Composition, form of production and packaging
Capsules hard, gelatinous, size 2, with a lid of blue color, opaque and with a white body, opaque. The capsule is inscribed with white "BMS", "100mg" and blue - "3623". Contents of the capsules: a mixture of powder and granules from white to light yellow.
1 caps.
atazanavir 100 mg
[PRING] lactose monohydrate, crospovidone, magnesium stearate.
The composition of the shell of the capsule body : titanium dioxide (E171), gelatin; capsule capsules: FD & C Blue No. 2 (E132), titanium dioxide (E171), gelatin.
6 pcs. - blisters (10) - packs of cardboard.
60 pcs. - polyethylene bottles (1) - cardboard packs.
Capsules hard, gelatinous, size 1, with a lid of blue color, opaque and with a blue body, opaque. The capsule is inscribed with white "BMS", "150mg" and blue - "3624". Contents of the capsules: a mixture of powder and granules from white to light yellow.
1 caps.
atazanavir 150 mg
[PRING] lactose monohydrate, crospovidone, magnesium stearate.
The composition of the shell of the capsule body : FD & C Blue No. 2 (E132), titanium dioxide (E171), gelatin; capsule capsules: FD & C Blue No. 2 (E132), titanium dioxide (E171), gelatin.
6 pcs. - blisters (10) - packs of cardboard.
60 pcs. - polyethylene bottles (1) - cardboard packs.
Capsules hard, gelatinous, size в„–0, with a cap of blue color, opaque and with a blue body, opaque. The capsule is marked with white "BMS", "200mg" and blue - "3631". Contents of the capsules: a mixture of powder and granules from white to light yellow.
1 caps.
atazanavir 200 mg
[PRING] lactose monohydrate, crospovidone, magnesium stearate.
The composition of the shell of the capsule body : FD & C Blue No. 2 (E132), titanium dioxide (E171), gelatin; capsule capsules: FD & C Blue No. 2 (E132), titanium dioxide (E171), gelatin.
6 pcs. - blisters (10) - packs of cardboard.
60 pcs. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
PHARMACHOLOGIC EFFECT
Antiviral drug, azapeptide inhibitor of HIV protease. Atazanavir selectively inhibits virus-specific processing of viral Gag-Pol proteins in HIV-infected cells, preventing the formation of mature virions and infecting other cells.
PHARMACOKINETICS
The pharmacokinetic properties of atazanavir were evaluated in healthy adult volunteers and HIV-infected patients. There was no significant difference between the two groups.
Suction and distribution
Multiple administration of Reytaz at a dose of 400 mg 1 time / day simultaneously with light food showed the establishment of C ss max atazanavir in plasma approximately 2.7 hours after administration. Stable C ss atazanavir is achieved between 4 and 8 days of admission.
The use of reatase together with food improves its bioavailability and reduces pharmacokinetic variability.
The binding of atazanavir to serum proteins is 86%. The degree of binding to proteins does not depend on the concentration. To the same extent, does atazanavir bind to? 1- glycoprotein and albumin. Atazanavir is defined in the cerebrospinal fluid and seminal fluid.
Metabolism
In general, atazanavir is metabolized with the participation of the CYP3A4 isoenzyme to oxidized metabolites. Metabolites are excreted in bile, both in free and in glucuronized form. An insignificant portion of atazanavir is metabolized by N-dealkylation and hydrolysis.
Excretion
After a single intake of 14 C-atazanavir at a dose of 400 mg in feces and urine, respectively, 79% and 13% of the total radioactivity were determined. The proportion of unchanged active substance in feces and urine was about 20% and 7%, respectively. The mean T 1/2 of atazanavir in healthy volunteers and HIV-infected adult patients was about 7 hours when taking atazanavir 400 mg / day with light food.
INDICATIONS
- treatment of infections caused by HIV (in combination with other antiretroviral drugs).
DOSING MODE
The decision to initiate therapy is taken by a doctor with experience in the treatment of HIV infections.
The drug is taken orally .
Assign adults in a dose of 400 mg 1 time / day during meals or at a dose of 300 mg in combination with ritonavir at a dose of 100 mg 1 time / day during meals.
Reyataz in the form of powder is indicated for patients who can not swallow the capsule.
If the measuring spoon, complete with the powder, is filled in accordance with the following requirements, then it contains 1.5 g of powder, which corresponds to 50 mg of atazanavir: the measuring spoon should be without top, and carefully align the powder with the edges of the measuring spoon, removing the excess back to bottle, with a knife or spatula. It is inadmissible to press the contents of a spoon or try to achieve an equalization of the powder with the edges of the spoon by shaking it or tapping on the edge of the vial, when removing the excess powder back into the vial. The powder can be mixed with water, milk, apple juice or yoghurt.
After the powder has been mixed with the above products, it should be used within 6 hours. Do not mix powder with solvents inside the vial.
When prescribing Reyatase simultaneously with didanosine, the latter should be taken 2 hours after taking Reatase.
Patients with renal insufficiency do not need dose adjustment.
Patients with hepatic insufficiency of mild degree of Reatase should be used with caution. Patients with a moderate degree of liver failure are recommended to reduce the dose of Reatase to 300 mg 1 time / day.
The use of reatase in combination with ritonavir in patients with hepatic insufficiency has not been studied, this combination should be used with caution in patients with moderate hepatic insufficiency.
Clinical studies of the drug did not include a sufficient number of patients aged 65 years and older. Based on the pharmacokinetic data, dose adjustment according to age is not required.
SIDE EFFECT
Most often and at least in the presence of a possible connection with the administration of the drug Reatase and one or more reverse transcriptase inhibitors: nausea (24%), jaundice (12%), headache (11%) and abdominal pain (11%). Jaundice was noted as a few days later, and several months after the start of treatment, the withdrawal of the drug in this regard was required in less than 1% of patients.
Lipidystrophy of moderate or higher intensity, noted with the use of Reytaz and one or more reverse transcriptase inhibitors, with at least a possible connection with regimens was noted in 5% of patients.
The following incidence of adverse reactions in adult patients was determined in the following grades: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10000, <1/1000) and extremely rarely (<1/10000).
From the immune system: infrequently - allergic reactions (including urticaria).
From the side of the central nervous system: often - headaches, insomnia, peripheral neurologic symptoms; infrequently - disturbing dreams, memory loss, confusion, drowsiness, anxiety, depression, sleep disturbances.
From the side of the digestive system: very often - jaundice; often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting; infrequently - perversion of taste, flatulence, gastritis, pancreatitis, aphthous stomatitis, dry mouth, hepatitis; rarely - hepatosplenomegaly.
Dermatological reactions: often - a rash; infrequently - alopecia, itching; rarely - vasodilation, vesicle-bulbous rash.
From the musculoskeletal system: infrequently - arthralgia; muscular atrophy, myalgia; rarely - myopathy.
From the urinary system: infrequently - hematuria, frequent urination, proteinuria; rarely - pain in the kidney, nephrolithiasis.
From the side of the organ of vision: often - icteric sclera.
From the side of metabolism: often - lipodystrophy; infrequently - anorexia, increased appetite, weight loss, weight gain.
From the side of the reproductive system: infrequently - gynecomastia.
On the part of laboratory indicators: the most common abnormalities detected in patients treated with Reatase and one or more reverse transcriptase inhibitors are an increase in total bilirubin, with a predominance of increased bilirubin (unbound), an increase in the level of amylase, creatine kinase, ALT, a decrease in the number of neutrophils, elevated levels of AST, increased levels of lipase.
Other: often - general weakness; infrequently - pain in the chest, fatigue, fever, general malaise.
CONTRAINDICATIONS
- Hereditary metabolic disorders (galactose intolerance, lactose deficiency and impaired absorption of glucose and galactose);
- simultaneous reception with rifampicin;
- Patients suffering from phenylketonuria (the composition of the powder Reataz includes aspartame, which is a source of phenylalina);
- age up to 18 years;
- Hypersensitivity to atazanavir and other components of the drug.
Reyataz should not be used concomitantly with rifampicin. Atazanavir is metabolized mainly by the isoenzyme CYP3A4, therefore, it is not recommended to use Reyatase together with preparations inducing CYP3A4. These include preparations of St. John's wort (Hypericum perforatum), drugs that are substrates of the isozyme SURZA4 cytochrome P 450 with a narrow therapeutic range (for example, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil and ergot alkaloids, especially ergotamine, dihydroergotamine, ergonovine, methylergonovine) .
Caution should be applied to Reatase in combination with ritonavir in patients with moderate degree of liver failure. It is not recommended to prescribe Reyataz in combination with ritonavir in patients with severe hepatic insufficiency.
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical studies of the safety of the drug during pregnancy have not been conducted.
Application in pregnancy is possible in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus.
Do not use the drug during lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients suffering from kidney failure: dose adjustment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Atazanavir is metabolized mainly in the liver, so use the drug in patients with hepatic insufficiency, should be cautious because of the possible increase in its concentration. In patients with viral hepatitis B or C, or with a marked increase in transaminase levels prior to treatment, the risk of a further increase in the level of transaminases increases.
SPECIAL INSTRUCTIONS
Patients should be warned that antiretroviral therapy does not prevent the risk of HIV transmission through the blood or during sexual intercourse, therefore, precautions should be taken.
In patients receiving Reyataz, there have been cases of reversible increases in indirect (free) bilirubin associated with inhibition of UDP-glucuronosyltransferase (UGT). There is no long-term safety data for patients who have a continuous increase in bilirubin levels more than 5 times compared to normal. The possibility of prescribing an alternative to Reatase antiretroviral therapy may be considered, if jaundice or yellowing of the sclera presents cosmetic problems for patients.Decreased dose of reatase is not recommended. the long-term effectiveness of reduced doses has not been established.
A rash usually from mild to moderate degree (maculopapular rash) is observed during the first 3 weeks from the beginning of Reatase therapy. In most patients, the rash disappeared within 2 weeks with continued therapy. The use of reatase should be discontinued with the development of severe rash.
Carefully
Against the background of treatment with protease inhibitors, some HIV-infected patients have hyperglycemia, diabetes mellitus, or decompensation of existing diabetes. In some cases, diabetic ketoacidosis was noted.
Atazanavir is metabolized mainly in the liver, so use the drug in patients with hepatic insufficiency, should be cautious because of the possible increase in its concentration. In patients with viral hepatitis B or C, or a marked increase in transaminase levels prior to treatment, the risk of a further increase in the level of transaminases increases.
In patients with hemophilia type A and B, bleeding is described against treatment with protease inhibitors, incl. spontaneous cutaneous hemorrhages and hemarthroses. Some of these patients required the introduction of factor VIII. More than half of the patients treated with protease inhibitors continued or resumed after the break. The causal relationship between protease inhibitor therapy and these cases has not been established. Patients with hemophilia should be warned about the possibility of such complications.
OVERDOSE
Symptoms: jaundice is possible due to an increase in the level of indirect bilirubin (without other signs of liver dysfunction) and heart rhythm disturbance (prolongation of the PR interval).
Treatment: gastric lavage, provocation of vomiting to remove a drug that has not been absorbed into the blood, reception of activated carbon, control of basic physiological parameters and ECG, monitoring of the general condition of the patient. There is no specific antidote.
Since atazanavir is extensively metabolized in the liver and binds to proteins, dialysis is ineffective for removing the drug from the body.
DRUG INTERACTION
Atazanavir is metabolized in the liver with the participation of cytochrome P 450 isozymes and is an inhibitor of CYP3A4. The combined use of reatase and other drugs metabolized primarily by CYP3A4 (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) can lead to an increase in plasma concentrations of one of them and an increase or prolongation of its therapeutic and side effects.
The combined use of reatase and preparations inducing CYP3A4, such as rifampin, can lead to a decrease in plasma atazanavir concentration and a decrease in its therapeutic effect. The combined use of Reatase and preparations that inhibit CYP3A4 can lead to an increase in the concentration of atazanavir in the blood plasma.
Antiretroviral drugs for HIV treatment
Nucleoside reverse transcriptase inhibitors
Tablets didanosine markedly reduce the effect of atazanavir, because the antacids contained in the tablets didanosine reduce the acidity of the gastric juice. Reyataz does not affect the efficacy of didanosine. Therefore, preparations of didanosine should be taken 2 hours after taking the drug Reataz.
Nucleotide reverse transcriptase inhibitors
Tenofovir reduces the effect of atazanavir with simultaneous application.
Non-nucleoside reverse transcriptase inhibitors
Efavirenz reduces the effect of atazanavir with simultaneous application.
The study of co-administration of drugs Reatase + ritonavir and nevirapine was not conducted. It is suggested that nevirapine, as an inducer of CYP3A4, is able to reduce the effect of atazanavir. Because of the lack of data, the combined use with reatase and ritonavir is not recommended.
Protease Inhibitors
Indinavir is able to induce hyperbilirubinemia (increased concentration of indirect bilirubin) by inhibiting UGT. Therefore, simultaneous use with the drug Reatase is not recommended.
The effect of saquinavir (in the form of soft gelatin capsules) decreases when taken together with Reatase. There is no data to give the appropriate recommendations for dosing the combination.
With the simultaneous use of reatase and ritonavir, the concentration of atazanavir increases.
Simultaneous use of a combination of Reatas + ritonavir with other protease inhibitors is not recommended.
Other drugs
Antacids and preparations containing antacids reduce the acidity of gastric contents and reduce the absorption of atazanavir. Reyataz should be prescribed 2 hours before or 1 hour after taking such drugs.
With the simultaneous administration of amiodarone, lidocaine (parenteral), quinidine, an increase in their concentrations is possible with reatase. When using such combinations, more caution is required, it is recommended to monitor the therapeutic concentration of these drugs. Quinidine is contraindicated in the combined use of reatase with ritonavir.
Atazanavir inhibits UGT and can affect the metabolism of irinotecan, increasing its toxicity. It is not recommended to use Simvastatin and lovastatin simultaneously.
With the simultaneous use of reatase and diltiazem, the action of diltiazem and its metabolite (deacetyl-dithiazema) increases. It is recommended to reduce the dose of diltiazem by 50% and ECG monitoring.
Bepridil can potentiate the development of severe and / or life-threatening reactions. Contraindicated use of bepridil and Reatase in combination with ritonavir.
If you need to simultaneously apply calcium channels to other blockers, such as felodipine, nifedipine, nicardipine and verapamil, titration of their dose, ECG monitoring is indicated.
With the simultaneous use of inhibitors of HMG-CoA reductase (simvastatin, lovastatin, atorvastatin, cerivastatin) with reatase, the effect of atorvastatin and cerivastatin may increase. There may be an increased risk of developing myopathy, including rhabdomyolysis (use caution when using these combinations).
The blockers of histamine H2-receptors and proton pump inhibitors reduce the concentration of atazanavir in the blood serum, which can lead to a decrease in the therapeutic activity of the drug or to the development of resistance. Take these medications separately. To avoid unwanted interactions, it is recommended that you take Reytaz or Reytaz in combination with ritonavir at bedtime.
When the joint application of cyclosporin, tacrolimus, sirolimus and Reyataz may increase blood levels of immunosuppressants recommended therapeutic monitoring of their concentrations.
Clarithromycin concentration increases when combined with Reyataz that can cause elongation QTc interval, however, when used together with Reyataz clarithromycin, the antibiotic dose to be reduced by 50%.
Peroralnye contraceptives (ethinyl estradiol, norethindrone) is not recommended to be taken with the drug Reyataz. In the presence of a concentration of atazanavir oral contraceptives increase. Reducing or increasing HDL insulin resistance may be due to an increase in the concentration of norethindrone, especially in women with diabetes. It is recommended to use the lowest effective dose of each component of the oral contraceptive. It is advisable to use other reliable methods of contraception.
Rifabutin activity when combined with Reyataz increases. When simultaneous administration of these drugs is recommended to decrease the dose of rifabutin and 75% (i.e., 150 mg every other day or three times a week).
Rifampicin together with the drug should not be used Reyataz. Rifampicin reduces the activity of most protease inhibitors by about 90%.
When combined with the use of protease inhibitors, PDE5 inhibitors (sildenafil, tadalfil, vardenafil) may increase the last concentration and amplification of their side effects.
In the application of the antifungal agents triazoles group (ketoconazole and itraconazole) with atazanavir Reyataz without ritonavir concentration increases slightly. In combination with drugs Reyataz and ritonavir, ketoconazole and itraconazole can increase their concentration. Care must be taken when assigning ketoconazole and itraconazole in a daily dose of above 200 mg together with a combination of ritonavir and Reyataz.
The simultaneous use of warfarin Reyataz can cause significant and / or life threatening hemorrhage due to increased activity of warfarin. It is recommended to control the magnitude of INR.
Atazanavir is metabolized primarily of CYP3A4 isoenzyme, so taking Reyataz with drugs that induce of CYP3A4, is not recommended. These include drugs hypericum (Hypericum perforatum), drugs that are substrates isoenzyme SURZA4 cytochrome P 450 with a narrow therapeutic range (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil and ergot alkaloids, in particular ergotamine, dihydroergotamine, ergonovine, metilergonovin) .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in reach of children Mete at a temperature not higher than 25 В° C. Shelf life. - 2 years.
