blood transfusions. Anemia disappears 6 weeks after completion of zidovudine therapy.

Contraindications

Hypersensitivity to zidovudine or any other component of the drug;
Neutropenia/leukopenia (neutrophil count below 0.75×10⁹/L); anemia (hemoglobin below 75 g/L);
Concomitant use with stavudine, doxorubicin, other drugs that reduce the antiviral activity of zidovudine;
Childhood (with body weight less than 30 kg).

With caution

Bone marrow suppression, cyanocobalamin or folic acid deficiency, hepatic insufficiency, elderly age, obesity, hepatomegaly, hepatitis or any risk factors for liver disease, neutropenia/leukopenia (neutrophil count 0.75-1.0 ×10⁹/L): anemia (hemoglobin 75-90 g/L).

Use in Pregnancy and Lactation

Zidovudine crosses the placenta. The drug can be used during pregnancy before 14 weeks only if the potential benefit to the mother outweighs the possible risk to the fetus. The use of zidovudine after 14 weeks of pregnancy followed by its use in newborns leads to a reduction in the frequency of HIV transmission from mother to fetus. The long-term consequences of using zidovudine in children who received it in the intrauterine or neonatal periods are unknown. The possibility of a carcinogenic effect cannot be completely excluded.

If zidovudine is used during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use in Renal Impairment

Pediatric Use

The drug is contraindicated in children weighing less than 30 kg.

Geriatric Use

Special Precautions

Patients should be informed about the danger of simultaneous use of zidovudine with over-the-counter drugs and that the use of zidovudine does not prevent the risk of transmitting HIV to others through sexual contact or blood transfusion. Therefore, patients should take appropriate precautions.

Emergency prophylaxis for probable HIV infection

According to international recommendations, in case of probable infection with HIV through the blood of an HIV-infected person (e.g., through an injection needle), combined therapy with zidovudine and lamivudine should be urgently prescribed (within 1-2 hours of infection). In case of high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral therapy regimen. Prophylactic treatment is recommended for 4 weeks. Despite the rapid initiation of treatment with antiretroviral drugs, the possibility of seroconversion cannot be excluded.

Symptoms mistaken 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 the developed symptoms and the action of zidovudine is often very difficult to establish, especially in the advanced clinical picture of HIV infection. In such cases, dose reduction or discontinuation of the drug is possible.

Zidovudine does not cure HIV infection, and patients remain at risk of developing the full picture of the disease with immunosuppression and the occurrence of opportunistic infections and malignant neoplasms. In HIV infection, Zidovudine reduces the risk of developing opportunistic infections but does not reduce the risk of developing lymphomas.

Adverse reactions from the hematopoietic organs

Anemia (usually observed after 6 weeks from the start of zidovudine therapy, but sometimes may develop earlier), neutropenia (usually develops after 4 weeks from the start of zidovudine therapy, but sometimes occurs earlier), leukopenia can occur in patients with advanced clinical picture of HIV infection receiving Zidovudine, especially in high doses (1200-1500 mg/day), with reduced bone marrow reserve before starting therapy. During zidovudine administration in patients with advanced clinical picture of HIV infection, blood tests should be monitored at least once every 2 weeks for the first 3 months of therapy, and then monthly. In the early stage of HIV infection (when bone marrow hematopoiesis is still within normal limits), adverse reactions from the blood are rare, so blood tests are performed less frequently – depending on the general condition of the patient, once every 1-3 months.

If hemoglobin decreases to 75-90 g/L and/or the neutrophil count decreases to 0.75-1.0×10⁹/L, the daily dose of the drug should be reduced, or Zidovudine should be discontinued for 2-4 weeks until blood counts recover. Usually, the blood picture normalizes after 2 weeks, after which Zidovudine at a reduced dose can be re-prescribed. If anemia occurs, discontinuing the drug 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 be fatal both during zidovudine monotherapy and when zidovudine is used as part of combined antiretroviral therapy. The risk of developing these complications is higher in female patients. Signs of these complications may include general weakness, sudden unexplained weight loss, anorexia, digestive system symptoms (nausea, vomiting, abdominal pain), and respiratory system symptoms (rapid breathing or shortness of breath). If clinical or laboratory signs of lactic acidosis or toxic liver damage appear, zidovudine should be discontinued.

Redistribution of Subcutaneous Adipose Tissue

In some patients, combined antiretroviral therapy may be accompanied by redistribution/accumulation of subcutaneous adipose tissue, including a decrease in adipose tissue in the face and limbs, an increase in visceral fat, breast enlargement, and fat deposition on the back of the neck and back (‘buffalo hump’), as well as an increase in serum lipid concentrations and blood glucose concentrations.

Although one or more of the adverse reactions listed above, associated with a general syndrome often called lipodystrophy, can be caused by many drugs from the classes of protease inhibitors and nucleoside reverse transcriptase inhibitors, accumulated data indicate differences between individual representatives of these drug classes in their ability to cause these adverse reactions.

In addition, the lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, older age, and the duration of antiretroviral therapy play an important, possibly potentiating, role in the development of this complication. The long-term consequences of these adverse reactions have not been established to date. Clinical examination of patients should include an assessment for signs of fat redistribution. Serum lipid and glucose concentrations should also be monitored. Lipid metabolism disorders should be managed as clinically indicated.

Myopathy

It should be considered that the development of myopathy symptoms (myalgia, weakness, increased CPK activity) in HIV-infected patients may be associated with the underlying disease. When using zidovudine at doses of 500 mg or 600 mg per day, drug-related myopathy is rare. If zidovudine-induced myopathy develops, the drug should be discontinued.

Immune Reconstitution Syndrome

In HIV-infected patients with severe immunodeficiency, initiation of antiretroviral therapy can cause an exacerbation of inflammation against the background of asymptomatic or indolent opportunistic infections, which can lead to serious clinical deterioration or worsening of symptoms. Such reactions are usually observed within the first few weeks or months after starting antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis pneumonia. Any symptoms of inflammation should be identified promptly and treated in a timely manner. Autoimmune diseases (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been observed in the context of immune reconstitution; however, the time of onset varied, and the disease could occur many months after initiation of therapy and have an atypical course.

Patients Co-infected with HIV and Hepatitis C Virus (HCV)

In vitro studies have shown that ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues, including zidovudine. Although no clear evidence of a pharmacokinetic or pharmacodynamic interaction between ribavirin and zidovudine has been found in patients with co-infection (HIV-1/HCV).

Exacerbation of ribavirin-induced anemia has been reported in HIV-infected patients receiving concurrent zidovudine therapy. The mechanism of this effect is currently unknown. Therefore, the concomitant use of ribavirin and zidovudine is not recommended. The antiretroviral therapy regimen should be switched to an alternative one not containing Zidovudine, especially in patients with a history of zidovudine-associated anemia.

Cases of hepatic failure (sometimes fatal) have been reported in HIV-1-infected patients with concomitant hepatitis C receiving combined antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. When zidovudine is used concomitantly with interferon alfa with or without ribavirin, patients should be closely monitored for signs of toxicity, especially hepatic failure, neutropenia, and anemia. If signs of toxicity increase, especially hepatic failure (> 6 points on the Child-Pugh scale), the doses of interferon alfa, ribavirin, or both should be reduced or discontinued. If myelosuppression occurs, interruption or discontinuation of zidovudine therapy should be considered.

Effect on Ability to Drive and Use Machines

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. If adverse reactions such as dizziness, drowsiness, lethargy, or seizures occur, refrain from performing these activities.

Overdose

Symptoms fatigue, headache, vomiting, hematological abnormalities.

Treatment symptomatic. Hemodialysis and peritoneal dialysis are not very effective in removing zidovudine from the body but accelerate the elimination of its metabolite, glucuronide.

Drug Interactions

Zidovudine is used as part of combined antiretroviral therapy together with other nucleoside reverse transcriptase inhibitors and drugs from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). The list of interactions below should not be considered exhaustive, but they are characteristic of drugs that require cautious use with zidovudine.

Lamivudine a moderate increase in the maximum blood concentration (28%) of zidovudine is observed when co-administered with lamivudine; however, the overall exposure (AUC) is not affected. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin Zidovudine reduces the blood concentration of phenytoin, requiring monitoring of phenytoin blood levels when co-administered with zidovudine.

Probenecid reduces glucuronidation and increases the mean half-life and AUC of zidovudine. Renal excretion of the glucuronide and zidovudine itself is reduced in the presence of probenecid.

Atovaquone Zidovudine does not affect the pharmacokinetic parameters of atovaquone. Atovaquone slows the glucuronidation of zidovudine (steady-state AUC of zidovudine increases by 33%, maximum glucuronide concentrations decrease by 19%). A change in the safety profile of zidovudine administered at doses of 500 or 600 mg per day is unlikely when used concomitantly with atovaquone for three weeks.

If longer concomitant use of these drugs is necessary, close monitoring of the patient’s clinical condition is recommended.

Clarithromycin reduces the absorption of zidovudine. The interval between taking the drugs should be at least 2 hours.

Valproic acid, fluconazole, methadone reduce the clearance of zidovudine, thereby increasing its systemic exposure.

Ribavirin the nucleoside analogue ribavirin is an antagonist of zidovudine. Concomitant use of zidovudine and ribavirin should be avoided.

Rifampicin the combination of zidovudine with rifampicin leads to a 48%±34% decrease in the AUC for zidovudine; however, the clinical significance of this change is unknown.

Stavudine Zidovudine may inhibit the intracellular phosphorylation of stavudine. Stavudine should not be used concomitantly with zidovudine.

Others drugs such as paracetamol, acetylsalicylic acid, codeine, methadone, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex may impair the metabolism of zidovudine through competitive inhibition of glucuronidation or direct inhibition of hepatic microsomal metabolism. The possibility of using these drugs in combination with zidovudine, especially for long-term therapy, should be approached with caution. The combination of zidovudine, especially in emergency therapy, with potentially nephrotoxic and myelotoxic drugs (e.g., pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to Zidovudine. Monitoring of renal function and blood counts is necessary, and the dose of the drugs should be reduced if required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

Medixlife (Author)

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