Reyataz^® (Capsules) Instructions for Use

ATC Code

J05AE08 (Atazanavir)

Active Substance

Atazanavir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

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 infection of other cells.

During treatment, some patients may develop resistance to the drug’s action (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 to varying degrees.

Resistance to atazanavir does not always preclude the sequential use of other HIV protease inhibitors.

In vitro resistance (in cell culture)

The sensitivity to atazanavir was studied in cell cultures isolated from patients who had not previously received Reyataz^®.

A clear trend towards reduced sensitivity to atazanavir was identified in cells showing a high level of multiple resistance to other HIV protease inhibitors.

In contrast, sensitivity to atazanavir was preserved in cells resistant to only 1-2 HIV protease inhibitors.

In vivo resistance

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

Patients previously not receiving antiretroviral therapy

Reyataz^® 400 mg (without ritonavir)

No cross-resistance was found between atazanavir and amprenavir.

Phenotypic analysis of isolated cells showed the development of resistance specific only to atazanavir and associated with increased sensitivity to other HIV protease inhibitors.

Reyataz^® 300 mg/ritonavir 100 mg

A study of the efficacy of the Atazanavir/ritonavir (or Atazanavir/lopinavir/ritonavir) combination in patients not previously receiving antiretroviral therapy showed that after 96 weeks of therapy, phenotypic resistance to atazanavir developed in only one case of therapeutic failure.

Patients previously receiving antiretroviral therapy

Reyataz^® or Reyataz^®/ritonavir

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

Pharmacokinetics

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

Absorption

With long-term use of Reyataz^® at a dose of 400 mg once daily with a light meal, the C_max of atazanavir in plasma was reached approximately 2.7 hours after administration.

The C_ss of atazanavir is achieved between days 4 and 8 of administration.

Taking Reyataz^® with food improves its bioavailability and reduces pharmacokinetic variability.

Taking the Reyataz^®/ritonavir combination with food improves the bioavailability of atazanavir.

Distribution

The binding of atazanavir to plasma proteins is 86%.

The degree of protein binding is concentration-independent.

Atazanavir binds to alpha₁-glycoprotein and albumin to a similar extent.

Atazanavir is detected in cerebrospinal and seminal fluid.

Metabolism

Atazanavir is primarily metabolized by the CYP3A4 isoenzyme to form oxidized metabolites.

Metabolites are excreted in bile, both in free form and as glucuronides.

A small portion of atazanavir is metabolized via N-dealkylation and hydrolysis.

Excretion

After a single dose of ¹⁴C-atazanavir 400 mg, 79% and 13% of the total radioactivity was detected in feces and urine, respectively.

The proportion of unchanged drug in feces and urine was about 20% and 7%, respectively.

The mean T_1/2 of atazanavir in healthy volunteers and HIV-infected adults was about 7 hours when atazanavir was administered at a dose of 400 mg/day with a light meal.

Indications

• HIV-1 infection in combination with other antiretroviral drugs in patients previously receiving or not receiving antiretroviral therapy.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally as part of combination therapy.

The decision to initiate therapy is made by a physician experienced in the treatment of HIV infection.

The efficacy and safety of using Reyataz^® in combination with ritonavir at a daily dose exceeding 100 mg have not been studied; the use of ritonavir doses exceeding 100 mg/day may alter the safety profile of Reyataz^® and is therefore not recommended.

Adults

Dosage regimen for patients not previously receiving antiretroviral therapy: Reyataz^® 400 mg once daily with food or Reyataz^® 300 mg and ritonavir 100 mg once daily with food.

Dosage regimen for patients previously receiving antiretroviral therapy Reyataz^® 300 mg and ritonavir 100 mg once daily with food.

The use of Reyataz^® without ritonavir is not recommended for patients with an unfavorable virological outcome of previously administered antiretroviral therapy.

Children

The doses of Reyataz^® for children aged 6 years and older are calculated based on body weight (as indicated in the table).

Doses for children should not exceed the doses used to treat adult patients.

Reyataz^® in capsule form is prescribed to children in combination with ritonavir (in capsule or tablet form).

Both drugs should be taken simultaneously, once daily with food.

Table. Calculation of Reyataz^® doses for children based on body weight

For children aged 13 years and older with a body weight of at least 40 kg, not previously receiving antiretroviral therapy and intolerant to ritonavir, Reyataz^® (without ritonavir) is prescribed at a dose of 400 mg/day with food.

For patients with renal impairment not on hemodialysis, no dose adjustment is required.

For patients on hemodialysis,not previously receiving antiretroviral therapy, Reyataz^® at a dose of 300 mg is prescribed only in combination with ritonavir at a dose of 100 mg.

Patients with severe renal impairment on hemodialysis and previously receiving antiretroviral therapy should not be prescribed Reyataz^®.

Caution should be exercised when prescribing Reyataz^®without ritonavir to patients with mild or moderate hepatic impairment.

For moderate hepatic impairment, it is recommended to reduce the dose to 300 mg once daily.

Reyataz^® (under any dosing regimen) should not be used in severe hepatic impairment.

The use of Reyataz^®in combination with ritonavir in patients with hepatic impairment has not been studied, therefore this combination should not be used in these patients.

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

Based on pharmacokinetic data, no dose adjustment based on age is required.

Combination Therapy

Didanosine didanosine should be taken on an empty stomach, and Reyataz^® with food, therefore, during combination therapy, it is recommended to take didanosine 2 hours after taking Reyataz^® with food.

Tenofovir it is recommended to use the combination of Reyataz^® 300 mg and ritonavir 100 mg together with tenofovir 300 mg (all drugs should be taken once daily with food).

The use of Reyataz^® (without ritonavir) together with tenofovir is not recommended.

Adverse Reactions

The most frequent adverse reactions of any severity, noted with the use of Reyataz^® and one or more nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors with a frequency of more than 10% and possibly related to therapy were: nausea (20%), jaundice (13%), and diarrhea (10%).

Jaundice was noted several days or months after the start of treatment and led to drug discontinuation in less than 1% of patients.

Moderate or severe lipodystrophy, noted with the use of Reyataz^® and one or more nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors, and possibly related to treatment, was observed in 5% of patients.

Definition of adverse reaction frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000) and very rare (<1/10,000).

From the central and peripheral nervous system: common – headache; uncommon – peripheral neuropathy, dizziness, memory loss, drowsiness, anxiety, depression, sleep disorders, dream changes, insomnia, disorientation.

From the digestive system common – abdominal pain, diarrhea, dyspepsia, nausea, vomiting; uncommon – anorexia, increased appetite, dry mouth, taste perversion, flatulence, gastritis, pancreatitis, aphthous stomatitis, abdominal distension.

From the hepatobiliary system very common – cholelithiasis; uncommon – hepatitis; rare – hepatosplenomegaly; postmarketing data (frequency not established) – cholelithiasis, cholecystitis, cholestasis.

From the skin: common – rash; uncommon – alopecia, pruritus, urticaria; rare – vasodilation, vesiculobullous rash, eczema.

From the musculoskeletal system: uncommon – arthralgia, muscle atrophy, myalgia; rare – myopathy.

From the urinary system uncommon – hematuria, frequent urination, proteinuria, nephrolithiasis; rare – kidney pain.

From metabolism: uncommon – weight loss, weight gain; postmarketing data (frequency not established) – hyperglycemia, diabetes mellitus.

From the cardiovascular system uncommon – increased blood pressure, syncope; rare – edema, palpitations; postmarketing data (frequency not established) – second and third degree AV block, QTc interval prolongation, torsades de pointes type cardiac arrhythmias.

From the respiratory system uncommon – dyspnea.

From the reproductive system uncommon – gynecomastia.

General disorders common – general weakness, fatigue, scleral icterus; uncommon – chest pain, fever, general malaise, allergic reactions.

There are isolated cases of bleeding, spontaneous skin reactions, and hemarthrosis in patients with hemophilia type A and B when using protease inhibitors.

Laboratory parameters the most common laboratory abnormality in patients receiving treatment that included Reyataz^® and one or more nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors was an increase in total bilirubin (87%), especially indirect (unconjugated) bilirubin in the blood serum.

Other significant laboratory parameter abnormalities were observed in ≥2% of patients: increased creatine phosphokinase activity (7%), increased ALT activity (5%), decreased neutrophil count (5%), AST activity (3%), increased lipase activity (3%).

Discontinuation of treatment due to adverse effects was required in 5% of patients, both those who had and had not received antiretroviral therapy.

Children

The safety profile of Reyataz^® in children aged 6 years and older is comparable to that in adult patients.

Most common: cough, fever, jaundice, scleral icterus, rash, vomiting, diarrhea, headache, peripheral edema, limb pain, nasal congestion, painful swallowing, dyspnea, rhinorrhea.

In rare cases asymptomatic second degree AV block.

From laboratory parameters : the most common grade 3 and 4 abnormalities – increased total bilirubin (≥ 3.2 mg/dL; 58%), neutropenia (9%), and hypoglycemia (4%).

Contraindications

• Severe hepatic impairment with any dosing regimen;
• Combination of Reyataz^®/ritonavir in patients with moderate and severe hepatic impairment;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Simultaneous administration of Reyataz^® with astemizole, terfenadine, cisapride, pimozide, bepridil, quinidine, triazolam, midazolam (for oral administration), ergot derivatives (especially ergotamine, dihydroergotamine, ergometrine, methylergometrine), preparations of St. John’s wort (Hypericum perforatum), HMG-CoA reductase inhibitors (simvastatin, lovastatin), indinavir, irinotecan, rifampicin, alfuzosin, sildenafil (when prescribed for the treatment of pulmonary arterial hypertension), salmeterol;
• Simultaneous administration of the Reyataz^®/ritonavir combination with quinidine;
• Age under 6 years;
• Hypersensitivity to atazanavir or any other component of the drug.

With caution the drug should be prescribed for diabetes mellitus, hyperglycemia, dyslipidemia, hyperbilirubinemia, nephrolithiasis, viral hepatitis, chronic active hepatitis, mild and moderate hepatic impairment (for atazanavir), hemophilia A and B, congenital long PR interval syndrome, congenital long QT interval syndrome, increased gastric acidity, concomitant use with nevirapine, efavirenz, corticosteroids.

Use in Pregnancy and Lactation

Reyataz^® should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

During pregnancy, the combination of Reyataz^® at a dose of 300 mg together with ritonavir at a dose of 100 mg once daily should be used.

Dose adjustment is usually not required; however, for women not previously receiving antiretroviral therapy, in the second and third trimesters of pregnancy, if Reyataz^® is prescribed together with tenofovir or histamine H₂-receptor blockers, the recommended dose of Reyataz^® is 400 mg together with ritonavir at a dose of 100 mg once daily.

Data on the simultaneous use of Reyataz^®, tenofovir, and histamine H₂-receptor blockers in pregnant women previously receiving antiretroviral therapy are insufficient.

In the postpartum period, no dose adjustment is required, but careful medical monitoring of the patient for adverse reactions should be ensured, as an increase in drug plasma concentration is possible during the first 2 months after delivery.

It is unknown whether the mother’s use of the drug during pregnancy contributes to the development of physiological hyperbilirubinemia and jaundice in the newborn, therefore careful monitoring in the prenatal period should be ensured.

There are also no data on whether Atazanavir passes into breast milk.

Due to the possibility of HIV transmission from mother to child through breast milk, as well as the risk of serious side effects in the child, breastfeeding while using the drug is not recommended.

Use in Hepatic Impairment

Reyataz^® should be prescribed with caution to patients with mild hepatic impairment.

For patients with moderate hepatic impairment, it is recommended to reduce the dose of Reyataz^® to 300 mg once daily.

The use of Reyataz^® in combination with ritonavir in patients with hepatic impairment has not been studied.

This combination should be used with caution in patients with moderate hepatic impairment.

It is not recommended to prescribe Reyataz^® in combination with ritonavir to patients with severe hepatic impairment.

Use in Renal Impairment

For patients with renal impairment no dose adjustment is required.

Pediatric Use

Contraindication: age under 18 years.

Geriatric Use

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

Based on pharmacokinetic data, no dose adjustment based on age is required.

Special Precautions

Patients should be warned that antiretroviral therapy does not prevent the risk of HIV transmission through blood or during sexual contact.

Patients must follow precautionary measures.

Diabetes mellitus/hyperglycemia

During treatment with protease inhibitors, hyperglycemia, the onset of diabetes mellitus, or decompensation of pre-existing diabetes has been observed in some HIV-infected patients.

In some cases, diabetic ketoacidosis has been observed.

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, including spontaneous skin hemorrhages and hemarthrosis, has been described during treatment with HIV protease inhibitors.

Some of these patients required administration of factor VIII.

In most cases, treatment with HIV protease inhibitors was continued or resumed after a break.

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

Redistribution of adipose tissue

Isolated cases of adipose tissue redistribution have been observed, manifested as central obesity, increase in dorsocervical fat pad (“buffalo hump”), peripheral and facial wasting, breast enlargement, and “cushingoid appearance”.

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

Immune Reconstitution Syndrome

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

Hepatic Insufficiency

Atazanavir is metabolized primarily in the liver; therefore, the drug should be used with caution in patients with hepatic insufficiency due to the possibility of increased concentration. In patients with hepatitis B or C virus or elevated liver transaminase levels prior to treatment initiation, the risk of further increase in transaminase activity is increased.

Hyperbilirubinemia

Cases of reversible increase in indirect (free) bilirubin, associated with inhibition of uridine diphosphate glucuronosyltransferase (UGT), have been observed in patients receiving Reyataz^®. It should be considered that an increase in transaminase activity observed with elevated bilirubin in patients receiving Reyataz^® may be caused by other conditions also accompanied by hyperbilirubinemia. There are no long-term safety data for patients with persistent bilirubin elevation more than 5 times the upper limit of normal. Consideration may be given to prescribing an alternative antiretroviral therapy to Reyataz^® if jaundice or scleral icterus presents cosmetic concerns for the patient. Dose reduction of Reyataz^® is not recommended because there are no data on the efficacy of the drug at reduced doses.

PR Interval Prolongation

Atazanavir may prolong the PR interval in some patients. Caution should be exercised when using the drug in patients with cardiac conduction disorders. Caution should be exercised when co-administering Reyataz^® with drugs that prolong the PR interval (e.g., atenolol, diltiazem, verapamil).

Rash

Maculopapular rash, usually mild to moderate, may occur within the first 3 weeks of starting therapy with Reyataz^®. In most patients, the rash resolves within 2 weeks with continued therapy. Administration of the drug should be discontinued if a severe rash develops. Stevens-Johnson syndrome, erythema multiforme, and toxic skin reaction (DRESS) including drug rash, eosinophilia, and systemic symptoms have also been reported.

Nephrolithiasis

Cases of nephrolithiasis have been reported in HIV-infected patients during post-marketing safety studies of Reyataz^®. If symptoms of nephrolithiasis occur, therapy should be temporarily interrupted or the drug should be discontinued.

Concomitant Use of Corticosteroids

If corticosteroid use is necessary, drugs that are not substrates of the CYP3A4 isoenzyme (beclomethasone) are recommended.

Osteonecrosis

Rare cases of osteonecrosis have been reported with long-term use of combination antiretroviral therapy, particularly in patients with risk factors (high body weight, alcohol consumption, concomitant use of corticosteroids). If a patient experiences joint pain or difficulty moving, the possibility of osteonecrosis should be considered.

Effect on Ability to Drive and Use Machines

No specific studies have been conducted to investigate the effect of Reyataz^® on the ability to drive vehicles and operate machinery.

Overdose

In clinical trials, single doses of up to 1200 mg in healthy volunteers were not associated with any adverse events. A single case of overdose in an HIV-infected patient who took 29.2 g of the drug (a dose 73 times the recommended 400 mg dose) was accompanied by asymptomatic bundle branch block and PR interval prolongation. These ECG signs resolved spontaneously. Expected symptoms of overdose include jaundice without changes in liver test results (due to increased indirect bilirubin concentration) and cardiac arrhythmia (PR interval prolongation).

Treatment of overdose with Reyataz^® should include monitoring of vital signs, observation of the patient’s general condition, ECG monitoring, gastric lavage, induction of vomiting to remove drug residue, and administration of activated charcoal.

Dialysis is not effective for removing the drug from the body because Atazanavir is characterized by extensive metabolism in the liver and high protein binding. There is no specific antidote.

Drug Interactions

Atazanavir is metabolized in the liver by cytochrome P450 isoenzymes and is an inhibitor of CYP3A4. Concomitant use of Reyataz^® and other drugs metabolized primarily by CYP3A4 (e.g., calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE inhibitors) may lead to an increase in the plasma concentration of one of them and cause an increase or prolongation of its therapeutic and side effects.

Concomitant use of Reyataz^® and drugs that induce CYP3A4 (rifampicin) may lead to a decrease in atazanavir plasma concentration and a reduction in its therapeutic effect. Concomitant use of Reyataz^® and drugs that inhibit CYP3A4 may lead to an increase in atazanavir plasma concentration.

The extent of CYP3A4-mediated interaction of atazanavir with other drugs (change in the effect of atazanavir or change in the effect of another drug) may change when Reyataz^® is taken with ritonavir, a potent CYP3A4 inhibitor.

For complete information on drug interactions with ritonavir, refer to the ritonavir prescribing information.

Drugs that should not be co-administered with Reyataz^®

Quinidine use with the Reyataz^®/ritonavir combination is contraindicated due to the risk of serious and life-threatening arrhythmias.

Rifampicin when atazanavir is co-administered with rifampicin, the plasma concentration of atazanavir is significantly reduced, leading to a decrease in therapeutic efficacy and the development of resistance to Reyataz^®. Concomitant use of atazanavir and rifampicin is contraindicated.

Irinotecan Atazanavir inhibits UGT and may affect the metabolism of irinotecan, increasing its toxicity; therefore, concomitant use of atazanavir with irinotecan is contraindicated.

Bepridil due to the high risk of life-threatening side effects, concomitant use with Reyataz^® is contraindicated.

Ergot derivatives (dihydroergotamine, ergotamine, ergometrine, methylergometrine) due to the high risk of life-threatening side effects, concomitant use with Reyataz^® is contraindicated. Manifestations of acute toxicity of ergot derivatives include peripheral vasospasm, limb ischemia.

Cisapride due to the high risk of life-threatening side effects (arrhythmia), concomitant use with Reyataz^® is contraindicated.

Lovastatin, simvastatin increased risk of myopathy, including rhabdomyolysis.

Inhaled beta₂-adrenergic agonists (salmeterol) increased risk of cardiovascular side effects characteristic of salmeterol, including QT interval prolongation, palpitations, sinus tachycardia. Co-administration of salmeterol and Reyataz^® is not recommended.

Pimozide due to the high risk of life-threatening side effects (arrhythmia), concomitant use with Reyataz^® is contraindicated.

Indinavir: combined use with Reyataz^® is not recommended, as both drugs can cause hyperbilirubinemia.

Midazolam, triazolam: concomitant use with Reyataz^® is contraindicated due to the possibility of increased midazolam/triazolam concentration and a high risk of prolonged sedative effect and respiratory depression.

Warfarin when co-administered with Reyataz^®, the risk of severe, life-threatening bleeding increases; therefore, this combination is not recommended.

St. John’s wort (Hypericum perforatum) preparations combination with Reyataz^® is contraindicated, as the plasma concentration of atazanavir may decrease, leading to loss of therapeutic effect and development of resistance.

For the drugs listed below, a dosage regimen adjustment may be required due to expected interaction.

Antiretroviral Agents for HIV Treatment

Nucleoside Reverse Transcriptase Inhibitors

Didanosine administration of enteric-coated didanosine capsules together with Reyataz^® or with Reyataz^® and/or ritonavir and food reduces the bioavailability of didanosine. Didanosine should be taken 2 hours after taking Reyataz^®.

Nucleotide Reverse Transcriptase Inhibitors

Tenofovir tenofovir reduces the activity of atazanavir when used concomitantly. Atazanavir increases the plasma concentration of tenofovir. High concentrations of tenofovir may enhance side effects associated with tenofovir, including effects on renal function; therefore, monitoring for tenofovir side effects in patients should be performed.

Non-Nucleoside Reverse Transcriptase Inhibitors

Efavirenz combination therapy with Reyataz^® and efavirenz leads to a decrease in the effect of Reyataz^® and should be avoided. If the use of this combination is absolutely necessary, it is permitted only in treatment-naive patients. In this case, Reyataz^® 400 mg and ritonavir 100 mg are administered as a single dose with food, and efavirenz 600 mg – on an empty stomach, before bedtime.

Nevirapine nevirapine, being an inducer of CYP3A4, reduces the effect of atazanavir. In addition, due to increased nevirapine concentration, its toxicity increases; therefore, this combination is not recommended.

HIV Protease Inhibitors

Boceprevir when co-administering Reyataz^® 300 mg/ritonavir 100 mg once daily with boceprevir 800 mg three times daily, the blood concentration of atazanavir decreases, while the concentration of boceprevir does not change significantly.

Saquinavir (soft gelatin capsules) the effect of saquinavir increases when taken concomitantly with Reyataz^®. There are no data to provide appropriate dosing recommendations for this combination.

Ritonavir when co-administered with Reyataz^®, the concentration of atazanavir increases.

Other HIV Protease Inhibitors concomitant use of the Reyataz^®/ritonavir combination with other HIV protease inhibitors is not recommended.

Other Drugs

Antacids and Buffered Medications

When co-administered with antacids and buffered medications, the plasma concentration of atazanavir decreases. Reyataz^® should be administered 2 hours before or 1 hour after taking such drugs.

Antiarrhythmic Drugs

Amiodarone, lidocaine (with parenteral administration), quinidine when used concomitantly with Reyataz^®, their concentrations may increase. Use in such combinations requires increased caution; monitoring of the plasma concentrations of these drugs is recommended. The Reyataz^®/ritonavir combination is contraindicated for co-administration with quinidine due to the possibility of serious or life-threatening reactions (arrhythmia).

Beta-Blockers

Atenolol: no clinically significant pharmacokinetic interaction is expected when Reyataz^® is co-administered with beta-blockers; therefore, no dosage adjustment is required.

Calcium Channel Blockers

Diltiazem: co-administration with Reyataz^® leads to an increase in the effect of diltiazem and its metabolite – desacetyldiltiazem. A 50% reduction in the diltiazem dose and ECG monitoring are recommended.

Felodipine, nifedipine, nicardipine and verapamil caution should be exercised when co-administering; dose titration of calcium channel blockers and ECG monitoring are necessary.

Endothelin Receptor Antagonists

Bosentan bosentan is metabolized via the CYP3A4 isoenzyme and is an inducer of it. The plasma concentration of atazanavir may decrease when Reyataz^® is co-administered with bosentan but without ritonavir. Therefore, the Reyataz^®/bosentan combination can only be used with ritonavir. The dosing regimens are as follows

1.Initiation of bosentan in patients taking Reyataz^®/ritonavir for at least 10 days: bosentan at a dose of 62.5 mg once daily or every other day (depending on individual tolerance).

2. Initiation of the Reyataz^®/ritonavir combination in patients taking bosentan: discontinue bosentan at least 36 hours before starting the Reyataz^®/ritonavir combination. No sooner than 10 days after starting the Reyataz^®/ritonavir combination, resume bosentan at a dose of 62.5 mg once daily or every other day (depending on individual tolerance).

HMG-CoA Reductase Inhibitors

Atorvastatin when co-administered with Reyataz^®, the effect of atorvastatin may be enhanced. The risk of myopathy, including rhabdomyolysis, may increase. Caution is necessary. The lowest effective doses of atorvastatin should be used in combinations with Reyataz^® or Reyataz^®/ritonavir.

Pravastatin, fluvastatin the potential for interaction in combinations with Reyataz^® or Reyataz^®/ritonavir is unknown.

Proton Pump Inhibitors

During treatment with Reyataz^®, proton pump inhibitors should be prescribed only if their use is strongly indicated.

When co-administering Reyataz^® 400 mg or the Reyataz^® 300 mg/ritonavir 100 mg combination with omeprazole 40 mg (all drugs once daily), plasma concentrations of atazanavir were significantly reduced, which may lead to a decrease in the therapeutic activity of the drug and the development of resistance.

For HIV patients without possible or documented decreased susceptibility to atazanavir, it is recommended to prescribe the Reyataz^® 400 mg/ritonavir 100 mg combination with omeprazole at a maximum dose of 20 mg once daily (or another drug from the proton pump inhibitor group at an equivalent dose).

Omeprazole at a dose of more than 20 mg/day (or another drug from the proton pump inhibitor group at an equivalent dose) is not recommended.

Histamine H₂-Receptor Antagonists

The plasma concentration of atazanavir was significantly reduced when co-administering Reyataz^® 400 mg once daily with famotidine 40 mg twice daily, which may lead to a decrease in therapeutic activity or the development of resistance.

In treatment-naive patients, Reyataz^® 400 mg can be used once daily with food 2 hours before and at least 10 hours after taking histamine H₂-receptor antagonists. However, a single dose of histamine H₂-receptor antagonists should not exceed a dose equivalent to famotidine 20 mg, and their total daily dose should not exceed a dose equivalent to 40 mg of famotidine.

Alternatively, Reyataz^® 300 mg with ritonavir 100 mg can be used once daily with food, 2 hours before and at least 10 hours after taking a single dose of histamine H₂-receptor antagonists comparable to 40 mg of famotidine. In treatment-experienced patients, the daily dose of histamine H₂-receptor antagonists should not exceed a dose equivalent to 40 mg of famotidine. In such patients, Reyataz^® 300 mg/ritonavir 100 mg should be used once daily with food 2 hours before and at least 12 hours after taking histamine H₂-receptor antagonists (once daily) at a dose equivalent to 40 mg of famotidine. Alternatively, Reyataz^® 300 mg/ritonavir 100 mg can be used once daily with food simultaneously with histamine H₂-receptor antagonists, 2 hours before and at least 10 hours after taking histamine H₂-receptor antagonists at a dose not exceeding that equivalent to 20 mg of famotidine. This dose can be taken once or twice daily. When prescribing the Reyataz^®/ritonavir and tenofovir combination with a histamine H₂-receptor antagonist to such patients, the doses Reyataz^® 400 mg and ritonavir 100 mg once daily should be used.

Immunosuppressants

Cyclosporine, tacrolimus, sirolimus when co-administering cyclosporine, tacrolimus, sirolimus and Reyataz^®, an increase in the blood concentrations of the immunosuppressants is possible; therefore, monitoring of their concentrations is recommended.

Antidepressants

Tricyclic antidepressants when co-administering Reyataz^® with tricyclic antidepressants, serious and/or life-threatening adverse reactions associated with antidepressants may occur. Monitoring of the concentrations of these drugs is recommended when co-administered with Reyataz^®.

Trazodone when co-administering trazodone with Reyataz^® or with the Reyataz^®/ritonavir combination, an increase in trazodone plasma concentration is possible. Nausea, dizziness, hypotension, and transient loss of consciousness have been reported with concomitant use of trazodone and ritonavir. When co-administering trazodone with CYP3A4 inhibitors such as Reyataz^®, lower doses of trazodone should be used.

Benzodiazepines

Midazolam is metabolized by the CYP3A4 isoenzyme. Although studies have not been conducted, significant increases in midazolam concentration can be expected when co-administering Reyataz^® and midazolam. The increase in midazolam concentration with oral administration will be significantly greater than with parenteral administration. Concomitant use of Reyataz^® with oral midazolam is contraindicated. There are no data on the simultaneous use of Reyataz^® with injectable midazolam; based on data from the simultaneous use of other HIV protease inhibitors with midazolam, a possible 3-4 fold increase in midazolam plasma concentration can be assumed. When co-administering Reyataz^® with injectable midazolam, caution should be exercised, and respiratory function and the duration of the sedative effect should be monitored. In some cases, dosage adjustment is necessary.

Macrolide Antibiotics

Clarithromycin when clarithromycin is co-administered with Reyataz^®, the concentration of clarithromycin increases, which may cause QT interval prolongation; therefore, the antibiotic dose should be reduced by 50%.

Oral Contraceptives

Ethinyl Estradiol and Norethisterone or Norgestimate when co-administered with Reyataz^®, the concentrations of ethinyl estradiol and norethisterone increase. Co-administration of the Reyataz^®/ritonavir combination with ethinyl estradiol and norgestimate decreases the mean concentration of ethinyl estradiol and increases the mean concentration of 17-deacetylnorgestimate, an active metabolite of norgestimate.

In case of co-administration of oral contraceptives and the Reyataz^®/ritonavir combination, contraceptives containing at least 30 mcg of ethinyl estradiol are recommended. If Reyataz^® is used without ritonavir together with contraceptives, the ethinyl estradiol content in oral contraceptives should not exceed 30 mcg. Caution should be exercised when co-administering Reyataz^® and oral contraceptives, as the effect of increased progestogen concentrations is unknown; the risk of acne, dyslipidemia, and insulin resistance may increase. With increased norethisterone concentration, a decrease in HDL concentration or an increase in insulin resistance is possible, especially in women with concomitant diabetes mellitus. The lowest effective doses of each component of the oral contraceptive should be used, and it is also advisable to use other reliable methods of contraception.

Co-administration of Reyataz^® or the Reyataz^®/ritonavir combination 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 mcg of ethinyl estradiol, has not been studied; therefore, these contraceptive methods should not be used in combination with Reyataz^®.

Gout Treatment Drugs

Colchicine colchicine is a substrate of the CYP3A4 isoenzyme, and its effect may be enhanced when used concomitantly with Reyataz^®.

Recommended doses of colchicine when used concomitantly with Reyataz^® are given below.

Acute gout attack: 0.6 mg – first dose, then – 0.3 mg 1 hour after the first dose. This regimen should not be used for more than 3 days.

Prophylaxis of acute gout attacks: if the usual dosing regimen was 0.6 mg twice daily, the dose should be reduced to 0.3 mg twice daily; if the usual dosing regimen was 0.6 mg once daily, the dose should be reduced to 0.3 mg every other day.

Familial Mediterranean Fever the maximum daily dose of colchicine is 0.6 mg. This dose can be divided into 2 doses – 0.3 mg twice daily.

Antituberculosis Drugs

Rifabutin the activity of rifabutin increases when co-administered with Reyataz^®. When these drugs are used concomitantly, a reduction in the rifabutin dose to 75% of the usual dose is recommended: 150 mg every other day or 3 times a week. Careful monitoring for adverse reactions is necessary in patients taking rifabutin and Reyataz^® or the Reyataz^®/ritonavir combination; further adjustment of the rifabutin dose may be required.

PDE5 Inhibitors

Use for Erectile Dysfunction

Sildenafil, Tadalafil, Vardenafil: When HIV protease inhibitors are co-administered with these PDE5 inhibitors, a significant increase in the concentrations of PDE5 inhibitors and an enhancement of their side effects are possible. Dose reductions are recommended: sildenafil – 25 mg no more frequently than every 48 hours when used with or without ritonavir; tadalafil – 10 mg no more frequently than every 72 hours when used with or without ritonavir; vardenafil – 2.5 mg no more frequently than every 72 hours when used with ritonavir and 2.5 mg no more frequently than every 24 hours when used without ritonavir; monitoring for adverse reactions is necessary.

Use for Pulmonary Hypertension

Sildenafil concomitant use with Reyataz^® for pulmonary hypertension is contraindicated.

Tadalafil:

• For patients taking Reyataz^® for at least 7 days: tadalafil is prescribed at a dose of 20 mg once daily; the dose can be increased to 40 mg once daily (depending on individual tolerance);
• For patients taking tadalafil: discontinue tadalafil at least 24 hours before starting Reyataz^®. No earlier than 7 days after starting Reyataz^®, resume tadalafil at a dose of 20 mg once daily. The dose can be increased to 40 mg once daily (depending on individual tolerance).

Antifungal Drugs

Ketoconazole, Itraconazole, Voriconazole only the concomitant use of ketoconazole with Reyataz^® without ritonavir has been studied; atazanavir concentrations with this combination are slightly increased. Ketoconazole and itraconazole may increase plasma concentrations of atazanavir and ritonavir. Caution should be exercised when using ketoconazole and itraconazole in daily doses above 200 mg concomitantly with the Reyataz^®/ritonavir combination. Concomitant use of voriconazole with Reyataz^® and ritonavir is not recommended.

Anticoagulants

Warfarin due to enhanced warfarin activity, concomitant use with Reyataz^® may cause severe and/or life-threatening bleeding. Monitoring of INR is recommended.

Inhaled/Nasal Corticosteroids (interaction with ritonavir)

When ritonavir was co-administered with fluticasone propionate in healthy volunteers, cortisol concentration was significantly reduced. Concomitant use of the Reyataz^®/ritonavir combination with fluticasone propionate may lead to a similar effect. When ritonavir and inhaled (or intranasal) fluticasone propionate preparations were used concomitantly, systemic corticosteroid side effects developed (Cushing’s syndrome, adrenal cortex suppression).

Similar effects are possible with concomitant use of other corticosteroids metabolized by the CYP3A4 isoenzyme, for example, budesonide. Therefore, the use of the Reyataz^®/ritonavir combination with fluticasone propionate or other corticosteroids metabolized by CYP3A4 is justified only if the potential benefit of therapy outweighs the risk of systemic corticosteroid effects. When Reyataz^® (without ritonavir) and fluticasone propionate are used concomitantly, the plasma concentration of the latter may increase. Caution should be exercised and, if possible, preparations not containing fluticasone propionate should be used, especially with long-term use.

Substrates of Other Cytochrome P450 (CYP) Isoenzymes

Clinically significant interaction between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1 isoenzymes is not expected. Atazanavir is a weak inhibitor of CYP2C8. Caution should be exercised when co-administering Reyataz^® (without ritonavir) and drugs that are highly dependent on CYP2C8 and have a narrow therapeutic index (e.g., paclitaxel, repaglinide). When using the Reyataz^®/ritonavir combination with CYP2C8 substrates, clinically significant interaction is not expected.

Opioid Analgesics

Buprenorphine due to inhibition of CYP3A4 and UGT1A1 isoenzymes, when Reyataz^® or the Reyataz^®/ritonavir combination and buprenorphine were co-administered, concentrations of buprenorphine and norbuprenorphine increased. When the Reyataz^®/ritonavir combination was used with buprenorphine, no significant change in atazanavir plasma concentration was detected; use of the same combination but without ritonavir may lead to a significant decrease in atazanavir plasma concentration. When the Reyataz^®/ritonavir combination and buprenorphine are used concomitantly, careful monitoring of the patient’s condition (assessment of sedative effect and cognitive functions) is necessary. A reduction in the buprenorphine dose may be required.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.