2010/06/05

Abacavir+Lamivudine+Zidovudine

Trade name:
Trizivir

International name:
Abacavir + Lamivudine + Zidovudine (Abacavir + Lamivudine + Zidovudine)

Group Affiliation:
Antiviral agent

Description of the active substance (INN):
Abacavir + Lamivudine + Zidovudine

Dosage form:
coated tablets

Mode of action:
Combination antiviral drug. Abacavir, Lamivudine and Zidovudine - nucleoside analogues, inhibitors of the enzyme reverse transcriptase. Consistently metabolized by intracellular kinases to 5 "-triphosphate. Lamivudine triphosphate, abacavir and zidovudine triphosphate triphosphate are substrates and competitive inhibitors of HIV reverse transcriptase. The main mechanism of their antiviral activity is to introduce monofosfatnyh forms of these drugs in the chain of viral DNA, with subsequent rupture. Lamivudine, zidovudine and abacavir show a much lower affinity to the DNA polymerase of the host cells. Lamivudine and zidovudine have a high synergistic action and inhibit HIV replication in cell culture. Abacavir in vitro also showed a synergistic action with zidovudine and an additional effect in combination with lamivudine. In vitro derived strains HIV-1 resistant to abacavir. genotypic resistance due to specific changes in certain codons reverse transcriptase (codons M184V, K65R, L74V and Y115F) and evolves relatively slowly, due to multiple mutations of the virus, resulting in up to 8-fold increase in IC50 compared with a wild strain of HIV. In strains that are resistant to abacavir, there is a reduction in sensitivity to lamivudine, zalcitabine and / or didanosine, but sensitivity to zidovudine, and stavudine is maintained. Reduction of sensitivity to abacavir were noted in hospital strains of HIV isolated from patients with uncontrolled viral replication previously treated with other nucleoside inhibitors, or resistant to them. ineffectiveness of initial combination therapy of abacavir, lamivudine and zidovudine is mainly due to mutations in one codon M184V, which supports the view of the need for second-line treatments. The development of cross-resistance between abacavir, zidovudine and lamivudine and protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely.

Indications:
HIV infection.

Contraindications:
Hypersensitivity, hepatic failure, neutropenia (less than 750/mkl), decreased Hb (less than 75 g / l or 4.65 mmol / l), children's age (12 years), body weight less than 40 kg, during laktatsii.C caution. Pregnancy.

Side effects:
From the CCC: cardiomyopathy. On the part of the digestive tract: nausea, vomiting, diarrhea, pain in upper abdominal, anorexia, pigmentation of oral mucosa, bloating, transient increase in activity of "liver" transaminase (ACT, ALT), serum amylase, hyperbilirubinemia, pancreatitis, marked hepatomegaly with steatosis. From the side of blood: anemia, erythrocytic germ cell aplasia of the bone marrow, neutropenia, thrombocytopenia, leukopenia, pancytopenia. From the Metabolic: lactic acidosis. From the musculoskeletal system: the defeat of the muscles rarely - rhabdomyolysis, myalgia, myopathy, arthralgia. the nervous system: headache, insomnia, peripheral neuropathy, paresthesia, dizziness, drowsiness, convulsions, anxiety, depression, reduced speed of thinking. On the part of the respiratory system: cough, shortness of breath. On the part of the skin: skin rash (without systemic symptoms), alopecia, pigmentation of nails and skin rash, itching, sweating, rarely - exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome). allergic reactions. Other: fever , lethargy, fatigue, malaise, anorexia, frequent urination, taste perversion, pain, chills, chest pain, flu-like syndrome, gynecomastia, asteniya.Peredozirovka. Treatment: observation of a doctor, if necessary - supportive therapy. Because lamivudine excreted by dialysis, the overdose could be applied long hemodialysis. At the same time, the effectiveness of hemodialysis and peritoneal dialysis is inadequate for the elimination of zidovudine, but its metabolite glucuronide excretion increases. The effectiveness of hemodialysis and peritoneal dialysis in overdose abacavir is not known.

Dosage and administration:
Inside, regardless of the meal. Adults and children over 12 years - 1 tablet 2 times a day. In renal insufficiency (CC less than 50 ml / min) required dose reduction of lamivudine and zidovudine, it would be preferable to appoint abacavir, lamivudine and zidovudine separately. When Hb value of less than 90 g / l (5.59 mmol / l) or neutrophil count below 1 thousand / ml abacavir, zidovudine and lamivudine should be nominated separately.

Cautions:
Treatment should be under the supervision of a physician with experience in management of HIV infected patients. In appointing the elderly patients should pay particular attention to the possible age decline of renal function and changes in blood indices. HIV-infected patients, more frequently in women, with the use of antiretroviral nucleoside analogs including abacavir, lamivudine, zidovudine, were observed lactic acidosis and severe hepatomegaly with steatosis, leading to death. The drug should be used with caution in the presence of risk factors for liver disease and cancel in the case of lactic acidosis or signs of hepatotoxicity. Zidovudine, particularly in the high dose (1200-1500 mg / day) can cause anemia, neutropenia and leukopenia in patients with signs suppression of bone marrow function prior to treatment, especially when deployed clinical picture of HIV infection with the concentration of CD4 cells less 100/mkl. The risk of neutropenia increases in the case of source reduction in the number of neutrophils, Hb, and cyanocobalamin. During the period of treatment should be carefully monitored blood parameters. Gematotoksichnost usually develops within 4-6 weeks of therapy. For patients with a comprehensive clinical picture of HIV infection is recommended to perform blood tests every 2 weeks during the first 3 months of therapy and then monthly. In the early stage of HIV infection - every 1-3 months. Patients with severe anemia and bone marrow suppression (Hb less than 90 g / l or neutrophil count less than 1 thousand / ml) required dosage adjustment of zidovudine, it would be preferable to abacavir, lamivudine and zidovudine separately. Pancreatitis is rare in the abacavir, zidovudine and lamivudine, and it is not clear is whether his development with their drug use or HIV infection. In case of clinical and laboratory signs of pancreatitis drug overturned. Some patients with chronic hepatitis B with lamivudine cancellation can appear clinical and laboratory signs of recurrence of hepatitis. If you remove the drug in patients coinfected with hepatitis B virus must be monitored to determine liver function and serological markers of viral replication. During the period of treatment may develop opportunistic infections and other complications of HIV infection, so patients should be under the supervision of a physician with experience treating these diseases. Patients should be informed that current antiretroviral therapy does not prevent HIV infection through sexual contact or through infected blood to them. It should comply with the relevant precautions. Abacavir, lamivudine and zidovudine should be used separately if necessary, dose adjustment of one of the components.

Interaction:
Clinically significant interactions between abacavir, zidovudine and lamivudine were observed. Abacavir: did not inhibit the metabolism associated with ZA4 isoenzymes, CYP3A4, CYP2C9, CYP2D6 cytochrome P450 and does not increase hepatic metabolism, so the probability of interaction with antiretroviral protease inhibitors and drugs, is metabolized with the participation of isoenzymes of cytochrome P450 is low. The metabolism of abacavir is violated or combined with ethanol, which is accompanied by an increase in AUC by 41% and has no clinical significance. Abacavir has no effect on the metabolism of ethanol. With simultaneous use of abacavir at a dose of 600 mg 2 times a day and methadone C max of abacavir snizhalaetsya 35%, a TCmax increased by 1 h the AUC does not change. These data have clinical significance. Abacavir increases the systemic clearance of methadone by 22%, so sometimes you may need dosage adjustment of methadone. Retinoids are derived from the body by the enzyme alcohol dehydrogenase, so there may be interactions with abacavir. Lamivudine: appointment of trimethoprim / sulfamethoxazole at a dose of 160 mg/800 mg causes an increase in exposure to lamivudine 40% In the absence of renal insufficiency, dose adjustment of lamivudine is not required. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. Lamivudine may inhibit the intracellular phosphorylation zalitsitabina. The drug is not recommended for use in conjunction with zalcitabine. Zidovudine: the combined use of zidovudine and lamivudine leads to an increase of 13% of zidovudine exposure and a 28% increase Cmax in the plasma, but the total exposure (AUC) was not significantly disturbed and does not require dose adjustment. Zidovudine does not affect the pharmacokinetics of lamivudine. The concentration of phenytoin in the blood of patients receiving zidovudine, usually low, but in some cases it may be increased, so the concentration of phenytoin when combined it with the drug should be monitored. Drugs that block tubular secretion increases T1 / 2 and AUC of zidovudine by reducing glyukuronirovaniya, with renal excretion of glucuronide (and possibly zidovudine itself) is reduced. Because the nucleoside analogue ribavirin is an antagonist of zidovudine, should avoid this combination of drugs. Rifampicin reduces the AUC of zidovudine by 48 * 34%, but the clinical significance of this change is not known. Zidovudine may inhibit the intracellular phosphorylation of stavudine, stavudine therefore should not be mixed with the drug. The combination with potentially nephrotoxic and mielosupressivnymi drugs (pentamidine, dapsone, pyrimethamine, sulfamethoxazole / trimethoprim, amphotericin B, flutsitozin, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to zidovudine. In cases where such treatment is necessary, carefully monitor renal function and blood parameters, if necessary - dose was reduced. With extreme caution the drug should be used in combination with ASA, codeine, morphine, methadone, indomethacin, ketoprofenom, naproksenom, oksazepamom, lorazepam, cimetidine , clofibrate, dapsone, inosine pranobeksom because they violate its metabolism through competitive inhibition glyukuronirovaniya or direct suppression of microsomal oxidation in the liver.