Zidovudine - instructions for use, dose, side effects, contraindications

Synthetic analogue of nucleosides. Inside the cage zidovudine phosphorylated to the active metabolite - zidovudine-5'-triphosphate. Zidovudine triphosphate inhibits reverse transcriptase of HIV by interrupting the synthesis of virus DNA after insertion into the nucleotide chain. Zidovudine triphosphate weakly inhibits cellular DNA polymerase alpha and gamma.

In combination with other antiviral [HIV] agents increases the amount of CD4^I cells.

Pharmacokinetics:

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 is fast, food intake does not affect the pharmacokinetics of zidovudine. Bioavailability of 54-74%. The time to reach the maximum concentration in the plasma is 0.5-1.5 hours. The apparent volume of distribution is 1-2.2 l / kg.The connection with plasma proteins is less than 38%.

Metabolised in the liver. The main metabolite is zidovudine glucuronide, the area under the concentration-time curve (AUC) of which is 3 times greater than the zidovudine AUC. After ingestion, 14% of zidovudine and 74% of its metabolite are found in the urine. After intravenous administration, 3'-amino-3'-deoxythymidine was also detected in the blood, the AUC of which is 5 times smaller than that of zidovudine. Systemic clearance - 1-2 l / h / kg, renal clearance - 0.3-0.4 l / h / kg. The ratio of zidovudine concentration in the cerebrospinal fluid and plasma is 0.62 / 1 (0.05-2.6 / 1).

In individuals with chronic renal insufficiency (creatinine clearance (CC) 16-18 ml / min) AUC 2800-3400 ng * h / ml, half-life (T_1/2) - 1.4 hours. With hepatic insufficiency, the zidovudine clearance decreases. T_1/2 - 0.5-Hr.

Pharmacokinetics in children under 3 months: T_1/2 - about 13 hours, bioavailability in newborns is less than 14 days more, and clearance and T_1/2 slowed down than in children older than 14 days.

Pharmacokinetics in children from 3 months. up to 12 years: the basic pharmacokinetic parameters coincide with those in adults. The main way of metabolism is the conversion into zidovudine glucuronide. After intravenous administration, 29% is excreted by the kidneys unchanged, 45% - in the form of zidovudine glucuronide.

Indications:

Treatment of HIV infection caused by HIV-1 (as part of combination antiretroviral therapy), in adults and children weighing more than 30 kg. Prevention of transplacental HIV infection of the fetus (during pregnancy, in childbirth, in newborns born from HIV-infected mothers).

Contraindications:

Hypersensitivity to zidovudine or any component of the drug; neutropenia / leukopenia (the number of neutrophils is less than 0.75x 109 / l or 750 / μl); anemia (hemoglobin below 75 g / l or 4.65 mmol / l); simultaneous reception with stavudine, doxorubicin, other drugs that reduce antiviral activity of zidovudine; children with body weight less than 30 kg.

Carefully:

Inhibition 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 x10⁹/ l or 750-1000 / μl); Anemia (hemoglobin 75-90 g / l).

Pregnancy and lactation:

Zidovudine penetrates the placenta. It is not recommended to appoint women until 14 weeks of pregnancy. If you need to use the drug before the 14th week of pregnancy, you should carefully correlate the intended benefit to the mother and the potential risk to the fetus.Women, regardless of HIV infection, are not allowed to breast-feed due to the threat of infection of the child.

Dosing and Administration:

Inside, not liquid, with a sufficient amount of liquid, regardless of food intake.

Adults and children weighing more than 30 kg: at 600 mg per day in 2 divided doses in combination with other antiretroviral drugs. When the hemoglobin content is reduced by 25% from the initial, the number of neutrophils by 50% of the initial daily dose is reduced by 2 times or temporarily canceled. After restoring the parameters, the dose can be increased again to the original daily value.

Treatment is stopped if the hemoglobin content is less than 75 g / l or the number of neutrophils is below 0.75 * 10⁹l.

Prevention of transplacental transmission of HIV: 300 mg twice a day, starting at 36 weeks of gestation before the onset of labor, then 300 mg every 3 hours until the baby is separated from the mother (umbilical cord).

Patients with impaired liver function.

In liver failure, there may be a need for correction of the dosing regimen, but existing data are insufficient to develop recommendations for dosing.If control of zidovudine concentration in plasma is not possible, it is recommended to pay attention to signs of drug intolerance and, if necessary, to increase the interval between doses.

Patients with impaired renal function.

With QC more than 10 ml / min, correction of dosing regimens is not required. In severe disorders of kidney function (QC less than 10 ml / min), the recommended dose of zidovudine is 300 mg once a day.

Patients of advanced age.

There are no specific recommendations for changing the dosing regimen in elderly patients; should take into account the age-related decline in kidney function and changes in peripheral blood.

Side effects:

From the hematopoiesis: myelosuppression, anemia, neutropenia, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia with bone marrow hypoplasia, aplastic or hemolytic anemia.

From the digestive system: nausea, vomiting, dyspepsia, dysphagia, anorexia, taste distortion, abdominal pain, diarrhea, flatulence, bloating, pigmentation or ulceration of the oral mucosa, hepatitis, hepatomegaly with steatosis, jaundice, hyperbilirubinemia, increased activity of "liver" enzymes, pancreatitis .

From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, weakness, lethargy, decreased mental performance, tremor, convulsions; anxiety, depression, confusion, mania.

From the sense organs: macular edema, amblyopia, photophobia, vertigo, hearing loss.

From the respiratory system: shortness of breath, cough, rhinitis, sinusitis.

From the cardiovascular system: cardiomyopathy, fainting.

From the urinary system: rapid or difficult urination, hypercreatininaemia.

From the endocrine system and metabolism: lactate-acidosis, gynecomastia.

From the musculoskeletal system: myalgia, myopathy, muscle spasm, myositis, rhabdomyolysis, increased activity of CK, LDH.

From the skin: pigmentation of nails and skin, increased sweating, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions: skin rash, itching, hives, angioedema, vasculitis, anaphylactic reactions.

Other: malaise, back and chest pain, fever, flu-like syndrome, pain syndrome of various locations, chills, increased serum amylase activity, development of secondary infection, redistribution of adipose tissue.

Overdose:

Symptoms: increased manifestations of dose-dependent side effects. Treatment: gastric lavage, Activated carbon, symptomatic therapy.

Hemodialysis and peritoneal dialysis are ineffective in eliminating zidovudine, but accelerate the elimination of the glucuronic metabolite.

Interaction:

Paracetamol increases the incidence of neutropenia due to inhibition of zidovudine metabolism (both drugs are glucuronized). Inhibitors of microsomal liver enzymes (incl. acetylsalicylic acid, morphine, codeine, indomethacin, valproic acid, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, inosine pranobex) increase the concentration of zidovudine in plasma.

Drugs that are nephrotoxic and myelosuppressive (dapsone, pentamidine, pyrimethamine, amphotericin B, flucytosine, ganciclovir, vincristine, vinblastine, interferon alfa, doxorubicin, cotrimoxazole), increase the risk of toxic effects of zidovudine.

Probenicid and other tubular secretion inhibitors prolong the half-life of zidovudine.

When combined with phenytoin, it is possible to change the concentration of the latter in the blood.

Zidovudine increases the concentration of fluconazole in plasma. There is synergistic effect with other drugs used against HIV (especially lamivudine), with respect to HIV replication in cell culture.

Stavudine reduces the effectiveness of zidovudine in vitro, so their simultaneous use is not recommended.

Rifampicin reduces the concentration of zidovudine in the plasma, which can lead to a decrease in the effectiveness of the latter (not recommended at the same time).

Absorption of zidovudine decreases with simultaneous administration with clarithromycin; in this regard, it is recommended to take these drugs at intervals of two hours.

Radiation therapy enhances the myelosuppressive effect of zidovudine. Nucleoside analogues that disrupt DNA replication, such as ribavirin, can in vitro reduce the antiviral activity of zidovudine. Simultaneous use of such drugs with zidovudine is not recommended.

Simultaneous use of zidovudine and doxorubicin is not recommended due to mutual weakening of activity of each of the drugs in vitro.

Simultaneous application with ganciclovir, interferon alfa, ribavirin, etc.drugs that oppress bone marrow hematopoiesis, incl. cytostatic agents may increase the hematotoxicity of zidovudine.

Special instructions:

During treatment it is necessary to carry out a systematic control of the picture of peripheral blood: 1 every 2 weeks for the first 3 months of therapy, then - once a month.

Hematologic changes usually appear 4-6 weeks after the start of therapy (anemia and neutropenia develop more often against a background of high doses of zidovudine (1.2-1.5 g / day) in patients with a decrease in CD4⁺cells, with started HIV infection (with a reduced reserve of bone marrow before the start of therapy), deficiency of cyanocobalamin. With a decrease in hemoglobin by more than 25% or a decrease in the number of neutrophils by more than 50% compared to the baseline, a blood test is performed more often. Lactate acidosis and severe hepatomegaly with steatosis can be fatal, so when clinical or laboratory signs of these conditions appear zidovudine should be canceled. Risk factors for lactate acidosis are female sex, obesity, long-term use of antiviral agents that are nucleoside analogues.Estimating the tolerability of the drug, it should be borne in mind that skin rash, dizziness, weakness, headache, anorexia, diarrhea, myalgia, anemia, thrombocytopenia can be a manifestation of HIV infection itself and secondary diseases associated with it, rather than the toxic effect of zidovudine.

Zidovudine should not be prescribed with other drugs containing zidovudine. In patients receiving zidovudine as part of combined antiviral therapy, there may be a syndrome of reactivation of immunity, which may require medical intervention. Zidovudine can cause redistribution / accumulation of fatty tissue, in particular, central obesity, the accumulation of fatty tissue in the dorso-cervical region ("buffalo" hump), thinning of fatty tissue in the limb or face area, breast augmentation, "Cushingoid" face.

Antiretroviral therapy does not prevent the transmission of HIV through sexual contact and through infected blood.

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

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets 300 mg.

Packaging:

For 60 tablets covered with a film sheath in a plastic bottle filled with cotton wool, sealed with aluminum foil, sealed with a screwed plastic cover. 1 bottle together with the instruction for use is placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000207

Date of registration:14.02.2011

The owner of the registration certificate:Aurobindo Pharma Co., Ltd.Aurobindo Pharma Co., Ltd. India

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Zidovudine (Zidovudine)