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

lactose monohydrate 82.2 mg / 109.6 mg; crospovidone 16.2 mg / 21.6 mg, magnesium stearate 1.1 mg / 1.4 mg, hard gelatin capsule *, ink ** for the inscriptions on the capsule shell.

* The composition of the capsule shell is 150, 200 mg: titanium dioxide, gelatin, water, aluminum based on indigo carmine (FD&C №2).

** - Composition of white ink for inscriptions on shell capsules - shellac, titanium dioxide, isopropanol, ammonium hydroxide, propylene glycol, n-butanol, simethicone. Composition of blue ink for inscriptions on capsule shells - shellac, ethanol anhydrous, isopropanol, butanol, propylene glycol, ammonia, aluminum based on indigo carmine (FD&C №2).

Description:

Dosage of 150 mg:

Hard gelatin capsules, No. 1. Capsule cap - blue opaque, capsule body - greenish-blue opaque. The capsule is inscribed with white color: "BMS", "150mg", and the blue one - "3624".

Contents of the capsule: a mixture of powder and granules from white to light yellow.

Dosage of 200 mg:

Hard gelatin capsules, No. 0. Capsule cap - blue opaque, capsule body - blue opaque. The capsule is inscribed with white color: "BMS", "200mg", "3631".

Contents of the capsule: a mixture of powder and granules from white to light yellow.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.08 Atazanavir

Pharmacodynamics:

Atazanavir is an azapeptide inhibitor of HIV-1 protease. This substance selectively inhibits virus-specific processing of viral Gag-Pol proteins in HIV-infected cells, preventing the formation of mature virions and infecting other cells. In the course of treatment, some patients may develop resistance (resistance) to the action of the drug (specific resistance) or to the action of both atazanavir and other HIV protease inhibitors (cross resistance).

Resistance and cross-resistance

Resistance and cross-resistance to HIV protease inhibitors have been observed in varying degrees of its manifestation.Resistance to atazanavir is not always an obstacle to the consistent use of other HIV protease inhibitors.

Resistance in vitro (in cell culture)

Sensitivity to atazanavir was studied on the culture of cells isolated from patients who had not previously received Reatase®.

A clear tendency towards a decrease in sensitivity to atazanavir strains has been revealed, which have revealed a high level of multiple resistance to other HIV protease inhibitors. In contrast, sensitivity to atazanavir persisted in strains resistant to only 1 -2 HIV protease inhibitors.

Resistance in vivo

Studies have shown a clear dependence of the development of resistance on whether the patient previously received antiretroviral therapy, and if so, whether atazanavir as the sole inhibitor of HIV protease or in combination with ritonavir.

Patients who have not previously received antiretroviral therapy:

Reataz® 400 mg (without ritonavir)

There was no evidence of cross-resistance between atazanavir and amprenavir. Phenotypic analysis of isolated strains showed the development of resistance, specific only for atazanavir and combined with increased sensitivity to other HIV protease inhibitors.

Reatase® 300 mg / ritonavir 100 mg

A study of the efficacy of the combination atazanavir / ritonavir (in comparison with the combination atazanavir / lopinavir / ritonavir) in patients who had not previously received antiretroviral therapy showed that in 96 weeks after initiation of therapy only phenotypic resistance to atazanavir developed in only one failure of therapy.

Patients who previously received antiretroviral therapy:

Reatase® or Reatase® / ritonavir

In most cases of failure of therapy at week 48, patients developed multiple resistance to different HIV protease inhibitors, rather than specific resistance to atazanavir.

Pharmacokinetics:

The pharmacokinetic properties of atazanavir were evaluated in healthy volunteers and HIV-infected patients.

Absorption: with long-term administration of the drug Reatas® at a dose of 400 mg once a day simultaneously with the intake of light food, the maximum equilibrium concentration of atazanavir in plasma is established approximately 2.7 hours after ingestion. A stable equilibrium concentration of atazanavir is achieved between the 4th and 8th days of admission.

Effect of food: The use of the preparation Reatas® together with food improves its bioavailability and reducespharmacokinetic variability. The combination of Reatas® / ritonavir with food improves the bioavailability of atazanavir.

Distribution: Atazanavir is 86% bound to serum proteins, with the degree of binding to proteins independent of concentration. To a similar extent, atazanavir binds to alpha-1 acid glycoprotein and albumin. Atazanavir is determined in cerebrospinal and seminal fluids.

Metabolism: atazanavir metabolized mainly through isoenzyme CYP3A4 with the formation of oxidized metabolites. Metabolites are excreted in bile in a free form or in the form of conjugates with glucuronic acid. A small portion of atazanavir is metabolized by Ndealkylation and hydrolysis.

Excretion: After a single administration ¹⁴C-atazanavir (400 mg), in feces and urine, respectively, 79% and 13% of the total radioactivity were determined. The proportion of unchanged atazanavir in feces and urine was, respectively, about 20% and 7% of the administered dose. The mean half-life of atazanavir in healthy volunteers and HIV-infected adults was about 7 hours when taken at a dose of 400 mg per day with light food.

Patients with hepatic insufficiency

Atazanavir is metabolized and excreted mainly by the liver. The effect of liver function abnormalities on the pharmacokinetic parameters after administration of the drug "Reatas" at a dose of 300 mg has not been studied, and the concentration of atazanavir with co-administration and without ritonavir may increase in patients with moderate to severe hepatic insufficiency.

Patients with renal insufficiency

In healthy volunteers, excreted in urine unchanged atazanavir was about 7% of the dose taken.

There are no pharmacokinetic data for patients with renal insufficiency who have taken the drug Reatase ® with ritonavir.

The use of the drug Reataz ® without ritonavir was studied in patients with severe renal failure, including those on hemodialysis who took the drug at a dose of 400 mg once a day. The results showed a decrease in pharmacokinetic parameters by 30-50% in patients on hemodialysis in comparison with patients with normal renal function. The mechanism of this decrease is unknown.

Age / gender

There were no clinically significant differences in pharmacokinetic parameters as a function ofage or sex of patients.

Pregnant women

The values of the maximum equilibrium concentration (Cmax) and the area under the curve (AUCs) for atazanavir were 26-40% higher in women in the postpartum period (4-12 weeks) than in HIV-infected non-pregnant patients. The minimum concentration of atazanavir in the postpartum period was approximately 2 times higher than that observed before in HIV-infected non-pregnant women.

Children

The magnitude of absorption of atazanavir in children is higher than in adult patients. In young children, there is an insignificant tendency to a higher clearance of the drug when rationing by body weight. The variability of pharmacokinetic parameters in children is also higher than in adults.

Race

Studies have not shown any effect of the race of patients on the pharmacokinetic parameters of atazanavir.

Indications:

HIV-1 infection, in combination with other antiretroviral drugs, in patients who received or did not receive antiretroviral therapy.

Contraindications:

- Hypersensitivity to atazanavir or any other component of the drug;

- Hepatic insufficiency of severe degree (9 or more points / class C according to the Child-Pugh classification) under any dosing regimens;

- Combination of Reatase® / ritonavir in patients with moderate to severe hepatic insufficiency;

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- Reatase ® in combination with astemizole, terfenadine, cisapride, pimozide, bepridil, quinidine (including for the preparation of Reataz® together with ritonavir), triazolam, midazolam (for oral administration), ergotamine derivatives (especially ergotamine, dihydroergotamine, ergometrine, methylergometrin) (with simvastatin, lovastatin), indinavir, irinotecan, rifampicin, alfuzosin, sildenafil (with its appointment for the treatment of pulmonary arterial hypertension), fats eterolom;

- Children under 6 years.

Carefully:

Diabetes mellitus, hyperglycemia, dyslipidemia, hyperbilirubinemia, nephrolithiasis, viral hepatitis, chronic active hepatitis, mild to moderate hepatic insufficiency (for atazanavir), mild liver failure (for atazanavir / ritonavir combination), hemophilia A and B, congenital lengthening syndrome P-R and P-Q, joint application of the drug with drugs that extend P-R and P-Q interval (e.g., atenolol, diltiazem, verapamil), the syndrome of congenital lengthening of the interval Q-T, reduced gastric acidity (increase in pH value of gastric juice), joint use with nevirapine, efavirenz, glucocorticosteroids, voriconazole.

Pregnancy and lactation:

Reatase ® should be used during pregnancy only if the potential benefit of using the mother exceeds the potential risk to the fetus.

During pregnancy, a combination of 300 mg of Reatas® should be used together with 100 mg of ritonavir once a day.

Dose adjustments are usually not required, however, for women who have previously received antiretroviral therapy, IIand IIIth trimesters of pregnancy, if the drug Reatase® is administered in conjunction with tenofovir or H2-histamine receptor antagonists, the recommended dose of the drug Reatase® is 400 mg together with 100 mg of ritonavir once a day. Data on the simultaneous use of the drug Reatase®, tenofovir and H2-histamine receptor antagonists in pregnant women who have previously received antiretroviral therapy is not enough.

In the puerperium, dose adjustment is not required, but careful medical observation of the patient for side effects should be ensured, as the concentration of the drug may increase within the first two months after delivery.

Because of the risk of developing severe hyperbilirubinemia and the potential risk of jaundice development in newborns, they should be monitored during the first days of life; In the prenatal period, additional fetal monitoring should be provided.

There is also no data on whether the atazanavir in breast milk. In connection with the possibility of HIV transmission from mother to baby with milk, as well as in view of the risk of serious side effects in the child, it is not necessary to breast-feed with the drug.

Dosing and Administration:

The drug is taken orally as part of a combination therapy. The decision to initiate therapy is taken by a physician with experience in the treatment of HIV infection. The efficacy and safety of the use of the drug Reatase ® in combination with ritonavir in a daily dose of more than 100 mg has not been studied; the use of doses of ritonavir exceeding 100 mg per day may alter the safety profile of the drug, Reatas®, so it is not recommended.

Adults

Dosing regimen for patients who have not previously received antiretroviral therapy:

- Reatase® 400 mg once a day with meals;

- Reatase® 300 mg and ritonavir 100 mg once a day with meals.

Dosing regimen for patients who had previously received antiretroviral therapy:

- Reatase® 300 mg and ritonavir 100 mg once a day with meals.

The use of the drug Reataz® without ritonavir is not recommended for patients with an adverse virologic outcome of previous antiretroviral therapy.

Children

Doses of the preparation Reatas ® for children from 6 years of age and older are calculated by body weight (see table below); Doses for children should not exceed the doses used to treat adult patients. Reatase® capsules are given to children in combination with ritonavir (in the form of capsules or tablets). Both drugs should be taken at the same time, once a day with meals.

Calculation of the doses of the preparation Reataz® for children by body weight

*Body weight (kg)*	*The dose of the drug Reatase® (mg)*	*The dose of ritonavir (mg)*
> 15 <20	150	100
>20 <40	200	100
>40	300	100

Children aged 13 years and over with a body weight of at least 40 kg, previously not receiving antiretroviral therapy and not carrying ritonavir, prescribe the preparation of Reatase ® (without ritonavir) at a dose of 400 mg per day with meals.

Children aged 13 years and over with a body weight of at least 40 kg, receiving jointly tenofovir, H2 receptor antagonists, or proton pump inhibitors, Reatase® can not be used without ritonavir.

Patients with renal insufficiency

Dose adjustment is not required for patients not on hemodialysis. For patients on hemodialysis who have not previously received antiretroviral therapy, the drug Reatase® 300 mg is prescribed only in combination with ritonavir 100 mg.

Patients with severe renal failure who are on hemodialysis and who have previously received antiretroviral therapy should not use Reatase ®.

Patients with hepatic insufficiency

Caution should be exercised when prescribing Reatas® without ritonavir to patients with mild to moderate hepatic impairment. For hepatic insufficiency of an average degree (7-8 points / class B according to the Child-Pugh classification), it is recommended to reduce the dose to 300 mg once a day.

Reatase ® in any dosing regimen should not be used for severe hepatic insufficiency. The use of the drug Reatase ® in combination with ritonavir in patients with hepaticinsufficiency has not been studied, so this combination should not be used in these patients.

Elderly patients

Clinical studies of the drug did not include a sufficient number of patients aged 65 years and older.

Based on the pharmacokinetic data, dosage adjustment based on age is not required.

Combination Therapy

Didanosine: didanosine should be taken on an empty stomach, and Reatas® during meals, so when combined therapy is recommended to take didanosine 2 hours after taking the drug Reataz ® with food.

Tenofovir: It is recommended to use a combination of Reatas® 300 mg and ritonavir 100 mg together with tenofovir 300 mg (all medications should be taken once a day during meals). The use of the drug Reatase ® (without ritonavir) together with tenofovir is not recommended.

Side effects:

Adults

The most frequent adverse reactions of any severity observed with the use of the preparation of Reatas® and one or more nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors (more than 10%, "very often") were: nausea (20%), jaundice (13%) and diarrhea (10%).

Jaundice was noted several days or months after the start of treatment and in less than 1% of patients led to the withdrawal of the drug. The moderate or severe degree of lipodystrophy noted with the administration of the drug Reatase® and one or more nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors, and possibly associated with treatment, was noted in 5% of patients.

The following are moderate or severe adverse reactions in accordance with the generally accepted classification:

"very often" (> 1/10), "often" (> 1/100, <1/10), "infrequently" (> 1/1000, <1/100), "rarely" (> 1/10000, <1/1000) and "very rarely" (<1/10000).

From the immune system:infrequently, allergic reactions.

From the central nervous system: often - headache, infrequently - peripheral neuropathy, dizziness, memory loss, drowsiness, anxiety, depression, sleep disturbances, change in the nature of dreams, insomnia, impaired orientation.

From the gastrointestinal tract: often - abdominal pain, diarrhea, indigestion, nausea, vomiting; infrequently - dry mouth, perversion of taste, flatulence, gastritis, pancreatitis, aphthous stomatitis, bloating.

From the skin and subcutaneous tissue: often - a rash; infrequently - baldness, itching, hives; rarely - vasodilatation, vesicle-bulbous rash, eczema, post-marketing data (frequency not established) - angioedema, Stevens-Johnson syndrome, erythema multiforme, toxic skin reaction (DRESS), including a drug rash, eosinophilia and systemic symptoms.

From the side of the musculoskeletal system and connective tissues: infrequently - arthralgia, muscular atrophy, myalgia; rarely - myopathy.

From the urinary system: infrequently - hematuria, frequent urination, proteinuria, nephrolithiasis; rarely - pain in the kidney, post-marketing data (frequency not established) - interstitial nephritis.

From the sense organs: often - icteric sclera.

From the side of metabolism: infrequently - anorexia, increased appetite, weight loss, weight gain, post-marketing data (frequency not established) - hyperglycemia, diabetes mellitus.

From the side of the reproductive system: infrequently - gynecomastia.

From the side of the cardiovascular system: infrequently - increased blood pressure, fainting, rarely - swelling, heart palpitations.

Postmarketing data (frequency not established) - atrioventricular (AY) blockade of the second and third degree, lengthening of the interval QTc, cardiac arrhythmias of the type "torsades des pointes".

On the part of the respiratory system: infrequently - shortness of breath.

From the liver and biliary tract: often - jaundice; infrequently - hepatitis; rarely - hepatosplenomegaly, post-marketing data (frequency is not installed) - cholelithiasis, cholecystitis, cholestasis.

General disorders: often - general weakness, fatigue; infrequently - chest pains, fever, malaise, gait disturbance.

There are some instances of bleeding, skin reactions and spontaneous hemarthrosis in patients with hemophilia type A and B at application of protease inhibitors, fat redistribution (lipodystrophy).

Most often (more than 10%, "very often") noted the following deviations in laboratory indicators patients receiving treatment, which consisted of Reyataz® and one or more nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors: increased total bilirubin (87%), especially indirect (unbound) serum bilirubin.

Other significant deviations in laboratory parameters were observed in> 2% of patients ("often"): increased activity of creatine phosphokinase (7%), increased activity of alanine aminotransferase (5%), decreased neutrophilic leukocyte count (5%), increased activity of aspartate aminotransferase (3%), increased lipase activity (3%). The withdrawal of treatment due to the development of side effects was required in 5% of patients, both those receiving and not receiving antiretroviral therapy.

Children

The safety profile of the drug Reatase ® in children 6 years and older is comparable to that of adult patients. The most frequent side effects are cough, fever, jaundice, yellowing sclera, rash, vomiting, diarrhea, headache, peripheral edema, pain in the extremities, nasal congestion, swallowing pain, shortness of breath, liquid discharge from the nose. In rare cases, asymptomatic atrioventricular (AV) blockade of the 2nd degree.

The most frequent (more than 10%, "very often") abnormalities in grade 3 and 4 laboratory tests in children were: an increase in total bilirubin (> 3.2 mg / dL, 58%), neutropenia (9%) and hypoglycaemia (4%).Other deviations of laboratory indicators of grade 3-4 were observed with a frequency of less than 3%.

Overdose:

In clinical trials, the intake of healthy volunteers doses of the drug to 1200 mg once was not accompanied by any undesirable phenomena.

The only case of drug overdose with an HIV-infected patient who took 29.2 g of the drug (a dose 73 times higher than the recommended dose of 400 mg) was accompanied by an asymptomatic blockade of both legs of the bundle and a lengthening of the interval PR. These ECG signs disappeared spontaneously. The expected symptoms of drug overdose are jaundice without changes in the results of liver tests (due to an increase in the concentration of indirect bilirubin) and heart rhythm disturbances (lengthening of the interval PR).

There is no specific antidote.

In case of an overdose of the drug, Reataz® should monitor the basic physiological parameters, monitor the overall condition of the patient, monitor the ECG, prescribe a gastric lavage, induce vomiting to remove remnants of the drug; the reception of activated carbon is recommended.

Dialysis is ineffective for removing the drug from the body, since atazanavir characterized by intensive metabolism in the liver and a high degree of binding to proteins.

Interaction:

Atazanavir is metabolized in the liver with the participation of the cytochrome P450 system; it is also an inhibitor of the isoenzyme CYP3A4, included in this system.

The combined use of the drug Reatas® and other drugs with the same metabolic pathways, (slow calcium channel blockers, some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase), immunosuppressants, phosphodiesterase inhibitors) can lead to an increase in the concentration of one of them in the plasma, which may lead to an increase in the severity or prolongation of its therapeutic and side effects.

The combined use of the drug Reatase® and isozyme inducing drugs CYP3A4 (rifampicin), can lead to a significant drop in the concentration of atazanavir in plasma and a decrease in its therapeutic activity as a result. The combined use of the drug Reatase® and preparations inhibiting the isoenzyme CYP3A4, can lead to an increase in the concentration of atazanavir in plasma.

Extent isoenzyme CYP3A4 - mediated interactions of atazanavir with other drugs (changes in the effect of atazanavir or a change in the effect of another drug) may change with the use of the drug Reataz ® with ritonavir, a potent inhibitor of the isoenzyme CYP3A4.

For completeness of information on the interactions of drugs with ritonavir, you should read the instructions for the use of ritonavir.

Drugs that should not be taken with Reatase®:

Quinidine: Use with the combination of Reatase ® / ritonavir is contraindicated in connection with the risk of serious and life-threatening arrhythmias.

Rifampicin: with the simultaneous use of atazanavir with rifampicin, the concentration of atazanavir in the blood plasma is significantly reduced, which leads to a decrease in therapeutic effectiveness and the development of resistance to the preparation of Reataz®.

The simultaneous use of atazanavir and rifampicin is contraindicated.

Irinotecan: Atazanavir inhibits UDP-glucuronosyltransferase (CGT) and can affect the metabolism of irinotecan, causing an increase in its toxicity, so the combined use of atazanavir with irinotecan is contraindicated.

Bepridil: due to the high risk of developing life-threatening side effects, joint application with the drug Reataz® is contraindicated.

Derivatives of ergotamine (dihydroergotamine, ergotamine, ergometrine, methylergomethrin): due to the high risk of developing life-threatening side effects, joint application with the drug Reataz® is contraindicated. Manifestations of acute toxicity of ergotamine derivatives: peripheral vasospasm, ischemia of extremities and other zones.

Cisapride: in connection with the high risk of development of life-threatening side effects (arrhythmia), joint application with the preparation of Reataz® is contraindicated.

Lovastatin, simvastatin: increased risk of myopathy, including rhabdomyolysis.

Inhaled beta2-adrenomimetics (salmeterol): increased risk of developing side effects from the cardiovascular system inherent in salmeterol, including the lengthening of the interval Q-T, palpitation, sinus tachycardia. The combined use of salmeterol and Reatase® is not recommended.

Pimozide: in connection with the high risk of development of life-threatening side effects (arrhythmia), joint application with the preparation of Reataz® is contraindicated.

Indinavir: combined use with the drug Reatase ® is not recommended, since both drugs can cause hyperbilirubinemia.

Midazolam, triazolam: joint use with the drug Reataz ® is contraindicated in connection with the possibility of increasing the concentration of midazolam / triazolam and a high risk of prolonging sedation and respiratory depression.

Warfarin: when used together with the drug Reatase ® increases the risk of developing severe, life-threatening bleeding, so this combination is not recommended.

Preparations of St. John's wort perfumed (Hypericum perforatum): combination with with the drug Reatas ® is contraindicated, since the concentration of atazanavir in plasma may decrease, leading to a loss of therapeutic effect and the development of resistance.

Astemizole: when combined with a combination of the drug Reatase ® / ritonavir, the risk of developing severe, life-threatening side effects increases, so this combination is not recommended.

Terfenadine: when combined with a combination of the drug Reatase ® / ritonavir, the risk of developing severe, life-threatening side effects increases, so this combination is not recommended.

Alfuzosin: in view of the potential increase in the concentration of alfuzosin, which may lead to the development of hypotension, a combined use with the combination of the drug Reatase® / ritonavir is not recommended.

For the drugs listed below, you may need to change the dosage regimen in connection with the expected interactions:

Antiretroviral drugs for HIV treatment

Nucleoside reverse transcriptase inhibitors:

Didanosine: the use of enteranasol-coated didanosine capsules together with the preparation of Reatase® or with preparations of Reatas® and / or ritonavir and food reduces the bioavailability of didanosine. Didanosine should be taken 2 hours after taking the drug Reatas ®.

Nucleotide reverse transcriptase inhibitors:

Tenofovir: Tenofovir reduces the activity of atazanavir with simultaneous application, atazanavir increases the concentration of tenofovir in blood plasma. High concentrations of tenofovir may exacerbate the side effects associated with taking tenofovir, including effects on kidney function, so monitor the side effects of tenofovir in patients.

Non-nucleoside reverse transcriptase inhibitors:

Efavirenz: combination therapy with Reatas® and efavirenz leads to a decrease in the effect of the drug, Reatas®, and should therefore be avoided. If the use of this combination is absolutely necessary, it is permitted to use it only in patients who have not previously received antiretroviral therapy. In this case, Reamaz® 400 mg and ritonavir 100 mg are given as a single dose during meals, and efavirenz - on an empty stomach, before bedtime.

Nevirapine: nevirapine, being an inducer of isoenzyme CYP3A4, reduces the effect of atazanavir. In addition, due to an increase in the concentration of nevirapine, its toxicity increases, so this combination is not recommended.

Protease inhibitors:

Boceprevir: when combined with Reatas® 300 mg / ritonavir 100 mg once daily with bocetrevir in a dose 800 mg three times a day, the concentration of atazanavir in the blood decreases, while the concentration of boceprevir does not change significantly.

Saquinavir (soft gelatin capsules): the effect of saquinavir increases when taken together with the preparation of Reataz®. There are no data allowing to give appropriate recommendations for dosing this combination.

Ritonavir: when combined with the preparation of Reatas ®, the concentration of atazanavir increases.

Other HIV protease inhibitors: simultaneous application of combination Reatase® / ritonavir with other HIV protease inhibitors is not recommended.

Other drugs

Antacids and buffering preparations: when combined with antacids and buffer preparations, the concentration of atazanavir in blood plasma decreases. Reatase® should be used 2 hours before or 1 hour after taking such drugs. Antiarrhythmic drugs:

Amiodarone, lidocaine (with parenteral administration), quinidine: while simultaneous application with the preparation of Reatas ®, it is possible to increase their concentrations. Admission in such combinations requires increased caution, it is recommended to monitor the concentration of these drugs in the plasma. The combination of Reatase® / ritonavir is contraindicated for joint use with quinidine because of the possibility of serious or life-threatening reactions (arrhythmia).

Beta-blockers:

Atenolol: with the simultaneous use of the drug Reatase ® with beta-blockers clinically significant pharmacokinetic interactions are not expected, therefore correction of the dosing regimen is not required.

Blocks of "slow" calcium channels:

Diltiazem: joint application with the preparation of Reatas ® leads to an increase in the action of diltiazem and its metabolite - deacetyl-dithiasem. It is recommended to reduce the dose of diltiazem by 50% and ECG monitoring.

Other blockers of "slow" calcium channels, such as felodipine, nifedipine, nicardipine and verapamil: caution should be exercised when combined, titration of the dose of "slow" calcium channel blockers, ECG monitoring is necessary.

Endothelin receptor antagonists (bosentan): bosentan is metabolized by isoenzyme CYP3A4, being its inductor. The concentration of atazanavir in plasma may decrease with simultaneous use of the preparation of Reatas ® with bosentan, but without ritonavir. In this regard, the combination of Reatas® / bosentan can only be used with ritonavir. The following are the dosing regimes:

- The appointment of bosentan to patients taking Reatase® / ritonavir for at least 10 days: bosentan in a dose of 62.5 mg once a day or every other day (depending on individual tolerability).

- Assign a combination of Reatase® / ritonavir to patients taking bosentan: stop taking bosentan at least 36 hours before taking the combination of Reatas® / ritonavir.Not earlier than 10 days after starting the combination of Reatas® / ritonavir, resumption of bosentan at a dose of 62.5 mg once a day or every other day (depending on individual tolerability).

Inhibitors of HMG-CoA reductase:

Atorvastatin: when combined with the preparation of Reatas ®, the effect of atorvastatin may be enhanced. The risk of myopathy, including rhabdomyolysis, may increase. Care must be taken. The lowest effective doses of atorvastatin should be used in combination with the drug Reatase® or Reatase® / ritonavir.

Rosuvastatin: The dose of rosuvastatin when combined with atazanavir should not exceed 10 mg / day. With simultaneous use of rosuvastatin and atazanavir, the risk of myopathy increases, including rhabdomyolysis.

Pravastatii, fluvastatin: the potential of interactions in combination with the drug Reatase® or Reatase® / ritonavir is unknown.

Proton Pump Inhibitors: During treatment with the preparation of Reatas ®, proton pump inhibitors are prescribed only if their use is highly indicated.

With the simultaneous use of the drug Reatas ® 400 mg or a combination of Reatas ® 300 mg / ritonavir 100 mg with omeprazole 40 mg (all preparations once a day) concentrations of atazanavir in blood plasma were significantly reduced,which can lead to a decrease in the therapeutic activity of the drug and to the development of resistance.

Patients with HIV in the absence of a possible or identified decrease in sensitivity to atazanavir are recommended to use a combination of Reatas® 400 mg / ritonavir 100 mg with omeprazole at a maximum dose of 20 mg once daily (or another drug from the proton pump inhibitor group at the equivalent dose).

It is not recommended to apply omeprazole at a dose of more than 20 mg per day (or another drug from the proton pump inhibitor group at the equivalent dose).

Blockers of H2-histamine receptors: the concentration of atazanavir in blood plasma was significantly reduced by the simultaneous use of the preparation of Reatas ® 400 mg once a day with famotidine 40 mg twice a day, which may lead to a decrease in the therapeutic activity of the drug or to the development of resistance.

In the treatment of patients who had not previously received therapy, Reatase® 400 mg can be applied once a day with food 2 hours before and no later than 10 hours after the use of H2-histamine receptor blockers. However, a single dose of H2-histamine receptor blockers should not exceed the dose corresponding to a dose of famotidine 20 mg, and the total daily dose should not exceed the dose corresponding to 40 mg of famotidine.

Alternatively, Reatas® 300 mg with ritonavir 100 mg can be applied once a day during meals, 2 hours before and not less than 10 hours after the use of H2-histamine receptor blockers in a single dose comparable to 40 mg famotidine.

In the treatment of patients who had previously received therapy, the daily dose of H2-histamine receptor blockers should not exceed the dose corresponding to 40 mg of famotidine. In such patients, Reatase® 300 mg / ritonavir 100 mg should be taken once a day with food 2 hours before and no later than 12 hours after the use of H2-histamine receptor blockers (once a day) at a dose corresponding to 40 mg famotidine . Alternatively, Reatas® 300 mg / ritonavir 100 mg can be applied once a day with meals simultaneously with H2-histamine receptor blockers, 2 hours before and not less than 10 hours after the use of H2-histamine receptor blockers in a dose not exceeding dose, which corresponds to 20 mg of famotidine. This dose can be taken once or twice a day. When such patients are prescribed a combination of Reatase® / ritonavir and tenofovir with the H2-histamine receptor blocker, the following dosing regimen should be used: Reatas® 400 mg and ritonavir 100 mg once daily.

Immunosuppressants (ciclosporin, tacrolimus, sirolimus): in joint application of cyclosporine, tacrolimus, sirolimus and the preparation of Reataz® is possible increasing the concentration of immunosuppressants in the blood, therefore, monitoring of their concentrations is recommended.

Antidepressants:

Tricyclic antidepressants: when combined with the use of the drug Reatase with tricyclic antidepressants, serious and / or life-threatening adverse reactions associated with antidepressants may occur. It is recommended to monitor the concentrations of these drugs when used together with the drug Reatase®.

Trazodone: with the combined use of trazodone with the drug Reataz® or with the combination of Reatas® / ritonavir, an increase in trazodone concentration in the blood plasma is possible. With the combined use of trazodone and ritonavir, nausea, dizziness, low blood pressure, and a brief loss of consciousness were reported. In the joint use of trazodone with inhibitors of isoenzyme CYP3A4, such as Reatase®, smaller doses of trazodone should be used.

Benzodiazepines: Midazolam is metabolized by isoenzyme CYP3A4. Despite the fact that no studies have been conducted, with the combined use of the drug Reatas ® and midazolam, one can expect a significant increase in the concentration of the latter. In this case, an increase in the concentration of midazolam with oral administration will be significantly higher than with parenteral administration. The use of the drug Reataz® together with midazolam for oral administration is contraindicated. Data on simultaneous use of the drug Reataz ® with midazolam in the form of injections are absent; on the basis of data on the simultaneous use of other HIV protease inhibitors with midazolam, a possible increase in the concentration of midazolam in the plasma is 3-4 times. With the combined use of the drug Reatase ® with injection midazolam should be careful, control the respiratory function and the duration of sedation. In some cases, a correction of the dosing regimen is necessary.

Antiepileptic drugs:

Carbamazepine: with the simultaneous administration of carbamazepine and the preparation of Reatas® without ritonavir, the concentration of atazanavir in blood plasma may decrease.In this regard, the simultaneous administration of carbamazepine and the preparation of Reataz® without ritonavir is not recommended. Because the ritonavir can increase the concentration of carbamazepine in blood plasma, in patients taking carbamazepine and those beginning treatment with the drug Reatase® and ritonavir, a dose reduction of carbamazepine may be required.

Phenytoin, phenobarbital: with the simultaneous administration of phenytoin or phenobarbital and the preparation of Reatas® without ritonavir, the concentration of atazanavir in the blood plasma may decrease. In this regard, the simultaneous administration of phenytoin or phenobarbital and the preparation of Reataz® without ritonavir is not recommended. Because the ritonavir can reduce the concentration of phenytoin and phenobarbital in the blood plasma, in patients taking phenytoin or phenobarbital in conjunction with the drug Reatase ® and ritonavir, a dose adjustment of phenytoin or phenobarbital may be required.

Lamotrigine: with the simultaneous use of lamotrigine and the preparation of Reatas ® with ritonavir, the concentration of lamotrigine in blood plasma may decrease. In this regard, you may need to adjust the dose of lamotrigine.With the simultaneous use of lamotrigine and the preparation of Reatas® without ritonavir, a decrease in the concentration of lamotrigine in the blood plasma was not observed, therefore, lamotrigine dose adjustment is not required.

Macrolide antibiotics:

Clarithromycin: with the combined use of clarithromycin with the preparation of Peytaz®, the concentration of clarithromycin increases, which can cause lengthening QT-interval, so the dose of antibiotic should be reduced by 50%.

Oral contraceptives:

Ethinylestradiol and norethisterone or norgestimate: when combined with the preparation of Reatas ®, concentrations of ethinylestradiol and norethisterone increase. The combined use of the combination of Reatas® / ritonavir with ethinyl estradiol and norgestimate reduces the average concentration of ethinylestradiol and increases the average concentration of 17-deacetylnorgestimate, the active metabolite of norgestimate.

In the case of combined use of oral contraceptives and a combination of Reatas ® / ritonavir, contraceptives with an ethinyl estradiol content of at least 30 μg are recommended. If Reatase® is used with contraceptives without ritonavir, the content of ethinylestradiol in oral contraceptives should not exceed 30 μg.With the combined use of the drug Reatase ® and oral contraceptives should be careful, because the effect of increasing the concentration of progestogens is unknown; the risk of developing acne, dyslipidemia and insulin resistance may increase. With increasing concentration norethisterone, it is possible to reduce the concentration of HDL or increase insulin resistance, especially in women with concomitant diabetes mellitus.

It is recommended to use the lowest effective doses of each component of oral contraceptive, it is also advisable to use other reliable methods of contraception. The combined use of the drug Reatase® or a combination of Reatas® / ritonavir with other forms of hormonal contraceptives (contraceptive patches, contraceptive vaginal rings, injectable contraceptives) or with oral contraceptives containing progestogens other than norethisterone or norgestimate, as well as with preparations containing less than 25 μg ethinylestradiol has not been studied, therefore these contraceptive methods should not be used in conjunction with the preparation of Reatas®.

Preparations for the treatment of gout (colchicine): colchicine is a substrate of isoenzyme CYP3A4, its effect can be enhanced when it is applied simultaneously with the preparation of Reatas ®.

Recommended doses of colchicine when used concomitantly with the preparation of Reataz® are given below.

Acute attack of gout: 0.6 mg - the first dose, then 0.3 mg an hour after the first dose. Repeated application of this scheme is possible not earlier than in 3 days.

Prevention of acute gout attacks:

- if the usual dosing regimen was 0.6 mg 2 times a day, the dose should be reduced to 0.3 mg 2 times a day;

- if the usual dosing regimen was 0.6 mg once a day, the dose should be reduced to 0.3 mg every other day.

Family Mediterranean fever: the maximum daily dose of colchicine is 0.6 mg. This dose can be divided into 2 doses - 0.3 mg 2 times a day.

Antimycobacterial drugs:

Rifabutin: The activity of rifabutin when used together with the preparation of Reatas® is increased. With the simultaneous administration of these drugs, a dose reduction of rifabutin to 75% of the usual dose is recommended: 150 mg every other day or three times a week. Careful monitoring of adverse reactions in patients taking rifabutin and Reatase® or a combination of Reatase® / ritonavir; further correction of the dose of rifabutin may be required.

Inhibitors of phosphodiesterase-5 (PDE-5):

Application for erectile dysfunction

Sildenafil, tadalafil, vardenafil: with the combined use of HIV protease inhibitors with phosphodiesterase-5 inhibitors, a significant increase in the concentration of phosphodiesterase-5 inhibitors and an increase in their side effects are possible. Dose reduction is recommended: sildenafil - 25 mg not more often than every 48 hours when applied with or without ritonavir; tadalafil - 10 mg not more often than every 72 hours when applied with or without ritonavir; vardenafil - 2.5 mg not more often than every 72 hours when used with ritonavir and 2.5 mg not more often than every 24 hours when used without ritonavir; monitoring of adverse reactions is necessary.

Application for pulmonary hypertension

Sildenafil: The use of together with the drug Reatase ® with pulmonary hypertension is contraindicated.

Tadalafil:

- for patients taking the drug Reataz® for at least seven days: tadalafil prescribe a dose of 20 mg 1 time per day. The dose can be increased to 40 mg once a day (depending on individual tolerability);

- for patients taking tadalafil: stop taking tadalafil at least 24 hours before taking Reataz®. Not earlier than seven days after the start of taking the drug Reataz ®, resume taking tadalafil 20 mg once a day. The dose can be increased to 40 mg once a day (depending on individual tolerability);

Antifungal preparations:

Ketoconazole, itraconazole: Only joint use of ketoconazole with the preparation of Reataz® without ritonavir was studied; Atazanavir concentrations increase slightly with this combination.

Ketoconazole and itraconazole can increase concentrations of atazanavir and ritonavir in blood plasma. Caution should be exercised when using ketoconazole and itraconazole in daily doses above 200 mg in combination with a combination of Reatase® / ritonavir.

Voriconazole: combined use of voriconazole (200 mg twice daily) with a combination of Reatas® / ritonavir in patients with at least one functional isoenzyme allele CYP2C19 led to a decrease in the concentrations of voriconazole and atazanavir in blood plasma. The combined use of voriconazole (200 mg twice daily) with the combination of Reatas® / ritonavir in patients without a functional isoenzyme allele CYP2C19 led to an increase in the concentrations of voriconazole and a decrease in the concentration of atazanavir in the blood plasma.

The combined use of voriconazole and the combination of Reatase® / ritonavir is recommended only when the potential benefit of voriconazole is greater than the risk. When using this combination therapy, careful monitoring of the side effects of voriconazole, as well as the efficacy of voriconazole and atazanavir, should be carried out, which may decrease.

Anticoagulants:

Warfarin: Because of the increased activity of warfarin, simultaneous use with the drug Reatase® can cause severe and / or life-threatening bleeding. It is recommended to monitor the international normalized attitude (INR).

Inhalation / nasal glucocorticosteroids (interaction with ritonavir): when ritonavir was used together with fluticasone propionate by healthy volunteers, the concentration of cortisol was significantly reduced due to a significant increase in the concentration of fluticasone in plasma. The combined use of a combination of Reatase® / ritonavir with fluticasone propionate may lead to a similar effect.

With the joint use of ritonavir and inhalation (or intranasal) preparations of fluticasone propionate, the development of systemic side effects of glucocorticosteroids (Isenko-Cushing syndrome, suppression of the adrenal cortex) was noted. Similar effects are possible and when combined with other glucocorticosteroids metabolized by isoenzyme CYP3A4, for example, budesonide. In this regard, the use of a combination of Reatas® / ritonavir together with fluticasone propionate or other glucocorticosteroids metabolized by isoenzyme CYP3A4, is justified only if the potential benefit of therapy exceeds the risk of systemic effects of glucocorticosteroids. When combined with Reatas® (without ritonavir) and fluticasone propionate, the concentration of the drug in the plasma may increase. Care should be taken and, if possible, drugs that do not contain fluticasone propionate, especially with prolonged use.

Substrates of other cytochrome P450 isoenzymes (CYP):

Clinically significant interactions between atazanavir and isozyme substrates CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2 or CYP2E1 not expected. Atazanavir - weak isoenzyme inhibitor CYP2C8. Caution should be exercised when using the drug Reatase ® (without ritonavir) and preparations heavily dependent on isoenzyme CYP2C8 and having a narrow therapeutic profile (for example, paclitaxel, repaglinide). When using a combination of Reatase® / ritonavir together with isoenzyme substrates CYP2C8 clinically significant interactions are not expected.

Narcotic analgesics:

Buprenorphine: in connection with the inhibition of isoenzymes CYP3A4 and UGT1A1 when combined with Reatas® or a combination of Reatase® / ritonavir and buprenorphine, concentrations of buprenorphine and norbuprenorphine were increased. With the use of the combination of Reatase ® / ritonavir and buprenorphine, no significant change in the concentration of atazanavir in plasma was detected; the use of the same combination, but without ritonavir, can lead to a significant decrease in the concentration of atazanavir in plasma. When the combination of Reatas® / ritonavir and buprenorphine is used concomitantly, careful monitoring of the patient's condition is necessary (evaluation of sedation and cognitive functions).You may need to reduce the dose of buprenorphine.

For the drugs listed below, clinically important interactions are not expected, so there is no need to adjust the dose of drugs:

Lamivudine + zidovudine: when combined with a 400 mg dose of Reatase ®, no significant changes in the concentrations of lamivudine and zidovudine were observed. Also, there is no significant change in the pharmacokinetic parameters of nucleoside reverse transcriptase inhibitors under the influence of ritonavir. Given these data, no significant change in the concentrations of lamivudine and zidovudine is expected when combined with the combination of the drug Reatase® / ritonavir.

Abacavir

When combined with a combination of the drug Reatase ® / ritonavir, no significant change in the concentration of abacavir is expected.

Raltegravir

When combined with a combination of the preparation of Reatas® / ritonavir, an increase in the area under the curve (AUCs) for raltegravir by 41%, the maximum equilibrium concentration of raltegravir (Cma) by 24%, the equilibrium concentration of raltegravir after 12 hours (C 12h) by 77%. Correction of doses of raltegravir is not required.

Fluconazole

When combined with the combination of the drug Reatas ® / ritonavir, no significant changes in the concentrations of atazanavir and fluconazole were observed. Correction of the dose is not required.

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.

Diabetes mellitus / hyperglycemia

Against the background of treatment with HIV protease inhibitors, some HIV-infected patients experience hyperglycemia, the onset of diabetes mellitus, or exacerbation of existing diabetes mellitus. In some cases, diabetic ketoacidosis was noted. A causal relationship between HIV protease inhibitor therapy and these cases has not been established.

Hemophilia

In patients with hemophilia type A and B, bleeding occurred during treatment with HIV protease inhibitors, including spontaneous cutaneous hemorrhages and hemarthrosis. Some of these patients required the introduction of a coagulation factor VIII. In most cases, treatment with HIV protease inhibitors has been continued or resumed after a break.

A causal relationship between HIV protease inhibitor therapy and these cases has not been established.

Redistribution of fatty tissue (lipodystrophy)

There were isolated cases of redistribution of fatty tissue, which was manifested by obesity in the central type, an increase in fatty tissue in the dorso-cervical zone ("buffalo hump"), weight loss of the limbs and face, breast augmentation, "Cushingoid face." A causal relationship between HIV protease inhibitor therapy and these cases has not been established.

Immunodeficiency Syndrome

In HIV-infected patients, at the onset of combined antiretroviral therapy, signs of an inflammatory response may appear in response to ongoing asymptomatic or residual opportunistic infections (caused by Mycobacterium avium, cytomegalovirus, Pneumocystis jiroveci or tuberculosis). A survey and appropriate treatment may be required.

There were cases of autoimmune diseases (for example, Graves' disease) that occurred with the restoration of immunity, but the time of onset of such diseases varied in different patients and could occur many months after initiation of atazanavir therapy.

Liver failure

Atazanavir is metabolized mainly in the liver, therefore in patients with hepatic insufficiency the drug should be used with caution because of the possible increase in its concentration.

In patients with viral hepatitis B or C, or the increased activity of transaminases noted prior to treatment, there is a risk of further increase in the activity of transaminases.

Hyperbilirubinemia

Patients receiving Reyataz ® experienced reversible increases in indirect (free) bilirubin associated with inhibition of UDP-glucuronosyltransferase (CGT). It should be noted that an increase in the activity of transaminases seen with elevated bilirubin in patients receiving Reatase® may be caused by other diseases also accompanied by hyperbilirubinemia.

There are no long-term data on the safety of use in patients with a long-lasting concentration of bilirubin, more than 5 times higher than normal. If jaundice or yellowing of the sclera presents a cosmetic problem for the patient, consideration may be given to the possibility of prescribing antiretroviral therapy, an alternative to Reatas®.

Reducing the dose of the drug Reatase® is not recommended because of the lack of data on the effectiveness of reduced doses.

Elongation P-Q and P-R interval

Atazanavir can lengthen P-Q and P-R interval in some patients. Care should be taken when using the drug in patients with impaired cardiac conduction. Care should be taken when using the drug together Reatase® with preparations that extend P-Q and P-R interval (e.g., atenolol, diltiazem, verapamil).

Elongation Q-T interval

The cases of elongation Q-T interval in some patients. Care should be taken when using the drug in patients with impaired cardiac conduction. Caution should be exercised when the preparation of Reatas® is used together with preparations that extend Q-T interval (e.g., clarithromycin, salmeterol).

Rash

Maculopapular rash, usually from mild to moderate, can be observed during the first 3 weeks from the beginning of therapy with the preparation of Pheamas®. In most patients, the rash disappears within 2 weeks with continued therapy. The use of the drug should be discontinued with the development of severe rash.Stevens-Johnson syndrome, erythema multiforme and toxic skin reaction may also be noted (DRESS)., including a drug rash, eosinophilia and systemic symptoms.

Nephrolithiasis and cholelithiasis

During post-marketing studies on the safety of the use of the drug Reatase ® in HIV-infected patients, cases of nephrolithiasis and / or cholelithiasis were noted. Some patients required hospitalization for necessary therapy, some patients experienced complications. If symptoms of nephrolithiasis and / or cholelithiasis are present, interrupt therapy temporarily or stop taking the drug completely.

Simultaneous reception of glucocorticosteroids

If it is necessary to take glucocorticosteroids, it is recommended to take drugs that are not substrates of the isoenzyme CYP3A4 (beclomethasone).

Simultaneous administration of nevirapine, efavirenz, voriconazole

Nevirapine, being an inducer of the isoenzyme CYP3A4, reduces the effect of atazanavir. In addition, due to an increase in the concentration of nevirapine, its toxicity increases, so this combination is not recommended.

Combination therapy with preparations of Reatas® and efavirenz leads to a decrease in the effect of the drug, Reatas®, and should therefore be avoided. If the use of this combination is absolutely necessary, it is allowed to use it only in patients who have not previously who received antiretroviral therapy. In this case, Reamaz® 400 mg and ritonavir 100 mg are given as a single dose during meals, and efavirenz - on an empty stomach, before bedtime. A joint application of voriconazole (200 mg twice daily) with a combination of Reatase® / ritonavir in patients with at least one functional isoenzyme allele CYP2C19 led to a decrease in the concentrations of voriconazole and atazanavir in blood plasma. Joint application voriconazole (200 mg twice daily) with a combination Reatase® / ritonavir in patients without a functional isoenzyme allele CYP2C19 led to an increase in the concentrations of voriconazole and a decrease in the concentration of atazanavir in the blood plasma. The combined use of voriconazole and the combination of Reatase® / ritonavir is recommended only when the potential benefit of voriconazole is greater than the risk. When using this combination therapy, careful monitoring of the side effects of voriconazole,as well as the efficacy of voriconazole and atazanavir, which may decrease.

Reduced acidity of gastric juice (increased pH value of gastric juice)

The concentration of atazanavir may decrease with an increase in the pH value of gastric juice, regardless of the reasons that caused this increase.

Osteonecrosis

In rare cases with combined antiretroviral therapy, cases of osteonecrosis have been observed for a long period of time, especially in patients with risk factors (high body weight, alcohol consumption, concomitant use of corticosteroids). When a patient has pain in joints or movement difficulties, development of osteonecrosis.

Children

There are no recommendations on the dosage regimen of the drug Reatase in children younger than 6 years. Reatase® should not also be administered to children under 3 months of age.

The safety profile of the drug Reatase ® in children 6 years and older is comparable to that of adult patients.

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

Special studies to study the effect of the drug Reatas® on the ability to drive vehicles and work with mechanisms have not been carried out.

Cases of dizziness were noted during treatment with the drug Reatas®.

Form release / dosage:Capsules 150 mg, 200 mg.

Packaging:6 capsules per blister A1 / A1. For 10 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not take the drug after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000029

Date of registration:26.01.2010

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA

Manufacturer: & nbsp

BRISTOL-MYERS SQUIBB, S.r.L. Italy

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp28.01.2014

Illustrated instructions

Instructions

Reatase® (Reyataz®)