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

Excipients: torospovidon - 16.50 mg / 22.0 mg / 33.0 mg, lactose monohydrate - 81.0 mg / mg 108.0 / 162.0 mg Sodium stearyl fumarate - 1.65 mg / mg 2.20 / 3.30 mg.

Composition of hard gelatin capsules:

For a dosage of 150 mg:

Capsule body: titanium dioxide - 2.0000 mg, gelatin - up to 100 mg;

cap capsule: dye Ponce 4R - 0.2401 mg, dye sunset yellow - 1.2753 mg, titanium dioxide - 1.5004 mg, gelatin - up to 100 mg.

For the dosage of 200 mg:

Capsule body: titanium dioxide - 2.0000 mg, gelatin - up to 100 mg;

capsule cap: titanium dioxide - 1.0000 mg, dye sunset yellow - 1.0000 mg, gelatin - up to 100 mg.

For a dosage of 300 mg:

Capsule body: titanium dioxide - 2.0000 mg, gelatin - up to 100 mg;

capsule cap: titanium dioxide - 2,600 mg; dye quinoline yellow - 0.4343 mg, dye sunset yellow - 0.0057 mg, gelatin - up to 100 mg.

Description:

For a dosage of 150 mg: hard gelatin capsules number 1, body white, lid orange.

For a dosage of 200 mg: hard gelatin capsules №0, body white, lid orange.

For a dosage of 300 mg: hard gelatin capsules №00, white body, yellow lid.

Contents of the capsules - a mixture of powder and granules white or white with a yellowish hue.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.08 Atazanavir

Pharmacodynamics:

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 the drug. There was a clear tendency to decrease sensitivity to atazanavir cells, which found a high level of multiple resistance to other HIV protease inhibitors. In contrast, sensitivity to atazanavir persisted in cells 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, atazanavir as the sole inhibitor of HIV protease or in combination with ritonavir.

Patients who have not previously received antiretroviral therapy:

Atazanavir 400 mg (without ritonavir)

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

Atazanavir 300 mg / ritonavir 100 mg

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

Patients who previously received antiretroviral therapy:

Atazanavir or atazanavir / 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 the long-term administration of atazanavir in a dose of 400 mg once a day, simultaneously with the intake of easily assimilable food, the maximum equilibrium concentration (C_mOh) atazanavir in plasma is established approximately 2.7 hours after administration. Steady equilibrium concentration of atazanavir is achieved between the 4th and 8th days of admission.

Effect of food

The use of atazanavir together with food improves its bioavailability and reducespharmacokinetic variability. The combination of atazanavir / ritonavir with food improves the bioavailability of atazanavir.

Distribution

Atazanavir is 86% bound to serum proteins, and the degree of binding to proteins is independent of concentration. To a similar extent atazanavir binds to α1-acid glycoprotein and albumin. Atazanavir is determined in cerebrospinal and seminal fluids.

Metabolism

Atazanavir is 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 injection of 14C-atazanavir (400 mg) in faeces and urine, respectively, 79 and 13% of the total radioactivity was determined. The proportion of unchanged atazanavir in faeces and urine was, respectively, about 20 and 7% of the administered dose. Average T_1/2Atazanavir in healthy volunteers and HIV-infected adults was about 7 hours when taken at a dose of 400 mg per day with easily digestible food.

Pharmacokinetics in special groups

Patients with hepatic insufficiency

Atazanavir is metabolized and excreted mainly by the liver. The effect of liver function abnormalities on the pharmacokinetic parameters 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 took atazanavir with ritonavir.

The use of atazanavir 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 compared with patients with normal renal function. The mechanism of this decline is not known.

Age / gender

There were no clinically significant differences in pharmacokinetic parameters, depending on the age and sex of the patient.

Pregnant women

The values of the maximum equilibrium concentration (C_mOh) and the area under the pharmacokinetic curve (AUFROM_s) 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 higher than in adults.

Race

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

Indications:Treatment of 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 failure of severe degree (class C according to the Child-Pugh classification) under any dosing regimens;

- combination atazanavir / ritonavir in patients with moderate to severe hepatic insufficiency (Child-Pugh class B and C);

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

- in patients with severe renal failure who are on hemodialysis and who have previously received antiretroviral therapy;

- atazanavir in combination with astemizole, terfenadine, cisapride, pimozide, bepridil, quinidine (including atazanavir / ritonavir combination), triazolam, midazolam (for oral administration), ergotamine derivatives (especially ergotamine, dihydroergotamine, ergometrine, methylergometrin), St. John's wort preparations (with simvastatin, lovastatin), quetiapine (including in combination with ritonavir), rifampicin, alfuzosin, sildenafil (with its appointment for the treatment of pulmonary arterial hypertension, th hypertension;

- children weighing less than 35 kg - for a dosage of 300 mg, less than 15 kg - for a dosage of 150 mg and 200 mg (atazanavir / ritonavir); children's age till 13 years (atazanavir).

Carefully:

- Diabetes,

- hyperglycemia,

- dyslipidemia,

- hyperbilirubinemia,

- nephrolithiasis,

- viral hepatitis,

- chronic active hepatitis,

- violations of liver function of mild and moderate severity (class A and B according to the Child-Pugh classification) (for atazanavir),

- disorders of liver function of mild severity (class A according to Child-Pugh classification) (for combination atazanavir / ritonavir),

- haemophilia A and B,

- congenital lengthening syndrome PR and PQ,

- joint use of the drug with drugs that extend PR and PQ interval (e.g., atenolol, diltiazem, verapamil),

- congenital lengthening syndrome QT,

- reduced gastric acidity (increase in pH of gastric juice),

- joint application with indinavir, irinotecan, nevirapine, efavirenz, glucocorticosteroids, voriconazole, salmeterol, clarithromycin, bocetrevir, tenofovir dizoproxil fumarate, carbamazepine, phenytoin, phenobarbital, lamotrigine, cyclosporine, tacrolimus, sirolimus, amiodarone, lidocaine (for parenteral use), fluticasone, sildenafil, tadalafil, vardenafil, atorvastatin, pravastatin, fluvastatin, buprenorphine, substrates of other cytochrome P450 isoenzymes (CYP).

Pregnancy and lactation:

Pregnancy

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

A moderate amount of data in pregnant women (from 300 to 1000 pregnancies) showed no toxicity of atazanavir in the form of malformations in the fetus. Studies in animals showed no signs of toxicity in relation to the reproductive system.

Breast-feeding

Atazanavir was found in breast milk, as confirmed by data from a study in rats. There is no evidence of the effect of atazanavir on the secretion of breast milk. In connection with the possibility of transmitting HIV from mother to baby with milk, and also because of the risk of serious side effects in the child, it is not recommended to breast-feed while using the drug.

Fertility

In preclinical studies of the influence of atazanavir on fertility and embryonic development atazanavir changed the estrous cycle, without affecting fertility.

Dosing and Administration:

The drug is taken orally, without chewing, as part of a combination therapy. The decision to initiate therapy is taken by a doctor with experience in the treatment of HIV infections.The efficacy and safety of using atazanavir 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 / day can alter the safety profile of atazanavir, so it is not recommended.

Adults

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

- Atazanavir 400 mg once a day with meals;

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

Dosage regimen for patients who had previously received antiretroviral therapy:

Atazanavir 300 mg and ritonavir 100 mg once a day with meals.

The use of atazanavir without ritonavir is not recommended for patients with an adverse virologic outcome of previous antiretroviral therapy.

Children

Atazanavir doses for children 6 years and older are calculated by body weight (see table below); Doses for children should not exceed the doses used to treat adult patients. Atazanavir is 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 doses of atazanavir for children by body weight

Body weight (kg)	The dose of atazanavir (mg)	The dose of ritonavir (mg)
15-35	200	100
>35	300	100

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, atazanavir 300 mg is given only in combination with ritonavir 100 mg.

Patients with severe renal failure who are on hemodialysis and who have previously received antiretroviral therapy, atazanavir prescribe is contraindicated.

Patients with hepatic insufficiency

Caution should be exercised when administering atazanavir without ritonavir to patients with impaired hepatic or mild liver function (Child-Pugh class A and B). For violations of the liver function of moderate severity (class B according to the Child-Pugh classification) in patients who have not previously received antiretroviral therapy, it is recommended to reduce the dose to 300 mg once a day. Atazanavir at any regimens of dosing contraindicated to use in violations of liver function of a serious degree (class C according to the Child-Pugh classification). The use of atazanavir in combination with ritonavir in patients with hepatic insufficiency has not been studied,this combination should be used with caution in patients with mild liver function disorders (class A Child-Pugh classification) and is contraindicated in patients with violations of liver function of moderate and severe severity (class B and C according to Child-Pugh classification).

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 atazanavir - during meals, so when combined therapy is recommended to take didanosine 2 hours after taking atazanavir with food.

Tenofovir: a combination of atazanavir 300 mg and ritonavir 100 mg with tenofovir 300 mg is recommended (all medications should be taken once a day during meals). The use of atazanavir (without ritonavir) together with tenofovir is not recommended.

Side effects:

Adults

The most frequent adverse reactions of any severity,Ataxanavir and one or more nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors (> 10%, "very often") were: nausea (20%), jaundice (13%), and diarrhea (10%). Among patients who received atazanavir 300 mg and ritonavir 100 mg, the most frequent adverse reaction was jaundice (19%).

In most cases, jaundice was observed several days or months after the start of treatment and in less than 1% of patients the drug was withdrawn. Lipodystrophy of moderate or severe degree, noted with the administration of atazanavir 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, infrequent - fainting, peripheral neuropathy, dizziness, memory loss, drowsiness, anxiety, depression, sleep disorders,change in the nature of dreams, insomnia, disregard of orientation.

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

From the skin side and subcutaneous tissue: often - a rash; infrequently - baldness, itching, hives; erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), toxic skin rash, angioedema (post-registration data); rarely - vasodilation, vesiculo-bullous rash, eczema; Stevens-Johnson syndrome (post-registration data).

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

From the urinary system: infrequently - hematuria, frequent urination, proteinuria, nephrolithiasis (post-registration data), interstitial nephritis; rarely - pain in the kidney area.

From the side of the organ of vision: often - icteric sclera.

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

On the part of the reproductive system: infrequently - gynecomastia.

From the cardiovascular system: infrequently - increased blood pressure; tachycardia of the "torsade de pointes"(postregistration data), rarely - swelling, heart palpitations, lengthening interval QTc (post-registration data).

Post-registration data (frequency not established) - atrioventricular (AV) blockade II and III degree.

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

From the liver and bile ducts: often - jaundice; infrequently - hepatitis; cholelithiasis, cholestasis (post-registration data); rarely - hepatosplenomegaly, cholecystitis (post-registration data).

General disorders: often fatigue; infrequently - chest pain, fever, malaise, weakness, redistribution of fatty tissue (lipodystrophy); rarely - gait disturbance.

There have been isolated cases of bleeding, spontaneous skin reactions and hemarthrosis in patients with haemophilia type A and B with the use of protease inhibitors.

Most often (more than 10%, "very often"), the following laboratory abnormalities were observed in patients receiving treatment, which included atazanavir and one or more nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors: an increase in total bilirubin (87%), especially indirect (unbound) bilirubin in serum.

Other significant deviations in laboratory parameters were observed in> 2% of patients ("often"): increased activity of creatine phosphokinase (7%), increased activity of alanine aminotransferase (ALT) / serum glutamine-pyruvic transaminase (5%), a decrease in the number of neutrophilic leukocytes (5%) , an increase in activity of aspartate aminotransferase (AST) / serum glutaminosuschial acetic transaminase (3%), an increase in 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.

In 2% of patients who received atazanavir a competitive increase in ALT / AST and total bilirubin of grade 3-4 was noted.

Description of individual side effects

- In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, inflammatory responses may occur in response to asymptomatic or residual opportunistic infections.There have also been cases of autoimmune diseases (eg, Graves' disease), but the timing of the onset of these diseases varied in different patients and could occur many months after initiation of atazanavir therapy.

- With the use of combined antiretroviral therapy for a long period of time, cases of osteonecrosis have been observed, especially in patients with risk factors (high body mass index, immunosuppression, alcohol use, concomitant use of corticosteroids).

- Metabolic parameters - the ratio and content of lipids and glucose in the blood may increase during antiretroviral therapy.

- Rash and associated syndromes - a rash in the form of maculopapular skin rashes from mild to moderate severity usually can occur within the first 3 weeks after initiation of atazanavir therapy.

- Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), a toxic skin rash was noted with the use of atazanavir.

Children

The safety profile of atazanavir in children 6 years and older is comparable to that of adult patients.

The most frequent (more than 10%, "very often") deviation of laboratory indicators of 3rd and 4th degree in children was an increase in total bilirubin (> 2.6 x VGN, 45%). The most common side effects of grade 2-4 were cough (21%), fever (18%), jaundice / yellowing sclera (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), pain in the extremities (6%), nasal congestion (6%), soreness in swallowing (6%), dyspnea (6%), liquid discharge from the nose (6% ). In rare cases, asymptomatic atrioventricular (AV) blockade of I and II degree (<2%).

Patients with hepatitis B and / or C

Patients with concomitant chronic hepatitis B and / or C are more likely to increase the activity of hepatic transaminases compared to uninfected patients. There was no difference in the incidence of bilirubin increase in patients with hepatitis B and / or C and in uninfected patients.

The incidence of hepatitis during treatment or increased transaminase activity in patients with concomitant chronic hepatitis B and / or C was comparable with atazanavir and regimen regimens.

Patients with concomitant chronic hepatitis B and / or C are at greater risk of developing severe and potentially fatal adverse reactions from the liver.

Overdose:

Symptoms

In clinical trials, the intake of healthy doses of atazanavir to 1200 mg by a single volunteer was not once accompanied by any undesirable events.

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 signs on the ECG 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).

Treatment

There is no specific antidote. In case of an overdose of atazanavir, the main physiological parameters should be monitored, the patient's general condition monitored, ECG monitored, gastric lavage prescribed, vomiting to remove drug residues, activated charcoal.

Dialysis is ineffective for removing the drug from the body, tk. 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 atazanavir and other drugs with the same metabolic pathways (slow calcium channel blockers, some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors), immunosuppressants, phosphodiesterase inhibitors) may result 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.

Joint use of atazanavir 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.

Joint use of atazanavir and isozyme inhibitory drugs CYP3A4, can lead to an increase in the concentration of atazanavir in plasma.

The severity of the 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 atazanavir 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.

Preparations, the joint administration of which with atazanavir is contraindicated

Quinidine	Use with the atazanavir / ritonavir combination is contraindicated because of 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 efficacy and development of resistance to atazanavir. The simultaneous use of atazanavir and rifampicin is contraindicated.
Bepridil	Due to the high risk of developing life-threatening side effects, joint use with atazanavir is contraindicated.
Derivatives of ergotamine (dihydroergotamine, ergotamine, ergometrine, methylergomethrin)	Due to the high risk of developing life-threatening side effects, joint use with atazanavir is contraindicated. Manifestations of acute toxicity of ergotamine derivatives: peripheral vasospasm, ischemia of extremities and other zones.
Cisapride	Due to the high risk of life-threatening side effects (arrhythmia), joint use with atazanavir is contraindicated.
Lovastatin, simvastatin	Increased risk of myopathy, including rhabdomyolysis.
Pimozide	Due to the high risk of life-threatening side effects (arrhythmia), joint use with atazanavir is contraindicated.
Midazolam (for parenteral use), triazolam	Joint use with atazanavir is contraindicated in connection with the possibility of increasing the concentration of midazolam / triazolam and a high risk of prolonging sedation and respiratory depression.
Preparations of St. John's wort perfumed (Hypericum perforatum)	Combination with atazanavir is contraindicated, as the concentration of atazanavir in the plasma may decrease, leading to a loss of therapeutic effect and the development of resistance.
Astemizole	When combined with atazanavir / ritonavir combination, the risk of severe, life-threatening side effects increases, so this combination is contraindicated.
Terfenadine	When combined with atazanavir / ritonavir combination, the risk of severe, life-threatening side effects increases, so this combination is contraindicated.
Alfuzosin	In view of the potential increase in the concentration of alfuzosin, which may lead to the development of hypotension, a joint use with the combination atazanavir / ritonavir is contraindicated.
Sildenafil (for use in pulmonary hypertension)	Application together with the drug atazanavir with pulmonary hypertension is contraindicated.
Quetiapine	Contraindicated joint use of the combination atazanavir / ritonavir and quetiapine because of the increased risk of side effects associated with quetiapine. An increase in the concentration of quetiapine in plasma can lead to the development of coma.

For the drugs listed below, it may be necessary to change the dosage regimen in connection with the expected interactions

Antiretroviral drugs for HIV treatment
Nucleoside reverse transcriptase inhibitors
Didanosine	The use of didanosine capsules coated with an enteric-coated membrane (400 mg) together with atazanavir or with preparations atazanavir (300 mg) and / or ritonavir (100 mg) and food reduces the bioavailability of didanosine. Didanosine should be taken 2 hours after taking atazanavir.There was no significant effect on the concentration of atazanavir when combined with didanosine; taking together with food reduces the concentration of didanosine.
Nucleotide reverse transcriptase inhibitors
Tenofovir disoproxil fumarate	Tenofovir disoproxil fumarate reduces the activity of atazanavir with simultaneous application, atazanavir increases the concentration of tenofovir disoproxil fumarate in blood plasma. High concentrations of tenofovir, dizoproxil fumarate, may increase the side effects associated with its administration, including effects on kidney function, so monitor the side effects of tenofovir disoproxil fumarate in patients. In the case of a joint administration of tenofovir with dysoproxyl fumarate atazanavir (300 mg) should be administered together with ritonavir (100 mg); the dose of tenofovir dizoproxil fumarate is 300 mg (for all drugs, single doses, with food).
Non-nucleoside reverse transcriptase inhibitors
Efavirenz	Combined therapy with drugs atazanavir and efavirenz leads to a decrease in the effect of atazanavir, so it should 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. Wherein atazanavir in a dose of 400 mg and ritonavir in a dose of 200 mg prescribed 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	Combined application of combination atazanavir 300 mg / ritonavir 100 mg once a day with boceprivir 800 mg (3 times a day) leads to a decrease in the concentration of atazanavir in the blood, which in turn can be a reason for the decrease in the effectiveness of therapy and loss of control over the infection. This combination can be prescribed only in exceptional cases to patients with undetectable viral load of HIV and in patients with HIV strains without suspicion of resistance to the chosen therapy. Strong clinical and laboratory monitoring of patients' viral load should be provided.
Saquinavir (soft gelatin capsules)	The effect of saquinavir increases with co-administration with atazanavir.There are no data allowing to give appropriate recommendations for dosing this combination.
Ritonavir	When combined with atazanavir, the concentration of atazanavir increases.
Other HIV protease inhibitors	Simultaneous use of the combination atazanavir / ritonavir with other HIV protease inhibitors is not recommended.
Other drugs
Antacids and buffers	When combined with antacids and buffers, the concentration of atazanavir in plasma is reduced. Atazanavir should be used 2 hours before or 1 hour after taking such drugs.
Antiarrhythmic drugs
Amiodarone, lidocaine (with parenteral administration), quinidine	At simultaneous application with atazanavir 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.
Beta-blockers
Atenolol	With the simultaneous use of atazanavir with beta-blockers, clinically significant pharmacokinetic interactions are not expected, so correction of the dosing regimen is not required.
Blocks of "slow" calcium channels
Diltiazem	Joint use with atazanavir 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	Care should be taken when using together, titration of the dose of "slow" calcium channel blockers, ECG monitoring is necessary.
Endothelin receptor antagonists (bosentan)	Bozentan is metabolized by isoenzyme CYP3A4, being its inductor. The concentration of atazanavir in plasma may decrease with simultaneous use of atazanavir with bosentan, but without ritonavir. In this regard, the combination atazanavir / bosentan can be used only with ritonavir. The following are the dosing regimes: 1. The appointment of bosentan to patients taking atazanavir / 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). 2. The appointment of the atazanavir / ritonavir combination to patients taking bosentan: stop taking bosentan at least 36 hours before taking the atazanavir / ritonavir combination.Not earlier than 10 days after the initiation of atazanavir / ritonavir, resumption of bosentan at a dose of 62.5 mg once a day or every other day (depending on individual tolerability).
ANDHMG-CoA reductase inhibitors
Atorvastatin	When combined with atazanavir, the effect of atorvastatin may be enhanced. The risk of myopathy, including rhabdomyolysis, may increase. Care must be taken to monitor side effects. The lowest effective doses of atorvastatin should be used in combination with atazanavir or atazanavir / 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.
Pravastatin, fluvastatin	The potential for interactions with atazanavir or atazanavir / ritonavir is unknown.
Proton Pump Inhibitors	During treatment with atazanavir, proton pump inhibitors are prescribed only if their use is highly indicated. With the simultaneous use of atazanavir 400 mg or combination atazanavir 300 mg / ritonavir 100 mg with omeprazole 40 mg (all drugs once a day) there is a significant decrease in the concentration of atazanavir in the blood plasma, 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 is recommended to use a combination of atazanavir 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 H₂-gistaminovyh receptors	With the simultaneous use of atazanavir 400 mg once daily with famotidine 40 mg twice daily, there was a significant reduction in the concentration of atazanavir in the blood plasma, which may lead to a decrease in the therapeutic activity of atazanavir or to the development of resistance. In the treatment of patients who had not previously received therapy, atazanavir 400 mg can be applied once a day with food 2 hours before and no less than 10 hours after the use of blockers H₂-gistaminovyh receptors.However, a single dose of H blockers₂-gistaminovyh receptors should not exceed the dose corresponding to a dose of famotidine 20 mg, and their total daily dose should not exceed the dose corresponding to 40 mg of famotidine. Alternatively, atazanavir 300 mg with ritonavir 100 mg can be applied once a day with meals, 2 hours before and not less than 10 hours after the use of blockers H₂-gistaminovyh receptors in a single dose, comparable with 40 mg famotidine. In the treatment of patients who had previously received therapy, the daily dose of blockers H₂-gistamine receptors should not exceed the dose corresponding to 40 mg of famotidine. In such patients, the combination atazanavir 300 mg / ritonavir 100 mg should be taken once a day with food 2 hours before and not less than 12 hours after the use of blockers H₂-gistaminovyh receptors (once a day) in a dose corresponding to 40 mg of famotidine. Alternatively, a combination of atazanavir 300 mg / ritonavir 100 mg can be applied once a day with meals simultaneously with blockers H₂- histamine receptors, 2 hours before and not less than 10 hours after the use of blockers H₂- Histamine receptors in a dose not exceeding the dose, which corresponds to 20 mg of famotidine.This dose can be taken once or twice a day. In the appointment of such patients combination atazanavir / ritonavir and tenofovir disoproxil fumarate with a blocker H₂-histamine receptors, the following dosing regimen should be used: atazanavir 400 mg and ritonavir 100 mg once a day. There is insufficient data to recommend the simultaneous use of atazanavir, tenofovir dizoproxil fumarate and antagonists H₂-gistamine receptors in pregnant women who had previously received antiretroviral therapy.
Immunosuppressants (ciclosporin, tacrolimus, sirolimus)	With the combined use of cyclosporine, tacrolimus, sirolimus and atazanavir, an increase in the concentration of immunosuppressants is possible in the blood, therefore, monitoring of their concentrations is recommended.
Antidepressants
Tricyclic antidepressants	With the simultaneous use of atazanavir 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 combined with atazanavir.
Trazodone	With the combined use of trazodone with atazanavir or with the combination atazanavir / 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 atazanavir, smaller doses of trazodone should be used.
Benzodiazepines	Midazolam is metabolized by isoenzyme CYP3A4. In spite of the fact that no studies have been conducted, with the simultaneous use of atazanavir and midazolam, a significant increase in the concentration of the latter can be expected. In this case, an increase in the concentration of midazolam with oral administration will be significantly higher than with parenteral administration. The use of atazanavir together with midazolam for oral administration is contraindicated. Data on simultaneous use of atazanavir 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.When joint use of atazanavir with injection midazolam should be careful, control the respiratory function and the duration of the sedation. In some cases, a correction of the dosing regimen is necessary.
Antiepileptic drugs
Carbamazepine	With the simultaneous administration of carbamazepine and atazanavir without ritonavir, the concentration of atazanavir in blood plasma may decrease. In this regard, the simultaneous administration of carbamazepine and atazanavir 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 atazanavir and ritonavir, caution should be exercised when taking these drugs together, and a dose reduction of carbamazepine may be required.
Phenytoin, phenobarbital	With the simultaneous administration of phenytoin or phenobarbital and atazanavir without ritonavir, the concentration of atazanavir in the blood plasma may decrease. In this regard, the simultaneous administration of phenytoin or phenobarbital and atazanavir without ritonavir is not recommended. Because the ritonavir can reduce the concentration of phenytoin and phenobarbital in the blood plasma, care must be taken when sharing phenytoin or phenobarbital with atazanavir and ritonavir together, and a dose adjustment for phenytoin or phenobarbital may be required.
Lamotrigine	When combined with lamotrigine and atazanavir with ritonavir, the concentration of lamotrigine in the blood plasma may decrease. In this regard, you may need to adjust the dose of lamotrigine. With the joint use of lamotrigine and atazanavir without ritonavir, a decrease in lamotrigine concentration in the blood plasma was not observed, therefore, lamotrigine dose adjustment is not required.
Macrolide antibiotics
Clarithromycin	With the combined use of clarithromycin with atazanavir, the concentration of clarithromycin increases, which may cause lengthening of the interval QT; There are no recommendations for reducing the dose of clarithromycin, and therefore care must be taken when using clarithromycin together with atazanavir.
Oral contraceptives
Ethinylestradiol and norethisterone or norgestimate	When combined with atazanavir concentrations of ethinyl estradiol and norethisterone increase. The combined use of the combination atazanavir / 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 atazanavir / ritonavir combination, contraceptives with an ethinylestradiol content of at least 30 μg are recommended. If, together with contraceptives, atazanavir without ritonavir, the content of ethinyl estradiol in oral contraceptives should not exceed 30 mcg. With the joint use of atazanavir and oral contraceptives, care should be taken, since the effect of increasing the concentration of progestogens is unknown; the risk of developing acne, dyslipidemia and insulin resistance may increase. With increasing concentrations of norethisterone, a decrease in HDL cholesterol or an increase in insulin resistance, especially in women with concomitant diabetes mellitus, is possible.It is recommended to use the lowest effective doses of each component of the oral contraceptive, it is also advisable to use other reliable methods of contraception. The combined use of atazanavir, or a combination of atazanavir / ritonavir with other forms of hormonal contraceptives (contraceptive patches, contraceptive vaginal ring, injectable contraceptives) or with oral contraceptives containing progestogens, different from norethisterone or norgestimate, as well as formulations containing less than 25 mcg ethinyl estradiol, not Therefore, these methods of contraception are not recommended in combination with atazanavir.
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 atazanavir. The recommended doses of colchicine when used concomitantly with atazanavir 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 combined with atazanavir increases. With the simultaneous administration of these drugs, a dose reduction of rifabutin to 150 mg every other day or three times a week is recommended. A careful monitoring of adverse reactions in patients (including neutropenia and uveitis), taking rifabutin and atazanavir or a combination of atazanavir / ritonavir in connection with a possible increase in the concentration of rifabutin; may require further correction of the dose of rifabutin to 150 mg twice a week in patients with intolerance to a dosage of 150 mg / 3 times a week. However, it should be borne in mind that a dosage of 150 mg twice a week may not provide the optimal concentration of rifabutin and lead to the possibility of resistance and ineffectiveness of treatment. Correction of the dose of atazanavir is not 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. It is recommended to reduce the dose: 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.
Tadalafil	For patients receiving atazanavir 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 atazanavir. Not earlier than seven days after the start of taking atazanavir, resume taking tadalafil at a dose of 20 mg once a day. The dose can be increased to 40 mg once a day (depending on individual tolerability).
Antifungal drugs
Ketoconazole, itraconazole	Only joint use of ketoconazole with atazanavir 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 the atazanavir / ritonavir combination.
Voriconazole	The combined use of voriconazole (200 mg, 2 times a day) with the combination of atazanavir / ritonavir in patients with at least one functional allele isoenzyme CYP2C19 resulted in a decrease in the concentrations of voriconazole and atazanavir in blood plasma. Joint use of voriconazole (200 mg twice daily) with atazanavir / ritonavir combination in patients without a functional isoenzyme allele CYP2C19 resulted in an increase in the concentrations of voriconazole and a decrease in the concentration of atazanavir in blood plasma. The combined use of voriconazole and a combination of atazanavir / ritonavir is recommended only in cases where the potential benefit outweighs the risk of application of voriconazole.If necessary, the appointment of voriconazole with atazanavir, if possible, requires genotyping patients for the presence of a functional isoenzyme allele CYP2CI9. If this combined therapy can not be avoided, careful monitoring of the side effects of voriconazole (in patients without functional alleles of the isoenzyme CYP2C19), as well as the efficacy of voriconazole and atazanavir (in patients with at least one functional isoenzyme allele CYP2C19), which may be reduced.
Anticoagulants
Warfarin	Because of the increased activity of warfarin, simultaneous use with atazanavir can cause severe and / or life-threatening bleeding. It is recommended to monitor the international normalized attitude (INR).
Corticosteroids
Inhalation / nasal glucocorticosteroids (interaction with ritonavir)	With the simultaneous use of ritonavir with fluticasone propionate by healthy volunteers, the concentration of cortisol was significantly reduced due to a significant increase in plasma fluticasone concentration.The combined use of the combination atazanavir / 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, with budesonide. In this regard, the use of the combination atazanavir / ritonavir together with fluticasone propionate or other glucocorticosteroids metabolized by the isoenzyme CYP3A4, is justified only if the potential benefit of therapy exceeds the risk of systemic effects of glucocorticosteroids. With the simultaneous use of atazanavir (without ritonavir) and fluticasone propionate, the concentration of the latter in the blood plasma can 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 is not expected. Atazanavir is a weak isoenzyme inhibitor CYP2C8. Caution should be exercised when atazanavir is used together (without ritonavir) and preparations heavily dependent on isoenzyme CYP2C8 and having a narrow therapeutic profile (for example, paclitaxel, repaglinide). When using the combination atazanavir / 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 in the combined use of atazanavir or atazanavir / ritonavir and buprenorphine combinations of buprenorphine and norbuprenorphine concentrations increased. When using the combination atazanavir / ritonavir with buprenorphine, there was no significant change in the concentration of atazanavir in plasma; the use of the same combination, but without ritonavir, can lead to a significant decrease in the concentration of atazanavir in plasma. With simultaneous applicationcombination atazanavir / ritonavir and buprenorphine requires careful monitoring of the patient's condition (evaluation of sedation and cognitive functions). You may need to reduce the dose of buprenorphine.
Irynotekan	Atazanavir inhibits UDP-glucuronosyltransferase (CGT) and may affect the metabolism of irinotecan, causing an increase in its toxicity, so when combined with atazanavir with irinotecan, patients should be monitored for the development of adverse reactions caused by taking irinotecan.
Indinavir	Atazanavir and indinavir may be the cause of the development of hyperbilirubinemia, therefore, the combined use of indinavir with atazanavir is not recommended.
Inhalation betaa₂- adrenomimetics (salmeterol)	An increased risk of cardiovascular side effects associated with salmeterol, including lengthening of the interval QT, palpitation, sinus tachycardia. Joint use of salmeterol and atazanavir is not recommended.

For the drugs listed below, no clinically relevant interactions are expected, in connection with which no dose adjustment is required

Lamivudine (150 mg twice daily) + zidovudine (500 mg twice daily)	When combined with atazanavir at a dose of 400 mg, no significant changes in the concentrations of lamivudine and zidovudine were observed. There is also 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 atazanavir / ritonavir combination.
Abacavir	When combined with atazanavir / ritonavir combination, no significant change in abacavir concentration is expected.
Raltegravir	When combined with the atazanavir / ritonavir combination, an increase in the area under the concentration-time curve was observed (AUC_s) for raltegravir by 41%, the maximum equilibrium concentration of raltegravir (FROM_mOh) by 24%, the equilibrium concentration of raltegravir after 12 h (C_12h) on 77%. Correction of doses of raltegravir is not required.
Fluconazole	When combined with atazanavir / ritonavir combination, no significant changes in the concentrations of atazanavir and fluconazole were observed.Correction of the dose is not required.
Methadone	Patients who are taking methadone on a regular basis are not expected to develop clinically significant interactions when combined with atazanavir.
Dapson, triietoprim / sulfamethoxazole, azithromycin, erythromycin	It is not expected the development of clinically significant interactions when combined with atazanavir.

Special instructions:

The administration of atazanavir is inappropriate for patients with multiple resistance to HIV protease inhibitors (more than 4 mutations). The choice of atazanavir for the treatment of patients who have previously received antiretroviral therapy should be based on data on individual resistance and the results of previous treatment.

Although effective suppression of antiretroviral replication of the virus significantly reduces the risk of HIV transmission during sexual intercourse, the risk of transmission can not be ruled out completely, and precautionary measures should be followed (use of the barrier method).

The efficacy and safety of using atazanavir in combination with ritonavir in a daily dose of more than 100 mg has not been studied; use of doses of ritonavir exceeding 100 mg per day,can change the safety profile of atazanavir (side effects from the cardiovascular system, hyperbilirubinemia), so it is not recommended. Only with the simultaneous use of the combination atazanavir / ritonavir and efavirenz may an increase in the dose of ritonavir to 200 mg 1 time per day, while it is necessary to provide clinical monitoring of the patient.

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.

Patients with hemophilia A or B should be aware of the possibility of increased bleeding.

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.

Patients with risk factors for the development of lipodystrophy (elderly age, long-term antiviral drugs, metabolic disorders) should be subject to clinical examination, including an external evaluation of the redistribution of fat.

Metabolic parameters / body weight

During antiretroviral therapy, weight gain, lipids and glucose in the blood can be noted. Such changes may be due to the treatment of the underlying disease, as well as the way of life.Control for lipids and blood glucose is provided according to recommendations for treatment of HIV infection. Disturbances in the metabolism of fats should be controlled according to clinical practice. When using combined antiretroviral therapy, including also joint use with oral contraceptives, there have been cases of development of dyslipidemia.

Immunodeficiency Syndrome

The development of the immune reconstitution syndrome was noted in patients receiving antiretroviral therapy, including atazanavir. In HIV-infected patients, as a result of the immune response at the onset of combined antiretroviral therapy, there may be signs of an inflammatory response in response to asymptomatic or residual opportunistic infections (cytomegalovirus retinitis, generalized and / or local mycobacterial infections caused by Mycobacteriumavium, pneumonia caused by Pneumocystis carinii, Pneumocystis jirovecior tuberculosis), which can lead to the development of serious clinical consequences or worsening of the patient's condition. Typically, such reactions develop during the first few weeks or months from the start of treatment. A survey and appropriate treatment should be conducted.

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 pre-existing liver dysfunction, including active chronic hepatitis, the incidence of liver function disorders increases with combined antiretroviral therapy. In this regard, it is necessary to regularly monitor the condition of such patients. In case of worsening, a decision may be made to suspend or stop atazanavir therapy.

In patients with viral hepatitis B or C or prior to the beginning of treatment with increased activity of transaminases, there is a risk of further increase in the activity of transaminases or decompensation of liver function.In such patients, laboratory monitoring of liver function should be performed before and during therapy with atazanavir.

Renal insufficiency

For patients not on hemodialysis, dose adjustment is not required. For patients on hemodialysis who have not previously received antiretroviral therapy, atazanavir is given only in combination with ritonavir.

Patients with severe renal failure who are on hemodialysis and who have previously received antiretroviral therapy, atazanavir apply contraindicated.

Hyperbilirubinemia

In patients who received atazanavir, cases of reversible increase in indirect (free) bilirubin associated with inhibition of UDP-glucuronosyltransferase (CGT) have been reported. It should be noted that an increase in the activity of transaminases, which is observed with increased bilirubin in patients receiving atazanavir, can be caused by other diseases, also accompanied by hyperbilirubinemia. Alternative antiretroviral therapy for atazanavir may be considered if jaundice or yellowing of the sclera is unacceptable to the patient.Decrease in the dose of atazanavir is not recommended, as this can lead to loss of therapeutic effect and development of resistance.

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. Indinavir may also be the cause of an increase in indirect (free) bilirubin associated with inhibition of UDP-glucuronosyltransferase (CGT). Therefore, its combined use with atazanavir is not recommended.

PQ interval extension

Atazanavir can prolong the PQ and PR interval in some patients. Care should be taken when using the drug in patients with impaired cardiac conduction (for example, atrio-ventricular blockade of II and III degree). Caution should be exercised when using together atazanavir with drugs that extend the PQ interval (for example, atenolol, diltiazem, verapamil).

Elongation of the QT interval

There were cases of prolongation of the QT interval in some patients, depending on the dose of atazanavir. Care should be taken when using the drug in patients with cardiac conduction disorders (for example,atrio-ventricular blockade of II and III degree or blockade of the bundle of His), and appoint it only if the potential benefit exceeds the possible risk from the use of the drug. Special care should be taken when using atazanavir together with drugs that extend the QT interval (for example, clarithromycin, salmeterol), as well as in patients with risk factors (bradycardia, congenital prolongation of the QT interval, electrolyte imbalance).

Rash

Maculopapular rash, usually from mild to moderate, can be observed during the first 3 weeks after initiation of atazanavir therapy.

The development of Stevens-Johnson syndrome, erythema multiforme, toxic skin rash and drug rash with eosinophilia and systemic symptoms (DRESS syndrome) has also been noted. Patients should be warned about possible signs and symptoms of the development of the rash. Possible skin reactions should be carefully monitored. The use of the drug should be discontinued with the development of severe rash. Careful monitoring of the skin condition allows for early diagnosis and immediately suspend the use of a suspicious drug.Patients who previously had the development of Stevens-Johnson syndrome and DRESS syndrome associated with atazanavir can not reapply it after the suspension of treatment.

Nephrolithiasis and cholelithiasis

During post-patient studies on the safety of atazanavir in HIV-infected patients, nephrolithiasis and / or cholelithiasis have been reported. Some patients required hospitalization for necessary therapy, some patients experienced complications. In some cases, the development of nephrolithiasis was accompanied by acute renal failure and impaired renal function. If symptoms of nephrolithiasis and / or cholelithiasis are present, interrupt therapy temporarily or stop taking the drug completely.

Simultaneous reception with other medications

It is not recommended simultaneous use of atazanavir with atorvastatin.

If you need to receive glucocorticosteroids It is recommended to take drugs that are not substrates of the isoenzyme CYP3A4 (beclomethasone).

Because the atazanavir is metabolized mainly through the isozyme CYP3A4, the combined use of atazanavir and drugs inducing the isoenzyme CYP3A4 is not recommended.

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.

Combined therapy with atazanavir and efavirenz leads to a decrease in the effect of atazanavir, so it should 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. Wherein atazanavir 400 mg and ritonavir 200 mg is given as a single dose during meals, and efavirenz - on an empty stomach, before bedtime.

Joint application voriconazole (200 mg twice daily) with the combination atazanavir / ritonavir in patients with at least one functional allele of the CYP2C19 isoenzyme resulted in a decrease in the concentrations of voriconazole and atazanavir in blood plasma. The combined use of voriconazole (200 mg twice daily) with the combination atazanavir / ritonavir in patients without a functional allele of the CYP2C19 isoenzyme resulted in 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 a combination of atazanavir / ritonavir is recommended only in cases where the potential benefit outweighs the risk of application of voriconazole.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.

Sildenafil, tadalafil, vardenafil: with the combined use of HIV protease inhibitors with phosphodiesterase-5 inhibitors metabolized by the CYP3A4 isoenzyme and used to treat erectile dysfunction, a significant increase in the concentration of phosphodiesterase-5 inhibitors and an increase in their side effects associated with inhibition of phosphodiesterase-5 (eg, hypotension, priapism, visual impairment).

The use of the combination atazanavir / ritonavir together with fluticasone propionate or other glucocorticosteroids metabolized by the isoenzyme CYP3A4, is not recommended and is possible only if the potential benefit of therapy exceeds the risk of systemic effects of glucocorticosteroids, including Cushing's syndrome and suppression of adrenal cortex function.

Joint application salmeterol and atazanavir is not recommended in view of the increased risk of side effects from the cardiovascular system,inherent in salmeterol.

During treatment with atazanavir, simultaneous administration is not recommended proton pump inhibitors. They are appointed only in the event that their use is highly indicated. A thorough clinical monitoring of the patient's condition and the use of combination atazanavir 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).

Joint use of atazanavir from hormonal contraceptives or oral contraceptivescontaining progestogens other than norgestimate or norethindrone have not been studied and therefore not recommended.

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, when combined antiretroviral therapy is used for a long timeThere were cases of osteonecrosis, especially in patients with risk factors (high body mass index, immunosuppression, alcohol consumption, concomitant use of corticosteroids).

When a patient has pain in joints or difficulty in moving, the possibility of osteoncrosis development should be taken into account.

Lactose

Patients with a deficiency of lactase, a rare hereditary intolerance to lactose, glucose-galactose malabsorption, the use of the drug Simanod is contraindicated.

Children

Asymptomatic prolongation of the PR interval was more often observed in children compared with adult patients. Asymptomatic atrioventricular blockade of II and III degree was also noted in children. Caution should be exercised when combined with drugs that cause prolongation of the PR interval, and when the drug is used in patients with cardiac conduction disorders (for example, atrioventricular blockade of II and III degree or blockade of the bundle of His), and appoint it only if the potential benefit exceeds the possible risk of using the drug.It is recommended to monitor the function of the cardiovascular system in the presence of clinical symptoms (eg, bradycardia).

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

Special studies to study the influence of atazanavir on the ability to drive vehicles and work with mechanisms have not been conducted.

Form release / dosage:

Capsules, 150 mg, 200 mg and 300 mg.

Packaging:

Primary packaging of medicinal product

10 capsules per contour cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

At 30, 60, 90, 100, 120 capsules in a polymer can of polyethylene with a lid pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

Secondary packaging of medicinal product

By 3, 6, 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

On 1 bank together with instructions on application place in a pack from a cardboard.

Storage conditions:

In 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 the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004170

Date of registration:02.03.2017

Expiration Date:02.03.2022

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC

Information update date: & nbsp31.03.2017

Illustrated instructions

Instructions

Simanod (Simanodum)