Atazor – r

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATAZOR - R (ATAZOR - R)

Composition:

Active substances: atazanavir, ritonavir;

One film-coated tablet contains atazanavir sulfate equivalent to 300 mg of atazanavir, ritonavir 100 mg;

Excipients: lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, copovidone, sorbitan monolaurate, polysorbate 80, sodium stearyl fumarate;

Coating Opadry Yellow 15B82855*: hypromellose, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: capsule-shaped film-coated tablets of creamy-yellow color, embossed with "EM" on one side and "149" on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of HIV infection, combinations. ATC code J05AR23.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Atazanavir

Atazanavir is an azapeptide inhibitor of HIV-1 protease (PI). The compound selectively inhibits the viral processing of Gag-Pol polyproteins in cells infected with HIV-1, thereby preventing the formation of mature virions and the infection of other cells.

In vitro data have shown that atazanavir is active against tested strains of HIV-1 (including all studied isolates) and HIV-2 in various cell cultures.

Ritonavir, dosed as a pharmacokinetic enhancer.

Pharmacokinetic boosting by ritonavir is based on ritonavir's activity as a potent inhibitor of CYP3A-mediated metabolism. The extent of boosting depends on the metabolic pathway of the co-administered protease inhibitor, as well as the effect of the concomitant protease inhibitor on ritonavir metabolism. Maximum inhibition of the metabolism of the co-administered protease inhibitor is usually achieved with ritonavir doses ranging from 100 mg once daily to 200 mg twice daily, and depends on the accompanying protease inhibitor.

Ritonavir, dosed as an antiretroviral agent.

Inhibition of HIV protease renders this enzyme unable to process the gag-pol polyprotein precursor, resulting in the formation of morphologically immature HIV particles incapable of initiating new infection cycles. Ritonavir has selective affinity for HIV protease and low inhibitory activity against human aspartyl proteases.

Resistance.

Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients receiving therapeutic doses of ritonavir.

Reduced antiretroviral activity of ritonavir is primarily associated with protease mutations V82A/F/T/S and I84V. Accumulation of additional mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) may also contribute to resistance to ritonavir. In general, as resistance-associated mutations accumulate, susceptibility to other PIs may decrease due to cross-resistance. For specific information on protease mutations associated with reduced response to these agents, refer to the summary of product characteristics for other protease inhibitors or official data included in updated prescribing information.

Pharmacokinetics.

Absorption

Atazanavir at a dose of 300 mg (co-administered with 100 mg ritonavir) is rapidly absorbed, with time to maximum concentration (Tmax) of approximately 3 hours.

Atazanavir exhibits non-linear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax over the dose range of 200 to 800 mg once daily. Steady-state concentrations are reached by day 4–8, with accumulation of approximately 2.3-fold.

Ritonavir is not available in a parenteral formulation; therefore, the extent of absorption and absolute bioavailability of this formulation have not been studied. Time to maximum concentration (Tmax) remained constant with increasing dose—approximately 4 hours. Mean renal clearance was less than 0.1 L/h and was relatively constant across this dose range.

Effect of food

Administration of atazanavir with food improves its bioavailability and reduces pharmacokinetic variability. A single 400 mg dose of atazanavir tablets taken with a low-fat meal (357 kcal, 8.2 g fat, 10.6 g protein) increases atazanavir AUC by an average of 70% and Cmax by 57%, compared to fasting conditions.

Food slightly reduces the bioavailability of ritonavir in tablet form. A single 100 mg dose of ritonavir tablets taken with a moderate-fat (857 kcal, 31% of calories from fat) or high-fat meal (907 kcal, 52% of calories from fat) reduces ritonavir AUC and Cmax by an average of 20–23%.

Distribution

Atazanavir is 86% bound to plasma proteins, and the degree of protein binding is independent of concentration. Atazanavir binds to a similar extent to alpha-1-acid glycoprotein and albumin (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients receiving 400 mg atazanavir once daily with a low-fat meal for 12 weeks, atazanavir was detected in cerebrospinal and seminal fluids.

The apparent volume of distribution (VB/F) of ritonavir is approximately 20–40 L after a single 600 mg dose. The extent of ritonavir binding to human plasma proteins is approximately 98–99% and remains constant over a concentration range of 1.0 to 100 µg/mL. Ritonavir binds to both human α-1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinity.

Metabolism

Atazanavir is extensively metabolized in humans, primarily via mono- and di-oxygenation. Other minor metabolic pathways of atazanavir or its metabolites include glucuronidation, N-dealkylation, hydrolysis, and oxidative dehydrogenation. Two secondary metabolites of atazanavir are present in plasma.

Ritonavir is extensively metabolized by the hepatic cytochrome P450 system, primarily by the CYP3A isoenzyme and to a lesser extent by CYP2D6. Animal studies and in vitro experiments using human liver microsomes have shown that ritonavir is metabolized mainly by oxidation. Four metabolites of ritonavir have been identified in humans. The major metabolite is the oxidative isopropylthiazole metabolite (M-2), which has antiviral activity similar to that of the parent drug. However, the AUC of metabolite M-2 was approximately 3% of the parent drug's AUC.

Low doses of ritonavir have a pronounced effect on the pharmacokinetics of other protease inhibitors (and other drugs metabolized by CYP3A4), and other protease inhibitors may also affect the pharmacokinetics of ritonavir.

Elimination

After a single 400 mg dose of 14C-atazanavir, 79% and 13% of total radioactivity were recovered in feces and urine, respectively. The proportion of unchanged drug in feces and urine was approximately 20% and 7%, respectively.

Studies with radiolabeled ritonavir have shown that elimination of ritonavir in humans occurs primarily via the hepatobiliary system; approximately 86% of the radiolabel was recovered in feces, with some of the drug excreted unchanged. These studies indicate that renal elimination is not a major route of ritonavir excretion, consistent with findings from animal studies.

Special populations

Renal impairment.

There are no pharmacokinetic data on atazanavir with ritonavir in patients with renal impairment.

Hepatic impairment.

Atazanavir concentrations with or without ritonavir are expected to be increased in patients with moderate or severe hepatic impairment.

Age/sex.

No clinically significant pharmacokinetic differences based on age or sex have been observed.

Clinical characteristics.

Indications.

Used in combination with other antiretroviral agents for the treatment of HIV-1 infected adults.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Moderate to severe hepatic impairment.
• Concomitant use with simvastatin or lovastatin.
• Concomitant use with rifampicin.
• Concomitant use with the PDE5 inhibitor sildenafil when sildenafil is used for the treatment of pulmonary arterial hypertension.
• Contraindicated combination with medicinal products metabolized in the liver by the CYP3A4 isoenzyme of cytochrome P450 and having a narrow therapeutic index (quetiapine, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam (oral administration), and ergot alkaloids, including ergotamine, dihydroergotamine, ergonovine, methylergonovine).
• Concomitant use with products containing St. John's wort (Hypericum perforatum).
• Concomitant use of atazanavir with medicinal products whose elimination is associated with the CYP3A isoenzyme and for which increased blood concentrations may lead to serious and/or life-threatening consequences. These medicinal products are listed below in Table 1.

Table 1 Medicinal products whose concomitant use with atazanavir/ritonavir is contraindicated

Drug classes	Medicinal products that must not be used concomitantly with atazanavir/ritonavir	Comments
Alpha-1 adrenergic blockers	Alfuzosin	Elevated plasma concentrations of alfuzosin may lead to severe hypotension.
Antimycobacterial agents	Rifabutin	Concomitant use of ritonavir as an antiretroviral agent (at doses of 500 mg twice daily) and rifabutin is contraindicated due to increased serum concentrations of rifabutin and risk of adverse reactions, including uveitis. Recommendations for the use of ritonavir as a pharmacokinetic enhancer in combination with rifabutin are provided in the section "Interaction with other medicinal products and other forms of interactions".
Antibiotics	Rifampicin	The combination of rifampicin and atazanavir is contraindicated.
Ergot alkaloids	Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Elevated plasma concentrations of ergot derivatives may cause acute ergot toxicity, including vasoconstriction and ischemia.
Gastrointestinal motility agents	Cisapride	Elevated plasma concentrations of cisapride, resulting in an increased risk of serious arrhythmias associated with this drug.
Herbal medicinal products	St. John’s wort (Hypericum perforatum)	May lead to reduced plasma concentrations of atazanavir and reduced clinical effect of ritonavir. These effects may result in loss of therapeutic efficacy and development of resistance.
Antilipidemic agents HMG-CoA reductase inhibitors	Loxastatin, simvastatin	Elevated plasma concentrations of lovastatin and simvastatin. As a result, increased risk of myopathy, including rhabdomyolysis.
Microsomal triglyceride transfer protein inhibitor	Lomitapide	Increased plasma concentration of lomitapide
Long-acting beta-2 adrenergic agonists	Salmeterol	May increase the potential risk of cardiovascular adverse reactions associated with salmeterol
Phosphodiesterase-5 (PDE5) inhibitors	Sildenafil (when used for the treatment of pulmonary arterial hypertension)	Elevated plasma concentrations of sildenafil, leading to an increased risk of sildenafil-related adverse reactions (including hypotension and vasovagal syncope). Information on concomitant use with sildenafil in patients with erectile dysfunction is provided in the sections "Interaction with other medicinal products and other forms of interactions" and "Special warnings and precautions for use".
	Avanafil	Elevated plasma concentrations of avanafil.
	Vardenafil	Elevated plasma concentrations of vardenafil.
Analgesics	Pethidine, piroxicam, propoxyphene	Elevated plasma concentrations of pethidine, piroxicam and propoxyphene. Therefore, increased risk of serious respiratory depression, hematological disorders, or other serious adverse effects of these drugs.
Anti-anginal agents	Ranolazine	Elevated plasma concentration of ranolazine, which may lead to serious and/or life-threatening reactions.
Anticancer agents	Apalutamide	Apalutamide is a moderate to strong inducer of CYP3A4 and may lead to reduced exposure of lopinavir/ritonavir and potential loss of virological response. In addition, increased plasma concentrations of apalutamide may lead to serious adverse events, including seizures.
	Neratinib	Elevated plasma concentrations of neratinib may increase the frequency of serious and/or life-threatening reactions, including hepatotoxicity.
	Venetoclax	Increased plasma concentration of venetoclax. Increased risk of tumor lysis syndrome during initiation and dose escalation phases.
Antiarrhythmic agents	Amiodarone, bepridil, dronedarone, encainide, flecaïne, propafenone, quinidine	Elevated plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecaïne, propafenone, quinidine. As a result, increased risk of arrhythmias or other serious adverse effects of these drugs.
Antibiotics	Fusidic acid	Elevated plasma concentrations of fusidic acid and ritonavir.
Antifungal agents	Voriconazole	Concomitant use of ritonavir (400 mg twice daily or higher) and voriconazole is contraindicated due to reduced plasma concentrations of voriconazole and potential lack of therapeutic effect.
Antihistamines	Astemizole, terfenadine	Elevated plasma concentrations of astemizole and terfenadine. As a result, increased risk of serious arrhythmias associated with these drugs.
Antipsychotics/neuroleptics	Lurasidone	Elevated plasma concentration of lurasidone, which may lead to serious and/or life-threatening reactions.
	Quetiapine	Elevated plasma concentrations of quetiapine, which may lead to coma. Concomitant use with quetiapine is contraindicated.
	Clozapine, blonanserin, pimozide	Elevated plasma concentrations of clozapine, blonanserin and pimozide. As a result, increased risk of serious hematological disorders or other serious adverse events caused by these drugs.
Antigout agents	Colchicine	Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.
Sedatives/hypnotics	Chlordiazepoxide, diazepam, etizolam, flurazepam, oral midazolam, triazolam	Elevated plasma concentrations of chlordiazepoxide, diazepam, etizolam, flurazepam, oral midazolam and triazolam. As a result, risk of excessive sedation and respiratory depression. Warnings regarding parenteral midazolam administration are provided in the section "Interaction with other medicinal products and other forms of interactions".

Interaction with other medicinal products and other forms of interaction.

When atazanavir and ritonavir are used concomitantly, the metabolic interaction profile of the latter predominates, since ritonavir is a more potent inhibitor of the CYP3A4 isoenzyme than atazanavir.

Other interactions

Interactions between the atazanavir/ritonavir combination and protease inhibitors, other antiretroviral medicinal products, and other drugs are presented in the table below. The information in the table is based on clinical study data on atazanavir in healthy volunteers, unless otherwise specified. It is important to note that many of the studies were conducted using unboosted atazanavir, which differs from the approved dosing regimen.

Table 2

Interaction of atazanavir with other medicinal products

Medicinal product according to therapeutic group	Interaction	Recommendations for concomitant use
ANTIRETROVIRAL AGENTS
Protease inhibitors: concomitant use of atazanavir/ritonavir combination and other protease inhibitors has not been studied, but enhanced protease inhibitor effects are expected. Therefore, such combination is not recommended.
Ritonavir 100 mg once daily (atazanavir 300 mg once daily). Studies were conducted in HIV-infected patients.	Mechanism of interaction between atazanavir and ritonavir – inhibition of CYP3A4.	Ritonavir 100 mg once daily is used to boost atazanavir pharmacokinetics.
Indinavir	Indinavir effect is associated with indirect unconjugated hyperbilirubinemia due to inhibition of UGT (uridine diphosphate glucuronosyltransferase).	Concomitant use of atazanavir/ritonavir and indinavir is not recommended.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily (atazanavir 400 mg once daily)	No significant effect on lamivudine and zidovudine concentrations was observed.	Based on these data, and since ritonavir is not expected to have a significant effect on NRTI pharmacokinetics, concomitant administration of these medicinal products with atazanavir is not expected to significantly alter the effect of concurrently administered drugs.
Abacavir	No significant effect of atazanavir/ritonavir combination on abacavir exposure is expected.
Didanosine (buffered tablets) 200 mg/stavudine 40 mg (atazanavir 400 mg)	Didanosine tablets significantly reduce atazanavir effect, since didanosine tablets contain antacids that reduce gastric acidity. Atazanavir does not affect the efficacy of didanosine.	Didanosine products should be taken 2 hours after atazanavir/ritonavir administration.
Didanosine (enteric-coated tablets) 400 mg (atazanavir 300 mg once daily with ritonavir 100 mg once daily)	No changes in atazanavir concentrations were observed, but didanosine concentration decreased when taken with food.
Tenofovir disoproxil fumarate 300 mg once daily (atazanavir 300 mg once daily with ritonavir 100 mg once daily). Studies were conducted in healthy volunteers and HIV-infected patients.	Data from studies on atazanavir/ritonavir and tenofovir combination demonstrated efficacy in HIV infection treatment. The mechanism of interaction between atazanavir and tenofovir is unknown.	Close monitoring of patients is required due to the possibility of tenofovir-related adverse reactions, including renal disorders.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)	Atazanavir (evening): all taken with food Atazanavir AUC ↔0 % (↓9 % ↑10 %)* Atazanavir Cmax ↑17 % (↑8 % ↑27 %)* Atazanavir Cmin ↓42 % (↓51 % ↓31 %)*	This combination is not recommended.
Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 200 mg once daily)	Atazanavir (evening): all taken with food Atazanavir AUC ↔6 % (↓10 % ↑26 %)*/** Atazanavir Cmax ↔9 % (↓5 % ↑26 %)*/** Atazanavir Cmin ↔12 % (↓16 % ↑49 %)*/** *Compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin may negatively affect atazanavir efficacy. Mechanism of efavirenz/atazanavir interaction is induction of CYP3A4. **Based on historical comparison.
Nevirapine 200 mg twice daily (atazanavir 200 mg twice daily with ritonavir 100 mg once daily) Studies were conducted in HIV-infected patients.	Nevirapine AUC ↑26 % (↑17 % ↑36 %) Nevirapine Cmax ↑21 % (↑11 % ↑32 %) Nevirapine Cmin ↑35 % (↑25 % ↑47 %) Atazanavir AUC ↓19 % (↓35 % ↑2 %)* Atazanavir Cmax ↔2 % (↓15 % ↑24 %)* Atazanavir Cmin ↓59 % (↓73 % ↓40 %)* *Compared to atazanavir 300 mg/ritonavir 100 mg without nevirapine. This decrease in atazanavir Cmin may negatively affect atazanavir efficacy. Mechanism of nevirapine/atazanavir interaction is induction of CYP3A4.	This combination is not recommended.
Integrase inhibitors
Raltegravir 400 mg twice daily (atazanavir/ritonavir)	Raltegravir AUC ↑41 % Raltegravir Cmax ↑24 % Raltegravir C12hr ↑77 % Mechanism – inhibition of UGT1A1.	No dose adjustment of raltegravir is required.
Protease inhibitors
Boceprevir 800 mg three times daily (atazanavir 300 mg/ritonavir 100 mg once daily)	Boceprevir AUC ↔5 % Boceprevir Cmax ↔7 % Boceprevir Cmin ↔18 % Atazanavir AUC ↓35 % Atazanavir Cmax ↓25 % Atazanavir Cmin ↓49 % Ritonavir AUC ↓36 % Ritonavir Cmax ↓27 % Ritonavir Cmin ↓45 %	Concomitant use of atazanavir/ritonavir with boceprevir leads to reduced atazanavir effect, which may be associated with reduced efficacy and loss of control over HIV infection. This combination may be considered if necessary for HIV-infected patients with low viral load and viral strain if there is no suspicion of resistance to HIV treatment regimen. Close clinical and laboratory monitoring is required for patients with suppressed HIV infection.
ANTIBIOTICS
Clarithromycin 500 mg twice daily (atazanavir 400 mg once daily)	Dose reduction of clarithromycin may lead to subtherapeutic concentrations of 14-OH-clarithromycin. Mechanism of interaction is associated with induction of CYP3A4.	No dose recommendations; concomitant use of atazanavir/ ritonavir with clarithromycin should be used with caution.
ANTIFUNGAL AGENTS
Ketoconazole 200 mg once daily (atazanavir 400 mg once daily)	No significant effect on atazanavir concentration was observed.	Ketoconazole and itraconazole should be used with caution together with Atazor-R. High doses of ketoconazole and itraconazole (above 200 mg daily) are not recommended.
Itraconazole	Itraconazole, like ketoconazole, is a potent inhibitor and substrate of CYP3A4. Only concomitant use of ketoconazole and atazanavir without ritonavir was studied; atazanavir concentrations increased slightly when this combination was taken. Ketoconazole and itraconazole may increase atazanavir and ritonavir plasma concentrations.
Voriconazole 200 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily). Patients with at least one functional CYP2C19 allele.	In most patients with at least one functional CYP2C19 allele, decreased concentrations of voriconazole and atazanavir are expected.	Concomitant use of voriconazole and atazanavir/ritonavir combination is not recommended, except when benefit outweighs risk. Voriconazole treatment requires determination of patient CYP2C19 genotype. If this combination is necessary, clinical monitoring of efficacy of both drugs is recommended: atazanavir (virological response) and voriconazole (clinical signs) for patients with at least one functional CYP2C19 allele. For patients without functional CYP2C19 allele, clinical and laboratory monitoring of voriconazole efficacy is recommended to detect adverse reactions. If genotyping is not possible, full safety and efficacy monitoring is required.
Voriconazole 50 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily). Patients without functional CYP2C19 allele.	In a small number of patients without functional CYP2C19 allele, significant increase in voriconazole concentration is expected.
Fluconazole 200 mg once daily (atazanavir 300 mg and ritonavir 100 mg once daily)	Atazanavir and fluconazole concentrations did not change with concomitant use of atazanavir/ritonavir combination.	No dose adjustment required.
ANTITUBERCULOSIS AGENTS
Rifabutin 150 mg twice weekly (atazanavir 300 mg and ritonavir 100 mg once daily)	Atazanavir pharmacokinetics did not change when used with rifabutin.	Rifabutin dose should be 150 mg three times weekly on scheduled days (e.g., Monday, Wednesday, Friday). Close monitoring of patient is required due to risk of adverse reactions, including neutropenia and uveitis; dose adjustment of rifabutin may be needed. Further reduction to 150 mg twice weekly on scheduled days is recommended for patients for whom 150 mg rifabutin three times weekly is not acceptable. Dose of 150 mg twice weekly may not provide optimal rifabutin exposure; risk of resistance and treatment inefficacy exists. No need to adjust atazanavir/ritonavir dose.
Rifampicin	Rifampicin is a strong inducer of CYP3A4 and causes a 72 % reduction in atazanavir area under the concentration-time curve (AUC), which may lead to virological inefficacy and development of resistance. Attempts to reduce the effect by increasing atazanavir dose or other protease inhibitors with ritonavir were associated with high frequency of liver-related adverse reactions.	Combination of atazanavir with rifampicin with concomitant low-dose ritonavir is contraindicated.
NEUROLEPTICS
Quetiapine	Due to CYP3A4 inhibition by the drug, quetiapine concentration increases.	Concomitant use of atazanavir/ritonavir and quetiapine is contraindicated due to increased quetiapine-dependent toxicity. Increased quetiapine plasma concentration may lead to coma.
H2-HISTAMINE RECEPTOR BLOCKERS
Without tenofovir
HIV-infected patients are recommended atazanavir/ritonavir at a dose of 300 mg/100 mg once daily.		For patients not receiving tenofovir: when atazanavir/ritonavir (300 mg/100 mg) and H2-histamine receptor blockers are used concomitantly, famotidine dose should not exceed 20 mg twice daily. If higher doses of H2-histamine receptor blockers are needed (e.g., famotidine 40 mg twice daily or equivalent), atazanavir/ritonavir dose may be increased from 300 mg/100 mg to 400 mg/100 mg.
Famotidine 20 mg twice daily	Atazanavir AUC ↓21 % (↓34 % ↓4 %)* Atazanavir Cmax ↓21 % (↓36 % ↓4 %)* Atazanavir Cmin ↓19 % (↓37 % ↑5 %)*
Famotidine 40 mg twice daily	Atazanavir AUC ↓24 % (↓36 % ↓11 %)* Atazanavir Cmax ↓23 % (↓36 % ↓8 %)* Atazanavir Cmin ↓25 % (↓47 % ↑7 %)*
In studies, healthy volunteers received increased doses of atazanavir/ritonavir 400 mg/100 mg once daily
Famotidine 40 mg twice daily	Atazanavir AUC ↑18 % (↑6.5 % ↑30 %)* Atazanavir Cmax ↑18 % (↑6.7 % ↑31 %)* Atazanavir Cmin ↑24 % (↑10 % ↑39 %)*
With tenofovir 300 mg once daily
HIV-infected patients receiving atazanavir/ritonavir at recommended dose of 300 mg/100 mg once daily		For patients receiving tenofovir: when the drug is used concomitantly with tenofovir and H2-histamine receptor blockers, atazanavir/ritonavir dose should be increased to 400 mg/100 mg. Dose equivalent to famotidine 40 mg twice daily should not be exceeded.
Famotidine 20 mg twice daily	Atazanavir AUC ↓21 % (↓34 % ↓4 %)* Atazanavir Cmax ↓21 % (↓36 % ↓4 %)* Atazanavir Cmin ↓19 % (↓37 % ↑5 %)*
Famotidine 40 mg twice daily	Atazanavir AUC ↓24 % (↓36 % ↓11 %)* Atazanavir Cmax ↓23 % (↓36 % ↓8 %)* Atazanavir Cmin ↓25 % (↓47 % ↑7 %)*
HIV-infected patients receiving atazanavir/ritonavir at increased dose of 400 mg/100 mg once daily
Famotidine 20 mg twice daily	Atazanavir AUC ↑18 % (↑6.5 % ↑30 %)* Atazanavir Cmax ↑18 % (↑6.7 % ↑31 %)* Atazanavir Cmin ↑24 % (↑10 % ↑39 %)*
Famotidine 40 mg twice daily	Atazanavir AUC ↔2.3 % (↓13 % ↑10 %)* Atazanavir Cmax ↔5 % (↓17 % ↑8.4 %)* Atazanavir Cmin ↔1.3 % (↓10 % ↑15 %)* *Compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg all as single dose with food. Compared to 300 mg atazanavir and 100 mg ritonavir without tenofovir disoproxil fumarate, atazanavir concentrations are expected to further decrease by approximately 20 %. Mechanism of interaction is decreased solubility of atazanavir due to increased gastrointestinal pH with H2-histamine receptor blockers.
PROTON PUMP INHIBITORS
Omeprazole 40 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)
Omeprazole 20 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)	Use of atazanavir 300 mg once daily with ritonavir 100 mg once daily. No significant reduction in AUC, maximum and minimum concentration was observed when atazanavir/ritonavir dose (400 mg/100 mg once daily) was increased, used without omeprazole over 12 hours. Similar results are expected with other proton pump inhibitors. Decreased atazanavir exposure may negatively affect drug efficacy. Mechanism of interaction is decreased atazanavir solubility due to increased gastrointestinal pH with proton pump inhibitors.	Concomitant use of atazanavir with ritonavir and proton pump inhibitors is not recommended. If such combination is considered necessary, patient monitoring is recommended with increased atazanavir dose to 400 mg with ritonavir 100 mg; proton pump inhibitor doses, including omeprazole, should not exceed 20 mg.
ANTACIDS
Antacids and other buffering agents	Decreased atazanavir plasma concentration may result from increased gastric pH if antacids or other buffering agents are used concomitantly with the drug.	The drug should be taken 2 hours before or 1 hour after antacids.
α1-ADRENERGIC ANTAGONISTS
Alfuzosin	Increased alfuzosin plasma concentration may lead to arterial hypotension. Mechanism of interaction is associated with induction of CYP3A4.	Concomitant use of alfuzosin and atazanavir/ritonavir is contraindicated.
ANTICOAGULANTS
Warfarin	Possible decrease or (rarely) increase in international normalized ratio (INR).	INR monitoring is recommended, especially at the beginning of therapy.
ANTIEPILEPTIC AGENTS
Carbamazepine	The drug may increase carbamazepine plasma levels due to inhibition of CYP3A4. Decreased drug exposure is not excluded.	Carbamazepine should be prescribed with caution together with the drug. If necessary, carbamazepine serum concentration should be monitored and dose adjusted accordingly. Close monitoring of therapeutic response is required.
Phenytoin, phenobarbital	Ritonavir may decrease phenytoin and/or phenobarbital plasma levels due to induction of CYP2C9 and CYP2C19. Decreased drug exposure is not excluded.	Phenytoin/phenobarbital should be prescribed with caution together with the drug. Dose adjustment of phenytoin or phenobarbital may be needed. Close monitoring of therapeutic response is required.
Lamotrigine	Concomitant use of the drug and lamotrigine may decrease lamotrigine plasma concentration due to induction of UGT1A4.	Lamotrigine and atazanavir/ritonavir should be prescribed with caution. If necessary, lamotrigine plasma concentration should be monitored and dose adjusted accordingly.
ANTINEOPLASTIC AGENTS AND IMMUNOSUPPRESSANTS
Antineoplastic agents
Irinotecan	Atazanavir inhibits UGT and may affect irinotecan metabolism, potentially leading to increased irinotecan toxicity.	Patients require close monitoring due to possible adverse reactions associated with irinotecan.
Immunosuppressants
Cyclosporine Tacrolimus Sirolimus	Concentrations of these medicinal products may increase with concomitant use with the drug due to inhibition of CYP3A4.	Monitoring of these medicinal product concentrations is recommended until plasma levels stabilize.
CARDIOVASCULAR MEDICINAL PRODUCTS
Antiarrhythmic agents
Amiodarone, lidocaine for systemic use, quinidine	Concentrations of these medicinal products may increase with concomitant use with the drug. Mechanism of interaction of amiodarone or lidocaine for systemic use and atazanavir – inhibition of CYP3A. Quinidine has a narrow therapeutic range and is contraindicated due to possible inhibition of CYP3A by the drug.	Caution and therapeutic monitoring of these drug concentrations are required. Concomitant use of quinidine is contraindicated.
Calcium channel blockers
Bepridil	Atazanavir/ritonavir should not be used in combination with medicinal products that are not CYP3A4 substrates and have a narrow therapeutic index.	Combination of the drug and bepridil is contraindicated.
Diltiazem 180 mg once daily (atazanavir 400 mg once daily)	No significant effect on atazanavir plasma concentration was observed. Concomitant use of atazanavir with diltiazem has not been studied. Mechanism of diltiazem/atazanavir interaction – inhibition of CYP3A4.	At the beginning of treatment, diltiazem dose should be reduced by 50 %, with further titration as needed and heart monitoring via ECG.
Verapamil	Verapamil serum concentration may be increased due to inhibition of CYP3A4.	Concomitant use of verapamil and atazanavir/ritonavir should be used with caution.
CORTICOSTEROIDS
Fluticasone propionate intranasal 50 mcg 4 times daily for 7 days (ritonavir, 100 mg capsules, twice daily)	Fluticasone propionate plasma levels significantly increased, while cortisol levels decreased by approximately 86 %. Adverse reactions are most commonly expected with inhaled fluticasone propionate. With concomitant use of ritonavir and inhaled (or intranasal) fluticasone propionate products, development of systemic corticosteroid adverse reactions (Cushing's syndrome, adrenal cortex suppression) was observed; similar effects are possible with concomitant use with other systemic corticosteroids metabolized by CYP3A4 isoenzyme, e.g., budesonide. Systemic effect of fluticasone propionate on ritonavir plasma levels is unknown. Mechanism of interaction is associated with induction of CYP3A4.	Concomitant use of fluticasone propionate and atazanavir/ritonavir is not recommended, except when potential benefit of therapy outweighs risk of systemic adverse reactions from systemic corticosteroids. Consideration should be given to reducing glucocorticoid dose due to local and systemic adverse effects or using glucocorticoids that are not CYP3A4 substrates (e.g., beclomethasone). Additionally, when discontinuing glucocorticoid therapy, dose should be tapered gradually over a prolonged period.
AGENTS USED IN ERECTILE DYSFUNCTION
PDE-5 inhibitors
Sildenafil, tadalafil, vardenafil	Sildenafil, tadalafil, and vardenafil are metabolized via CYP3A4. Concomitant use of the drug with PDE-5 inhibitors may lead to significant increase in PDE-5 inhibitor concentrations and enhanced adverse reactions, such as arterial hypotension, visual disturbances, priapism. Mechanism of interaction is associated with induction of CYP3A4.	Patients should be warned about adverse effects when using PDE-5 inhibitors for erectile dysfunction treatment together with Atazor-R. Cases of pulmonary arterial hypertension have been reported with use of sildenafil and Atazor-R.
HERBAL MEDICINAL PRODUCTS
St. John's wort (Hypericum perforatum)	Concomitant use of St. John's wort products and Atazor-R may lead to significant decrease in atazanavir plasma levels. This effect is due to induction of CYP3A4. Risk of loss of therapeutic effect and development of resistance exists.	Combination of St. John's wort products and Atazor-R is contraindicated.
HORMONAL CONTRACEPTIVES
Ethinylestradiol 25 mcg + norgestimate (atazanavir 300 mg once daily and ritonavir 100 mg once daily)	Increased progestin effect may lead to adverse reactions such as insulin resistance, acne, dyslipidemia, skin spots.	Contraceptives containing at least 30 mcg ethinylestradiol are recommended. The patient must strictly adhere to prescribed contraceptive doses. Concomitant use of Atazor-R with other hormonal contraceptives or oral contraceptives containing norgestimate or progesterone has not been studied, therefore such combination is not recommended. An alternative reliable contraceptive method is recommended.
Ethinylestradiol 35 mcg + norethindrone (atazanavir 400 mg once daily)
ANTILIPIDEMIC AGENTS
HMG-CoA reductase inhibitors
Simvastatin Lovastatin	Simvastatin and lovastatin are largely metabolized via CYP3A4, and their blood concentration may increase with concomitant use with atazanavir/ritonavir.	Concomitant use of simvastatin and lovastatin with atazanavir/ritonavir is contraindicated due to increased risk of myopathy, including rhabdomyolysis.
Atorvastatin	Risk of myopathy, including rhabdomyolysis, increases with atorvastatin use, which is also metabolized via CYP3A4.	Concomitant use of Atazor-R with atorvastatin is not recommended. If atorvastatin use is necessary, the lowest atorvastatin dose should be prescribed and patient monitored.
Pravastatin Fluvastatin	Not studied. Data suggest possible increased exposure to pravastatin and fluvastatin with concomitant use with protease inhibitors. Pravastatin is not metabolized via CYP3A4, while fluvastatin is partially metabolized via CYP2C9.	Should be used with caution.
INHALED ß-AGONISTS (ANTI-ASTHMATIC AGENTS)
Salmetrol	Concomitant use of salmeterol with atazanavir/ritonavir may lead to increased salmeterol plasma concentration and increased salmeterol-associated adverse reactions. Mechanism of interaction is associated with induction of CYP3A4.	This combination is not recommended.
OPIOIDS
Buprenorphine, stable dose once daily (atazanavir 300 mg once daily with ritonavir 100 mg once daily)	Mechanism of interaction – inhibition of CYP3A4 and UGT. Atazanavir concentration did not significantly change.	Close monitoring of patient (assessment of sedative effect and cognitive functions) is required with concomitant use of atazanavir and buprenorphine. Buprenorphine dose reduction may be needed.
Methadone, stable maintenance dose (atazanavir 400 mg once daily)	No significant effect on methadone concentration was observed. Administration of low-dose ritonavir (100 mg twice daily) did not significantly affect methadone concentration. Based on these data, interaction was not expected with concomitant use of methadone and atazanavir.	No dose adjustment is required when Atazor-R and methadone are prescribed concomitantly.
PULMONARY ARTERIAL HYPERTENSION
Sildenafil	Concomitant use of atazanavir/ ritonavir may lead to increased PDE-5 inhibitor concentration and enhanced PDE-5 inhibitor-related adverse effects. Mechanism of interaction is associated with induction of CYP3A4.	Data on safety and efficacy of atazanavir/ritonavir and sildenafil combination for pulmonary arterial hypertension treatment are not established. Sildenafil is contraindicated in pulmonary arterial hypertension treatment.
SEDATIVES
Benzodiazepines
Midazolam Triazolam	Midazolam and triazolam are metabolized via CYP3A4. Concomitant use of Atazor-R may cause significant increase in benzodiazepine plasma concentrations. No studies on interaction between atazanavir/ritonavir and benzodiazepines have been conducted. With use of other CYP3A4 inhibitors, midazolam plasma concentrations were significantly higher compared to oral midazolam. Data on parenteral midazolam use with other protease inhibitors indicate possible 3–4-fold increase in midazolam plasma levels.	Atazanavir/ritonavir should not be used with oral midazolam and triazolam. Caution should be exercised when using Atazor-R and parenteral midazolam. Concomitant use of Atazor-R with parenteral midazolam should be performed in intensive care units or similar facilities where emergency assistance is available in case of respiratory depression or prolonged sedation. Midazolam doses should be considered, especially if multiple doses are administered.

Ritonavir as a pharmacokinetic enhancer or antiretroviral agent.

Ritonavir has a high degree of similarity to certain cytochrome P450 (CYP) isoenzymes and can inhibit oxidation in the following order of intensity: CYP3A4 > CYP2D6. The concomitant use of ritonavir with drugs primarily metabolized by the CYP3A isoenzyme may lead to increased plasma concentrations of these medicinal products, thereby enhancing and prolonging their therapeutic effects and adverse reactions. For certain drugs (e.g., alprazolam), the inhibitory effect of ritonavir on CYP3A4 may diminish over time. Ritonavir also has a high affinity for P-glycoprotein and thus is capable of inhibiting this transporter. The inhibition of P-gp activity by ritonavir (with or without other protease inhibitors) may weaken over time (e.g., with digoxin and fexofenadine; see "Interactions of ritonavir with non-antiretroviral medicinal products administered concomitantly"). Ritonavir may induce glucuronidation and oxidation via CYP1A2, CYP2C8, CYP2C9, and CYP2C19 isoenzymes, thereby stimulating the biotransformation of certain drugs that undergo these metabolic pathways. This may lead to reduced systemic exposure to such drugs and decreased or shortened therapeutic effect.

Important information regarding drug interactions with ritonavir as a pharmacokinetic enhancer is provided in the package leaflet of the co-administered protease inhibitor.

Medicinal products affecting ritonavir concentrations.

Ritonavir plasma concentrations may be reduced by concomitant use of herbal preparations containing St. John’s wort (Hypericum perforatum). This is due to the induction of enzymes involved in the drug's metabolism. Herbal preparations containing St. John’s wort must not be used in combination with ritonavir. If a patient is already receiving St. John’s wort, treatment should be discontinued and, if possible, viral load levels should be determined. After discontinuation of St. John’s wort, ritonavir concentrations may increase, necessitating dose adjustments. The inducing effect of St. John’s wort persists for at least 2 weeks after discontinuation of the herbal preparation.

Other medicinal products that may affect ritonavir plasma concentrations include delavirdine, efavirenz, phenytoin, and rifampicin.

Medicinal products affected by the use of ritonavir.

Interactions of ritonavir with protease inhibitors, antiretroviral agents, and other non-antiretroviral drugs are described below.

Interaction of ritonavir with protease inhibitors.

Ampranavir. Ritonavir increases plasma concentrations of amprenavir (AUC ↑ 64%, Cmin ↑ 5-fold) due to inhibition of the CYP3A4 enzyme. Clinical studies have confirmed the safety and efficacy of administering 600 mg amprenavir twice daily concomitantly with 100 mg ritonavir twice daily.

Atazanavir. Ritonavir increases plasma concentrations of atazanavir (AUC ↑ 86%, Cmin ↑ 11-fold) due to inhibition of the CYP3A4 isoenzyme. Clinical studies have confirmed the safety and efficacy of administering 300 mg/day atazanavir together with 100 mg/day ritonavir in treatment-experienced patients.

Darunavir. Ritonavir increases plasma concentrations of darunavir (AUC ↑ 14-fold) due to inhibition of the CYP3A4 isoenzyme. A single dose of 600 mg darunavir should be administered concomitantly with 100 mg ritonavir twice daily to ensure its therapeutic effect. The interaction of ritonavir at doses exceeding 100 mg twice daily with concomitantly administered darunavir has not been studied.

Fosamprenavir. Ritonavir increases plasma concentrations of amprenavir (from fosamprenavir) (AUC ↑ 2.4-fold, Cmin ↑ 11-fold) due to inhibition of the CYP3A4 isoenzyme. Fosamprenavir should be administered with ritonavir to ensure therapeutic efficacy. Clinical studies have confirmed the safety and efficacy of administering 700 mg fosamprenavir twice daily together with 100 mg ritonavir twice daily. The interaction of ritonavir at doses exceeding 100 mg twice daily with concomitantly administered fosamprenavir has not been studied.

Indinavir. Ritonavir increases plasma concentrations of indinavir (AUC of indinavir ↑ 178%, AUC of ritonavir ↑ 72%) due to inhibition of the CYP3A4 isoenzyme. Appropriate doses for efficacy and safety of this combination have not been established. The minimal benefit of ritonavir-mediated pharmacokinetic boosting is achieved with doses exceeding 100 mg twice daily. Caution is advised when co-administering ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) due to the risk of nephrolithiasis exacerbation.

Nelfinavir. Ritonavir increases plasma concentrations of nelfinavir (AUC ↑ 20–39%) due to inhibition of the CYP3A4 isoenzyme. Appropriate doses for efficacy and safety of this combination have not been established. The minimal benefit of ritonavir-mediated pharmacokinetic boosting is achieved with doses exceeding 100 mg twice daily.

Saqunavir. Ritonavir increases plasma concentrations of saquinavir (AUC ↑ 15-fold, Cmin ↑ 5-fold) due to inhibition of the CYP3A4 isoenzyme. Saquinavir should only be administered in combination with ritonavir. 100 mg ritonavir twice daily and 1000 mg saquinavir twice daily provide systemic saquinavir exposure for over 24 hours, which can otherwise be achieved only by administering 1200 mg saquinavir three times daily.

In a clinical study, concomitant administration of rifampicin (600 mg once daily), saquinavir (1000 mg twice daily), and ritonavir (100 mg twice daily) resulted in acute hepatocellular toxicity with transaminase elevations >20 times the upper limit of normal within 1–5 days of co-administration. Due to the risk of severe hepatotoxicity, saquinavir/ritonavir must not be used concomitantly with rifampicin.

Symeprevir. Concomitant administration of 200 mg symeprevir once daily with 100 mg ritonavir may increase symeprevir plasma concentrations. Concomitant use of symeprevir and ritonavir is not recommended.

Tipranavir. Ritonavir increases plasma concentrations of tipranavir (AUC of tipranavir ↑ 11-fold, Cmin ↑ 29-fold, AUC of ritonavir ↓ 40%) due to inhibition of the CYP3A4 isoenzyme. Tipranavir should be administered with a low dose of ritonavir to ensure its therapeutic effect. Ritonavir at doses less than 200 mg twice daily should not be used with tipranavir, as the efficacy of the combination may be altered.

Interaction of ritonavir with antiretroviral agents other than protease inhibitors.

Didanosine. Since ritonavir at a dose of 600 mg twice daily is recommended to be taken with food, and didanosine at a dose of 200 mg twice daily should be taken on an empty stomach, these drugs should be administered with a 2.5-hour interval. AUC ↓ 64%. Dose adjustment is not necessary.

Delavirdine. Based on recent comparative data, the pharmacokinetics of delavirdine administered at 400 mg three times daily were not affected by ritonavir at 600 mg twice daily. When co-administering these drugs, consideration may be given to reducing the ritonavir dose (AUC of ritonavir ↓ 50%, Cmin of ritonavir ↑ 75%).

Efavirenz. A higher frequency of adverse reactions (such as dizziness, nausea, paresthesia) and laboratory abnormalities (e.g., elevated liver enzymes) was observed during concomitant administration of efavirenz (600 mg once daily) with ritonavir (500 mg twice daily) as an antiretroviral agent (AUC of efavirenz ↑ 21%, AUC of ritonavir ↑ 17%).

Maraviroc. Ritonavir increases plasma concentrations of maraviroc (AUC ↑ 161%, Cmin ↑ 28%) due to inhibition of the CYP3A4 isoenzyme. Maraviroc at a dose of 100 mg twice daily may be used with ritonavir at 100 mg twice daily to enhance the effect of maraviroc.

Nevirapine. Concomitant administration of 600 mg ritonavir twice daily with 200 mg nevirapine twice daily does not result in clinically significant changes in the pharmacokinetics of either nevirapine or ritonavir.

Raltegravir. Concomitant administration of 100 mg ritonavir twice daily and a single 400 mg dose of raltegravir results in a slight reduction in raltegravir levels (AUC ↓ 16%, Cmin ↓ 1%).

Zidovudine. Ritonavir at a dose of 300 mg four times daily may induce glucuronidation of zidovudine administered at 200 mg three times daily, leading to a slight reduction in zidovudine levels (AUC ↓ 25%). Dose adjustment is not necessary.

Interaction of ritonavir with non-antiretroviral medicinal products administered concomitantly.

α1-adrenoreceptor antagonists

Alfuzosin. Combination of ritonavir with alfuzosin may lead to increased plasma concentrations of alfuzosin and is therefore contraindicated.

Amphetamine derivatives

Amphetamine. Ritonavir as an antiretroviral agent is capable of inhibiting CYP2D6 and, as a result, increases concentrations of amphetamine and its derivatives. When co-administering these drugs (with ritonavir doses for antiretroviral therapy), careful monitoring for therapeutic and adverse effects is recommended.

Interaction of ritonavir with non-antiretroviral medicinal products administered concomitantly.

Analgesics

Buprenorphine, norbuprenorphine, glucuronide metabolites. Increased plasma concentrations of buprenorphine (AUC ↑ 57%, Cmax ↑ 77%), norbuprenorphine (AUC ↑ 33%, Cmax ↑ 108%), and its active metabolite do not lead to clinically significant pharmacodynamic changes in opioid-tolerant patients. Therefore, when co-administering buprenorphine at a dose of 16 mg once daily with ritonavir at 100 mg twice daily, dose adjustment is not required. If ritonavir is used in combination with other protease inhibitors and buprenorphine, the package leaflet of the co-administered protease inhibitor should be reviewed for specific dosing recommendations.

Pethidine, piroxicam, propoxyphene. Concomitant administration of ritonavir may lead to increased plasma concentrations of pethidine, piroxicam, and propoxyphene and is therefore contraindicated.

Fentanyl. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of fentanyl. When co-administering fentanyl and ritonavir, careful monitoring for therapeutic and adverse effects (including respiratory depression) is recommended.

Methadone. When co-administering a single 5 mg dose of methadone with ritonavir at 500 mg twice daily (as a pharmacokinetic enhancer or antiretroviral agent), consideration may be given to increasing the methadone dose due to induction of glucuronidation. AUC ↓ 36%, Cmax ↓ 38%. Based on the patient's clinical response to methadone treatment, dose adjustment should also be considered.

Morphine. When co-administering morphine and ritonavir (as a pharmacokinetic enhancer or antiretroviral agent), plasma concentrations of morphine may decrease due to induction of glucuronidation.

Anti-anginal agents

Ranolazine. Due to inhibition of CYP3A by ritonavir, increased ranolazine concentrations are expected. Concomitant administration of ritonavir with ranolazine is contraindicated.

Antiarrhythmic agents

Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine. Concomitant administration of ritonavir may lead to increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and is therefore contraindicated.

Digoxin. This interaction may occur due to P-glycoprotein-mediated efflux of digoxin induced by ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent. Elevated digoxin concentrations (AUC ↑ 86%) observed in patients receiving ritonavir may decrease over time due to induction.

Anti-asthmatic agents

Theophylline. A higher dose of theophylline (3 mg/kg three times daily) may be necessary when co-administered with ritonavir at 500 mg twice daily due to induction of CYP1A2 (AUC ↓ 43%, Cmax ↓ 32%).

Anticancer agents

Dasatinib, nilotinib, vincristine, vinblastine. When co-administered with ritonavir, serum concentrations of these drugs may be increased, leading to an increased frequency of adverse reactions.

Afatinib. Serum concentrations may increase due to inhibition of breast cancer resistance protein and acute inhibition of P-glycoprotein by ritonavir. The degree of increase in AUC and Cmax depends on the timing of ritonavir administration: 20 mg afatinib, single dose, and 200 mg ritonavir twice daily (1 hour before afatinib dose) – AUC ↑ 48%, Cmax ↑ 39%; 40 mg afatinib, single dose, and 200 mg ritonavir twice daily (concomitant administration) – AUC ↑ 19%, Cmax ↑ 4%; 40 mg afatinib, single dose, and 200 mg ritonavir twice daily (6 hours after afatinib dose) – AUC ↑ 11%, Cmax ↑ 0.5%. Caution is advised when prescribing afatinib in combination with ritonavir. Monitoring for possible adverse reactions associated with afatinib is necessary.

Abemaciclib. Serum concentrations may increase due to inhibition of CYP3A4 by ritonavir. Concomitant use of abemaciclib and ritonavir should be avoided. If concomitant use cannot be avoided, refer to the abemaciclib package leaflet. Careful monitoring for possible adverse reactions associated with abemaciclib is required.

Apalutamide. Apalutamide is a moderate to strong inducer of CYP3A4 and may lead to reduced ritonavir exposure and potential loss of virological response. Apalutamide serum concentrations may increase due to inhibition of CYP3A by ritonavir, potentially causing serious adverse events, including seizures. Concomitant use of ritonavir and apalutamide is contraindicated.

Ceritinib. Serum concentrations may increase due to inhibition of CYP3A and P-glycoprotein by ritonavir. Caution is advised when prescribing ceritinib in combination with ritonavir. Monitoring for possible adverse reactions associated with ceritinib is necessary.

Neratinib. Neratinib serum concentrations may increase due to inhibition of CYP3A by ritonavir. Concomitant use of neratinib and ritonavir is contraindicated due to the risk of serious and/or life-threatening reactions, including hepatotoxicity.

Encorafenib and ivosidenib. Serum concentrations of these drugs may increase due to inhibition of CYP3A by ritonavir. Concomitant use potentially increases the risk of adverse reactions such as QT interval prolongation.

Ibrutinib. Ritonavir inhibits CYP3A. Concomitant administration of ibrutinib and ritonavir may increase ibrutinib exposure, potentially leading to a serious risk of tumor lysis syndrome.

Venetoclax. Concomitant administration of venetoclax and ritonavir may increase the risk of tumor lysis syndrome during initial dosing and the ramp-up phase. For patients who have completed the ramp-up phase and are on a maintenance daily dose of venetoclax, the venetoclax dose should be reduced by at least 75% when used with strong CYP3A inhibitors (see venetoclax package leaflet).

Anticoagulants

Warfarin, S-warfarin, R-warfarin. Single administration of 5 mg warfarin with ritonavir at 400 mg twice daily leads to induction of CYP1A2 and CYP2C9, resulting in reduced R-warfarin concentrations (AUC ↑ 9%, Cmax ↓ 9%), but minimal effect on S-warfarin pharmacokinetics (AUC ↓ 33%). Reduced R-warfarin levels lead to decreased anticoagulation; therefore, when co-administered with ritonavir (administered as an antiretroviral agent or pharmacokinetic enhancer), anticoagulation parameters should be monitored.

Rivaroxaban. Inhibition of CYP3A and P-glycoprotein leads to increased plasma levels and enhanced pharmacodynamic effects of rivaroxaban (AUC ↑ 153%, Cmax ↑ 55%), which may increase the risk of bleeding. Therefore, administration of ritonavir at 600 mg twice daily is not recommended in patients receiving rivaroxaban at a single dose of 10 mg.

Vorapaxar. Serum concentrations may increase due to inhibition of CYP3A by ritonavir. Concomitant use of vorapaxar with ritonavir is not recommended.

Anticonvulsants

Carbamazepine. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of carbamazepine. When co-administering carbamazepine and ritonavir, careful monitoring for therapeutic and adverse effects is recommended.

Divalproex, lamotrigine, phenytoin. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent induces oxidation via CYP2C9 and glucuronidation, thereby increasing plasma concentrations of anticonvulsants. When co-administering these drugs with ritonavir, careful monitoring of anticonvulsant serum concentrations and therapeutic effects is recommended. Phenytoin may reduce ritonavir serum levels.

Antidepressants

Amtriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline. Ritonavir as an antiretroviral agent is capable of inhibiting CYP2D6 and, as a result, may increase plasma concentrations of amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, or sertraline. When co-administering these drugs with ritonavir at doses for antiretroviral therapy, careful monitoring for therapeutic and adverse effects is recommended.

Desipramine. AUC and Cmax of the 2-hydroxy metabolite decrease by 15% and 67%, respectively. When co-administering a single 100 mg dose of desipramine with 500 mg ritonavir twice daily, consideration should be given to reducing the desipramine dose.

Tramadol. Increased frequency of adverse reactions associated with a single 50 mg dose of tramadol is observed when co-administered with ritonavir at 200 mg twice daily used as a pharmacokinetic enhancer or antiretroviral agent (AUC ↑ 2.4-fold, Cmax ↑ 34%). This combination should be used with caution. Tramadol therapy should be initiated at the lowest dose. Clinical response and tolerability should be monitored.

Antigout agents

Colchicine. Increased colchicine concentrations are expected when co-administered with ritonavir. Life-threatening and fatal drug interactions have been reported in patients with renal and/or hepatic impairment receiving colchicine and ritonavir (inhibition of CYP3A4 and P-glycoprotein).

Antihistamines

Astemizole, terfenadine. Concomitant administration of ritonavir with astemizole and terfenadine may lead to increased plasma concentrations of the latter and is therefore contraindicated.

Fexofenadine. Ritonavir (as a pharmacokinetic enhancer or antiretroviral agent) may alter P-glycoprotein-mediated efflux of fexofenadine, leading to increased fexofenadine concentrations. Increased fexofenadine concentrations may decrease over time due to induction.

Loratadine. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of loratadine. When co-administering loratadine and ritonavir, careful monitoring for therapeutic and adverse effects is required.

Antibacterial agents

Fusidic acid. Concomitant administration of ritonavir with fusidic acid may lead to increased plasma concentrations of both fusidic acid and ritonavir and is therefore contraindicated.

Rifabutin, metabolite 25-O-deacetyl-rifabutin. Pharmacokinetic studies showed that concomitant administration of ritonavir at 500 mg twice daily and 150 mg rifabutin daily led to AUC ↑ 4-fold, Cmax ↑ 2.5-fold for rifabutin and AUC ↑ 38-fold, Cmax ↑ 16-fold for its active metabolite 25-O-deacetyl-rifabutin, respectively.

Due to the significant increase in rifabutin AUC, its concomitant use with ritonavir as an antiretroviral agent is contraindicated. Reducing the rifabutin dose to 150 mg three times weekly may be indicated for certain protease inhibitors when co-administered with ritonavir as a pharmacokinetic enhancer.

Rifampicin. Although rifampicin may induce ritonavir metabolism, some data suggest that when ritonavir at high doses (600 mg twice daily) is co-administered with rifampicin, the additional boosting effect of ritonavir is minimal or clinically insignificant on ritonavir concentrations during high-dose treatment. The effect of ritonavir on rifampicin is unknown.

Voriconazole. Concomitant administration of ritonavir, 400 or 100 mg twice daily, as an antiretroviral agent with voriconazole, 200 mg twice daily, is contraindicated due to reduced voriconazole concentrations (AUC ↓ 82% or 39%, Cmax ↓ 66% or 24%, respectively). Concomitant use of voriconazole with ritonavir as a pharmacokinetic enhancer should be avoided unless the benefit-risk assessment justifies voriconazole use.

Atovaquone. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent induces glucuronidation and, as a result, reduces atovaquone plasma concentrations. When co-administering atovaquone with ritonavir, careful monitoring of serum levels of both drugs and their therapeutic effects is required.

Bedaquiline. Drug interaction with ritonavir alone has not been studied. In a study of interaction between a single dose of bedaquiline and multiple doses of lopinavir/ritonavir, the AUC of bedaquiline increased by 22%. This increase is likely related to ritonavir, and a more pronounced effect may be observed during prolonged co-administration. Due to the risk of bedaquiline-related adverse events, combinations of bedaquiline and ritonavir should be avoided. If benefits outweigh risks, extreme caution is required when co-administering bedaquiline with ritonavir. More frequent monitoring of ECG and transaminase levels is recommended.

Clarithromycin, 14-hydroxy metabolite of clarithromycin. Due to the wide therapeutic window of clarithromycin, dose reduction is not necessary for patients with normal renal function. Concomitant use of clarithromycin at doses exceeding 1 g with ritonavir at 200 mg three times daily, administered as an antiretroviral agent or pharmacokinetic enhancer, is not recommended (clarithromycin: AUC ↑ 77%, Cmax ↑ 31%; 14-hydroxy metabolite of clarithromycin: AUC ↓ 100%, Cmax ↓ 99%). In patients with renal impairment, consideration should be given to reducing the clarithromycin dose: for patients with creatinine clearance of 30–60 mL/min, the dose should be reduced by 50%; for patients with creatinine clearance below 30 mL/min, the dose should be reduced by 75%.

Delamanid. Drug interaction with ritonavir alone has not been studied. In a drug interaction study with delamanid at 100 mg twice daily and lopinavir/ritonavir at 400/100 mg twice daily for 14 days in healthy volunteers, the concentration of the DM-6705 metabolite of delamanid increased by 30%. Due to the risk of QT prolongation associated with DM-6705, if concomitant use of delamanid with ritonavir is considered necessary, very frequent ECG monitoring is recommended throughout the delamanid treatment period.

Erythromycin, itraconazole. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of erythromycin and itraconazole. When co-administering ritonavir with erythromycin or itraconazole, careful monitoring for therapeutic and adverse effects is required.

Ketoconazole. Ritonavir at 500 mg twice daily inhibits CYP3A-mediated metabolism of ketoconazole administered at 200 mg daily. AUC ↑ 3.4-fold, Cmax ↑ 55%. Due to the high frequency of gastrointestinal and hepatic adverse reactions, consideration should be given to reducing the ketoconazole dose when co-administered with ritonavir, administered as an antiretroviral agent or pharmacokinetic enhancer.

Sulfamethoxazole/trimethoprim. Dose adjustment of sulfamethoxazole/trimethoprim (800 mg/160 mg single dose) is not required when co-administered with ritonavir (500 mg twice daily). AUC ↓ 20%/↑ 20%.

Antipsychotics/neuroleptics

Clozapine, pimozide. Concomitant administration of ritonavir with clozapine and pimozide may lead to increased plasma concentrations of the latter and is therefore contraindicated.

Haloperidol, risperidone, thioridazine. Ritonavir as an antiretroviral agent is capable of inhibiting CYP2D6 and, as a result, reduces plasma concentrations of haloperidol, risperidone, and thioridazine. When co-administering ritonavir with these drugs, careful monitoring for therapeutic and adverse effects is required.

Lurasidone. Increased lurasidone concentrations are expected due to inhibition of CYP3A by ritonavir. Concomitant administration with lurasidone is contraindicated.

Quetiapine. Caution is advised when co-administering ritonavir with quetiapine. It is expected that inhibition of the CYP3A isoenzyme by ritonavir will increase quetiapine concentrations, potentially leading to quetiapine-related toxicity.

Long-acting β2-agonist

Salmetrol. Ritonavir inhibits CYP3A4 and, as a result, is expected to markedly increase salmeterol plasma concentrations. Therefore, concomitant use of ritonavir with salmeterol is not recommended.

Calcium channel blockers

Amlodipine, diltiazem, nifedipine. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of calcium channel blockers. When co-administering ritonavir with these drugs, careful monitoring for therapeutic and adverse effects is required.

Endothelin receptor antagonists

Bosentan. Concomitant use of bosentan and ritonavir may increase steady-state maximum concentrations (Cmax) of bosentan and increase the AUC.

Riociguat. Serum concentrations may increase due to inhibition of CYP3A and P-glycoprotein by ritonavir. Concomitant use of riociguat with ritonavir is not recommended.

Ergot derivatives

Dihydroergotamine, ergometrine, ergotamine, methylergometrine. Concomitant administration of ritonavir with ergot derivatives may lead to increased plasma concentrations of the latter and is therefore contraindicated.

Drugs for gastrointestinal motility

Cisapride. Concomitant administration of ritonavir and cisapride may lead to increased plasma concentrations of the latter and is therefore contraindicated.

Direct-acting antiviral agents

Glecaprevir/pibrentasvir. Serum concentrations may increase due to inhibition of CYP3A4 by ritonavir. Concomitant use of glecaprevir/pibrentasvir and ritonavir is not recommended due to the risk of elevated ALT associated with increased plasma concentrations of glecaprevir.

Protease inhibitor

Symeprevir. Ritonavir increases plasma concentrations of symeprevir due to inhibition of CYP3A4 (AUC ↑ 7.2-fold, Cmax ↑ 4.7-fold). Concomitant use of ritonavir 100 mg twice daily and symeprevir 200 mg daily is not recommended.

HMG-CoA reductase inhibitors

Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin. HMG-CoA reductase inhibitors that significantly depend on CYP3A metabolism (e.g., lovastatin and simvastatin) have markedly increased plasma concentrations when combined with ritonavir as a pharmacokinetic enhancer or antiretroviral agent. Since increased concentrations of lovastatin and simvastatin may provoke myopathy, including rhabdomyolysis, combination of these drugs with ritonavir is contraindicated. Atorvastatin is less dependent on CYP3A. Although rosuvastatin elimination does not depend on CYP3A, prolonged rosuvastatin effect has been observed when co-administered with ritonavir.

The mechanism of this interaction is unclear but may involve transporter inhibition. When atorvastatin and rosuvastatin are used concomitantly with ritonavir as a pharmacokinetic enhancer or antiretroviral agent, doses of atorvastatin and rosuvastatin should be as low as possible. Pravastatin and fluvastatin metabolism does not depend on CYP3A, and their interaction with ritonavir is not expected. If treatment with HMG-CoA reductase inhibitors is indicated, pravastatin or fluvastatin are recommended.

Lomitapide. Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase lomitapide exposure up to 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated.

Hormonal contraceptives

Ethinylestradiol. When co-administered with ritonavir at 500 mg twice daily and a single 50 mcg dose of ethinylestradiol, ethinylestradiol concentrations may decrease (AUC ↓ 40%, Cmax ↓ 32%). Consider using barrier or other non-hormonal contraceptive methods concomitantly with ritonavir (as a pharmacokinetic enhancer or antiretroviral agent). Ritonavir may alter uterine bleeding patterns and reduce the effectiveness of contraceptives containing estradiol.

Immunosuppressants

Cyclosporine, tacrolimus, everolimus. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of cyclosporine, tacrolimus, and everolimus. When co-administering ritonavir with these drugs, careful monitoring for therapeutic and adverse effects is required.

Phosphodiesterase inhibitors

Avanafil. Single administration of 50 mg avanafil with ritonavir at 600 mg twice daily is contraindicated. AUC ↑ 13-fold, Cmax ↑ 2.4-fold.

Sildenafil. Co-administration of 100 mg sildenafil (for erectile dysfunction), single dose, with 500 mg ritonavir twice daily as a pharmacokinetic enhancer or antiretroviral agent should be done with caution, and sildenafil doses should not exceed 25 mg within 48 hours. AUC ↑ 11-fold, Cmax ↑ 4-fold. Concomitant use of sildenafil and ritonavir is contraindicated in patients with pulmonary arterial hypertension.

Tadalafil. Co-administration of 20 mg tadalafil (for erectile dysfunction), single dose, with 200 mg ritonavir twice daily as a pharmacokinetic enhancer or antiretroviral agent should be done with caution, using low doses (no more than 10 mg tadalafil every 72 hours) and under enhanced monitoring for adverse reactions. AUC ↑ 124%.

If tadalafil is used concomitantly with ritonavir in patients with pulmonary arterial hypertension, refer to the tadalafil package leaflet.

Vardenafil. Administration of 5 mg vardenafil, single dose, with 600 mg ritonavir twice daily is contraindicated. AUC ↑ 49-fold, Cmax ↑ 13-fold.

Antagonists of gonadotropin-releasing hormone receptors.

Elagolix. Concomitant use of elagolix with ritonavir may increase elagolix exposure due to inhibition of OATP, CYP3A, and P-gp. Serious adverse reactions with elagolix, such as suicidal ideation and increased liver transaminases, are known. Additionally, elagolix is a weak/moderate inducer of CYP3A, which may reduce ritonavir exposure. Refer to the elagolix package leaflet for dosing recommendations when used with strong CYP3A4 inhibitors.

Kinase inhibitors

Fostamatinib. Concomitant use of fostamatinib with ritonavir may increase exposure to the R406 metabolite of fostamatinib, leading to dose-dependent adverse reactions such as hepatotoxicity and neutropenia.

Direct-acting antiviral agents against hepatitis C virus.

Elbasvir/grazoprevir. Plasma concentrations may increase due to inhibition of CYP3A by ritonavir. Concomitant use of these drugs is contraindicated.

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir. For paritaprevir, AUC increases 2.17-fold, Cmax 2.04-fold, Cmin 2.36-fold. Paritaprevir exposure may increase when co-administered with ritonavir. Concomitant use is not recommended.

Sofosbuvir/velpatasvir/voxilaprevir. Serum concentrations of sofosbuvir, velpatasvir, and voxilaprevir may increase due to inhibition of P-gp, BCRP, and OATP1B1/3 by ritonavir. However, only the increase in voxilaprevir exposure is considered clinically significant. Concomitant use of ritonavir and sofosbuvir/velpatasvir/voxilaprevir is not recommended.

Sedatives/hypnotics

Chlordiazepoxide, diazepam, estazolam, flurazepam, oral and parenteral midazolam. Ritonavir in combination with chlordiazepoxide, diazepam, estazolam, and flurazepam may increase plasma concentrations of the latter and is therefore contraindicated.

Midazolam is extensively metabolized by the CYP3A4 enzyme. Concomitant administration with ritonavir may lead to a significant increase in benzodiazepine concentration. Interaction of ritonavir with benzodiazepines when co-administered has not been studied. Based on data from other CYP3A4 inhibitors, plasma concentrations of benzodiazepines are expected to be significantly higher when oral midazolam is used. Therefore, ritonavir should not be combined with oral midazolam, and caution is required when co-administering ritonavir with parenteral midazolam.

Based on data from concomitant administration of parenteral midazolam with other protease inhibitors, plasma midazolam concentration may increase 3–4-fold. If ritonavir must be co-administered with parenteral midazolam, treatment should be conducted in an intensive care unit or similar setting with careful clinical monitoring and appropriate medical support in case of respiratory depression and/or prolonged sedation. Consideration should be given to adjusting the midazolam dose, especially if more than one dose is administered.

Triazolam. Concomitant administration of 4 doses of 200 mg ritonavir and a single 0.125 mg dose of triazolam may lead to increased plasma concentrations of the latter (AUC ↑ >20-fold, Cmax ↑ 87%) and is therefore contraindicated.

Pethidine (metabolite – norpethidine). Due to the risk of increased metabolite concentrations (AUC of norpethidine ↑ 47%, Cmax ↑ 87%), which have both analgesic and CNS-stimulating activity, concomitant administration of a single oral 50 mg dose of pethidine with ritonavir at 500 mg twice daily is contraindicated. Increased norpethidine concentrations increase the risk of CNS adverse reactions (e.g., seizures).

Alprazolam. Ritonavir inhibits alprazolam metabolism (AUC ↑ 2.5-fold). The inhibitory effect of ritonavir administered at 500 mg twice daily disappears after 10 days of administration (AUC ↓ 12%, Cmax ↓ 16%). Caution is advised in the first days of co-administering alprazolam with ritonavir as a pharmacokinetic enhancer or antiretroviral agent, before alprazolam metabolism resumes.

Buspirone. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of buspirone. When co-administering ritonavir with buspirone, careful monitoring for therapeutic effects and adverse reactions is required.

Hypnotics

Zolpidem. The combination of 5 mg zolpidem and 4 doses of 200 mg ritonavir should be used with caution, and the patient should be carefully monitored for excessive sedative effect (AUC ↑ 28%, Cmax ↑ 22%).

Smoking cessation

Bupropion. Bupropion is primarily metabolized via CYP2B6. Concomitant administration of 150 mg bupropion with 100 mg or 600 mg ritonavir twice daily reduces bupropion levels (AUC ↓ 22% or 66%, Cmax ↓ 21% or 62%, respectively). This effect is believed to be due to bupropion metabolism. However, since ritonavir has demonstrated inhibition of CYP2B6 in vitro, the recommended bupropion dose should not be exceeded. No significant interaction with bupropion was observed after short-term (as opposed to long-term) use of low doses of ritonavir (200 mg twice daily for two days). Based on this observation, it can be assumed that decreased bupropion concentrations begin several days after starting ritonavir administration.

Steroids

Fluticasone propionate (inhaled, intranasal, or injectable), budesonide, triamcinolone. Systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression (plasma cortisol levels decreased by 86% in studies), have been observed in patients receiving ritonavir at 100 mg twice daily and inhaled or intranasal fluticasone propionate at 200 mcg once daily (AUC ↑ 350-fold, Cmax ↑ 25-fold). Similar effects may occur with other corticosteroids metabolized by CYP3A, such as budesonide. Therefore, concomitant use of glucocorticoids and ritonavir as an antiretroviral agent or pharmacokinetic enhancer is not recommended unless the potential benefit outweighs the risk of systemic corticosteroid effects. Consider reducing the glucocorticoid dose, ensuring careful monitoring of local and systemic effects, or switching to a glucocorticoid not metabolized by CYP3A4 (e.g., beclomethasone). Additionally, when discontinuing glucocorticoids, a gradual dose reduction over a prolonged period is necessary.

Dexamethasone. Ritonavir as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of dexamethasone. When co-administering ritonavir with dexamethasone, careful monitoring for therapeutic effects and adverse reactions is required.

Prednisolone. When co-administering 200 mg ritonavir twice daily with prednisolone at 20 mg, careful monitoring for therapeutic effects and adverse reactions is required. AUC of prednisolone metabolite increases by 37% and 28% after 4 and 14 days of ritonavir administration, respectively.

Thyroid hormone replacement therapy.

Levothyroxine. Interactions between ritonavir-containing drugs and levothyroxine have been reported. Patients receiving levothyroxine should have thyroid-stimulating hormone (TSH) levels monitored for at least one month after starting and/or stopping ritonavir treatment.

When ritonavir is co-administered with other medicinal products, refer to the package leaflet of the latter.

During combination therapy with ritonavir and disopyramide, mexiletine, or nefazodone, adverse reactions affecting the cardiovascular system and CNS have been reported. The possibility of drug interaction cannot be excluded.

Since ritonavir is highly protein-bound, consider the potential for increased therapeutic and toxic effects due to displacement of co-administered drugs from protein binding.

Ritonavir administered as a pharmacokinetic enhancer

Important information regarding interactions of medicinal products with ritonavir used as a pharmacokinetic enhancer is provided in the package leaflet of the co-administered protease inhibitor.

Proton pump inhibitors and H2-receptor antagonists. Proton pump inhibitors and H2-receptor antagonists (e.g., omeprazole or ranitidine) may reduce concentrations of co-administered protease inhibitors. For detailed information on the effect of concomitant use of acid-reducing agents, refer to the package leaflet of the protease inhibitor. Based on drug interaction studies with ritonavir-boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concomitant use of omeprazole or ranitidine slightly altered the efficacy of ritonavir used as a pharmacokinetic enhancer, despite minor changes in drug action (approximately 6–18%).

Special precautions for use.

Ritonavir is not a direct-acting antiretroviral agent against HIV-1 or AIDS. In patients receiving ritonavir or other antiretroviral therapy, opportunistic infections and other complications of HIV-1 infection may continue to develop.

Although effective viral suppression with antiretroviral therapy has been shown to substantially reduce the risk of sexual transmission of HIV, residual transmission risk cannot be excluded. Preventive measures should be taken in accordance with guidance from national competent authorities to avoid transmission of infection.

Prior to prescribing the medication, individual viral resistance and patient history should be evaluated.

Patients should be informed that antiretroviral therapy does not eliminate the risk of HIV transmission via blood or sexual contact, and therefore preventive measures should be taken.

Currently, there are insufficient data to recommend the drug at a defined dose for patients who have not previously been treated with antiretroviral agents.

The concomitant use of Atazohu-R with ritonavir at doses exceeding 100 mg once daily has not been clinically evaluated. Increasing the dose of ritonavir in combination with the drug is not recommended. Higher doses of ritonavir may alter the safety profile (e.g., may cause cardiotoxic effects, hyperbilirubinemia).

Only when atazanavir with ritonavir is prescribed together with efavirenz, may the dose of ritonavir be increased to 200 mg once daily.

Patients with concomitant diseases

Liver disease.

In patients with chronic hepatitis B or C receiving combined antiretroviral therapy, the risk of developing severe and potentially life-threatening hepatic adverse reactions is significantly increased. When administering combined antiretroviral therapy to patients with hepatitis B or C, refer to the appropriate instructions for medical use of these drugs.

In patients with pre-existing liver function abnormalities, including active chronic hepatitis, the frequency of liver function disorders may increase during combined antiretroviral therapy. Such patients should be closely monitored according to standard practice. If symptoms of worsening liver disease occur, consider interrupting or discontinuing treatment.

Kidney disease.

Since renal clearance of ritonavir is minimal, a reduction in overall clearance in patients with renal impairment is unlikely.

Cases of renal failure, impaired kidney function, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported during clinical use of tenofovir disoproxil fumarate.

Renal impairment.

Dose adjustment is not required. However, the combination of atazanavir/ritonavir is not recommended for patients undergoing hemodialysis.

QT interval prolongation

Atazanavir has caused mild asymptomatic prolongation of the QT interval in clinical studies.

Caution should be exercised when co-administering with drugs that prolong the QT interval (such as atenolol, diltiazem, verapamil). Atazanavir should be used with caution in patients with pre-existing cardiac conduction disorders (second-degree atrioventricular block or bundle branch block), and only when benefit outweighs the risk.

PR interval prolongation

Ritonavir has caused mild asymptomatic prolongation of the PR interval in several healthy adult volunteers. There have been isolated reports of second- or third-degree atrioventricular block in patients with a history of heart disease and conduction abnormalities, or in patients receiving drugs known to prolong the PR interval, when used concomitantly with ritonavir. The drug should be used with caution in such patients.

Patients with chronic diarrhea or malabsorption.

If diarrhea develops, additional evaluation is recommended. The relatively high incidence of diarrhea during ritonavir treatment may affect absorption levels and efficacy (due to poor adherence) of ritonavir or concomitant medications. Persistent vomiting and/or severe diarrhea caused by ritonavir may also affect kidney function. In patients with renal impairment, regular monitoring of kidney function is advisable.

Hemophilia.

In patients with hemophilia A and B, bleeding episodes, including spontaneous skin bruising and hemarthrosis, have been observed during protease inhibitor therapy. Some of these patients required factor VIII administration. In more than half of these patients, protease inhibitor therapy was continued or resumed after interruption. A causal relationship between bleeding and treatment is assumed, although the mechanism of action of protease inhibitors is not fully understood. Hemophilia patients should be informed about the possibility of such complications.

Body weight and metabolic parameters.

During antiretroviral therapy, increases in body weight and blood lipid and glucose levels may occur. These changes may be partially related to disease control and lifestyle. Regarding lipids, there is evidence that in some cases this is a result of treatment, while no convincing evidence has been obtained linking weight gain to a specific treatment regimen. Monitoring of lipid and glucose levels should be performed according to established guidelines for HIV infection management. Lipid abnormalities should be treated according to clinical practice.

Studies have shown that atazanavir/ritonavir causes less dyslipidemia compared to comparator drugs.

Diabetes mellitus and hyperglycemia.

Cases of newly diagnosed diabetes mellitus, hyperglycemia, and exacerbation of existing diabetes mellitus have been reported during treatment with protease inhibitors. In some cases, hyperglycemia was severe and associated with ketoacidosis. A significant proportion of these patients had underlying conditions requiring medication associated with the development of diabetes or hyperglycemia. Blood glucose levels should be monitored.

Lipodystrophy.

Combined antiretroviral therapy is associated with HIV-associated redistribution of adipose tissue (lipodystrophy). The long-term consequences of this phenomenon are currently unknown, and its mechanism is not fully understood. Currently, it is assumed that visceral lipomatosis is linked to the use of protease inhibitors, and lipoatrophy to nucleoside reverse transcriptase inhibitors (NRTIs). Increased risk of lipodystrophy is associated with individual factors such as older age, and medication-related factors such as longer duration of antiretroviral therapy and associated metabolic disturbances. Clinical examinations should include assessment for signs of fat redistribution. Serum lipid and fasting blood glucose levels should also be considered. Lipid metabolism disorders should be treated with appropriate medications.

Pancreatitis.

The possibility of pancreatitis should be considered in the presence of clinical symptoms (nausea, vomiting, abdominal pain) or changes in laboratory parameters (elevated serum lipase or amylase levels). Patients exhibiting these signs or symptoms should be evaluated, and if pancreatitis is diagnosed, ritonavir therapy should be discontinued.

Hyperbilirubinemia.

In patients receiving atazanavir, reversible increases in indirect (unconjugated) bilirubin levels have been observed, associated with inhibition of uridine diphosphate glucuronosyltransferase (UGT). It should be noted that elevated transaminase activity observed with increased bilirubin in patients receiving atazanavir may be due to other conditions also associated with hyperbilirubinemia. If jaundice or scleral icterus is undesirable for the patient, alternative antiretroviral therapy may be considered. Dose reduction of the drug is not recommended, as this may lead to loss of therapeutic effect or development of resistance. Indinavir use may cause unconjugated hyperbilirubinemia due to UGT inhibition. The combination of atazanavir and indinavir has not been studied and is therefore not recommended.

Phosphodiesterase inhibitors (PDE-5).

Sildenafil, tadalafil, or vardenafil should be prescribed with particular caution to patients receiving ritonavir for the treatment of erectile dysfunction. Concomitant use of ritonavir with these drugs is believed to significantly increase their concentrations and may lead to related adverse reactions such as arterial hypotension and prolonged erection. Concomitant use of sildenafil and ritonavir is contraindicated in pulmonary arterial hypertension. Concomitant use of avanafil or vardenafil with ritonavir is contraindicated.

HMG-CoA reductase inhibitors.

Metabolism of reductase inhibitors (simvastatin and lovastatin) is largely dependent on the CYP3A isoenzyme; therefore, due to the increased risk of myopathy up to rhabdomyolysis, concomitant use of ritonavir with simvastatin or lovastatin is not recommended. Caution should also be exercised or dose reduction considered when ritonavir treatment is administered concurrently with atorvastatin, which is less dependent on CYP3A metabolism. Elimination of rosuvastatin does not depend on CYP3A, but increased rosuvastatin exposure has been reported during concomitant use with ritonavir. The mechanism of this interaction is not fully understood, but theoretically may involve transporter inhibition. Lower doses of atorvastatin and rosuvastatin should be prescribed when used concomitantly with ritonavir. Metabolism of pravastatin and fluvastatin does not depend on CYP3A, so no significant interactions with ritonavir are expected. If reductase inhibitor treatment is necessary, pravastatin or fluvastatin is recommended.

Colchicine.

Life-threatening and fatal drug interactions have been reported in patients receiving colchicine and ritonavir.

Digoxin.

Ritonavir should be prescribed with particular caution to patients taking digoxin, as concomitant use of these drugs is believed to increase digoxin concentrations. Over time, elevated digoxin concentrations decrease. Patients already taking digoxin should have their digoxin dose reduced to half the usual dose during ritonavir therapy and should be under close medical supervision for several weeks after starting concomitant ritonavir and digoxin. Patients already receiving ritonavir should start digoxin treatment more gradually than usual. Digoxin concentrations should be monitored more closely than usual, with timely dose adjustments as necessary, based on clinical data, electrocardiographic findings, and digoxin levels.

Ethinylestradiol. Barrier and other non-hormonal contraceptive methods should be considered, as administration of ritonavir at therapeutic or lower doses concomitantly with contraceptives containing estradiol may reduce their effectiveness and alter the pattern of uterine bleeding.

Glucocorticoids. Concomitant use of ritonavir with fluticasone or other corticosteroids metabolized by the CYP3A4 enzyme system is not recommended, except when the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Trazodone. Ritonavir should be prescribed with particular caution to patients receiving trazodone. Trazodone is a CYP3A4 substrate; therefore, it is assumed that concomitant use of ritonavir increases trazodone concentrations. In a study of single-dose interaction involving healthy volunteers, adverse reactions such as nausea, dizziness, arterial hypotension, and syncope were observed.

Rivaroxaban. Use of ritonavir is not recommended in patients receiving rivaroxaban due to the risk of increased bleeding.

Riociguat. Concomitant use of ritonavir is not recommended due to the potential for increased riociguat concentration.

Vorapaxar. Concomitant use of ritonavir is not recommended due to the potential for increased vorapaxar concentration.

Delamanid. Concomitant use of delamanid with another potent CYP3A inhibitor (ritonavir) may increase the amount of delamanid metabolites associated with prolonged corrected QT interval. Therefore, if concomitant use of delamanid with ritonavir is necessary, frequent ECG monitoring is recommended throughout the delamanid treatment period.

Saquinavir. The dose of ritonavir should not exceed 100 mg twice daily. Increased incidence of adverse reactions has been observed with higher doses of ritonavir. Concomitant use of saquinavir and ritonavir has been associated with severe adverse effects, primarily diabetic ketoacidosis and liver function disorders, especially in patients with pre-existing liver disease. Saquinavir/ritonavir should not be prescribed with rifampicin due to the risk of severe hepatotoxicity (manifested by elevated liver transaminase levels) when all three drugs are taken simultaneously.

Tipranavir. Reports of clinical hepatitis and hepatic decompensation, including several fatal cases, have been associated with tipranavir use in combination with 200 mg ritonavir. Particular attention is required in patients with co-infection of chronic hepatitis B or C, as their risk of hepatotoxicity is significantly higher.

Doses of ritonavir lower than 200 mg twice daily should be used, as higher doses may affect the safety profile of this drug combination.

Fosamprenavir. Clinical evaluation of combined fosamprenavir use with ritonavir at doses higher than 100 mg twice daily has not been conducted. Increasing the dose of ritonavir is not recommended, as it may affect the safety profile of this combination.

Hepatic impairment. Atazanavir is primarily metabolized in the liver; therefore, the drug should be used with caution in patients with hepatic impairment due to the potential for increased concentration.

There are no data on the safety and efficacy of atazanavir use in patients with severe liver disease. In patients infected with hepatitis B and/or C virus, transaminase elevations were more frequently observed, but bilirubin concentration increases and hepatitis incidence did not differ from those in patients without this co-infection.

In patients with chronic hepatitis B or C, combined antiretroviral therapy increases the risk of severe potentially fatal liver damage. In patients with liver disease, including chronic active hepatitis, liver function disorders occur more frequently during combined antiretroviral therapy; therefore, such patients require careful medical monitoring. If worsening liver function is detected, antiviral drugs should be temporarily discontinued or discontinued.

Cholelithiasis.

Cholelithiasis has been reported during atazanavir use. Some patients required hospitalization for appropriate treatment, and some experienced complications. If signs of cholelithiasis do not resolve, atazanavir therapy should be temporarily or permanently discontinued.

Nephrolithiasis.

Nephrolithiasis has been reported during atazanavir use. Some patients required hospitalization for appropriate treatment, and some experienced complications. In some cases, nephrolithiasis was associated with acute renal failure or renal impairment. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency, inflammatory responses to asymptomatic or residual opportunistic microorganisms and severe clinical conditions or worsening symptoms may occur during combined antiretroviral therapy (cART). Such reactions are usually observed within the first few weeks or months after starting cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. All inflammatory symptoms should be evaluated, and appropriate treatment initiated if necessary.

Autoimmune disorders (e.g., Graves' disease) have also been reported to develop during immune reconstitution; however, the timing of adverse reactions may vary, and they may manifest several months after starting treatment.

Osteonecrosis.

Although the etiology of this condition is multifactorial (including corticosteroid use, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have occurred, particularly in patients with advanced stages of HIV disease and/or long-term combined antiretroviral therapy. If a patient experiences joint pain, stiffness, or difficulty moving, medical consultation is recommended.

Rashes and associated syndromes.

Maculopapular rashes, usually mild or moderate in severity, may occur within the first 3 weeks of atazanavir therapy.

Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS), and other severe skin reactions may occur during atazanavir use. Patients should be informed about possible signs and symptoms and advised to closely monitor for any skin reactions. Atazanavir use should be discontinued if a severe rash develops.

The best way to manage these events is early diagnosis and immediate discontinuation of the suspected drug. If a patient develops Stevens-Johnson syndrome or DRESS, atazanavir should not be used again.

Chronic kidney disease.

Chronic kidney disease has been reported in HIV-infected patients receiving atazanavir with or without ritonavir during post-marketing surveillance. A large observational study showed an association between increased incidence of chronic kidney disease and cumulative exposure to regimens containing atazanavir/ritonavir in HIV-infected patients with initially normal estimated glomerular filtration rate. This association was observed independently of the influence of tenofovir disoproxil. Regular monitoring of kidney function should be maintained throughout treatment (see section "Contraindications").

Interaction with other medicinal products.

Combination of atazanavir with atorvastatin is not recommended.

Concomitant use of atazanavir with nevirapine or efavirenz is not recommended.

If a combination of atazanavir with nucleoside reverse transcriptase inhibitors is necessary, the doses of atazanavir and ritonavir should be increased to 400 mg and 200 mg, respectively, when combined with efavirenz. Therapy should be administered under close medical supervision.

Atazanavir is primarily metabolized by CYP3A4. Concomitant use of atazanavir with drugs that inhibit CYP3A4 is not recommended.

PDE-5 inhibitors (sildenafil, tadalafil, and vardenafil) for the treatment of erectile dysfunction should be prescribed with particular caution; atazanavir and ritonavir should be prescribed at lower doses in such patients. Concomitant use of atazanavir with these drugs may significantly increase PDE-5 inhibitor concentrations and intensify adverse reactions such as arterial hypotension, visual disturbances, and priapism.

Concomitant use of voriconazole with atazanavir/ritonavir is not recommended unless the benefit of voriconazole use outweighs the risk.

In most patients, reduced exposure to atazanavir and voriconazole is not expected. In a small number of patients with functional CYP2C19 allele, voriconazole exposure may be significantly increased.

Concomitant use of atazanavir/ritonavir with fluticasone or other glucocorticoids metabolized by CYP3A4 is not recommended unless the potential benefit of systemic corticosteroid treatment outweighs the risk of adverse effects, including Cushing's syndrome and adrenal suppression.

Concomitant use of salmeterol with atazanavir/ritonavir increases the risk of cardiovascular adverse reactions associated with salmeterol. The combination of salmeterol and Atazohu-R is not recommended.

Atazanavir absorption may be reduced when gastric pH is increased for any reason.

Combination of atazanavir with proton pump inhibitors is not recommended.

If combination of atazanavir with proton pump inhibitors is necessary, medical supervision is recommended, and the atazanavir dose should be increased to 400 mg and ritonavir to 100 mg; proton pump inhibitor doses should not exceed the equivalent of omeprazole 20 mg.

Concomitant use of atazanavir/ritonavir with oral hormonal contraceptives containing progestin (except norgestimate) has not been studied. Therefore, this combination is not recommended.

Effect on laboratory test parameters.

Treatment of patients with resistance to multiple protease inhibitors (PIs) is ineffective (≥ 4 PI mutations).

The most common laboratory abnormalities observed in patients receiving medication containing atazanavir in combination with one or more nucleoside reverse transcriptase inhibitors (NRTIs) include: increased bilirubin levels, increased amylase, creatine kinase, alanine aminotransferase/serum glutamic-pyruvic transaminase levels, decreased neutrophil count, increased aspartate aminotransferase/serum glutamic-oxaloacetic transaminase levels, and increased lipase levels.

Lactose.

The drug should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted. Atazanavir should be used during pregnancy only if clearly needed. Animal studies have demonstrated toxic effects on reproductive function. Atazohu-R should be used during pregnancy only when the potential benefit of treatment outweighs the possible risk. In one study, grade 3 and 4 hyperbilirubinemia was observed in 30% of women receiving atazanavir/ritonavir at a dose of 300/100 mg and in 62% of women receiving atazanavir/ritonavir at a dose of 400/100 mg. No cases of lactic acidosis were reported during the study. It is unknown whether Atazohu-R, administered during pregnancy, may exacerbate physiological hyperbilirubinemia and lead to bilirubin encephalopathy in newborns and infants. Additional monitoring is required in the pre-delivery period.

Breastfeeding period

Atazanavir is excreted in breast milk. HIV-infected women should avoid breastfeeding due to the risk of infecting the infant.

Ability to affect reaction speed when driving or operating machinery.

Since somnolence and dizziness are known adverse reactions associated with the use of the drug, this should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Prescription of Atazor-R should be performed by a physician experienced in the treatment of HIV infection.

Dosing

The recommended dose of the drug is one tablet once daily orally with food.

The recommended oral dose of atazanavir/ritonavir depends on the patient's treatment history and concomitant medication use.

Dose adjustments are recommended when co-administered with H2-receptor blockers or proton pump inhibitors.

The dose of H2-receptor blockers should not exceed the equivalent of famotidine 40 mg twice daily. Atazanavir/ritonavir should be administered either simultaneously or at least 10 hours after administration of the H2-receptor blocker. Doses of proton pump inhibitors should not exceed the equivalent of omeprazole 20 mg daily and should be administered 12 hours before atazanavir/ritonavir.

Concomitant use of atazanavir/ritonavir with efavirenz is not recommended in patients who have previously received antiretroviral treatment.

Special Populations

Patients with Renal Impairment

Atazor-R is not recommended for patients undergoing hemodialysis. Before administering ritonavir to patients with renal impairment, the physician should refer to the dosing information provided in the package insert of the protease inhibitor prescribed concomitantly with ritonavir.

Patients with Hepatic Impairment

The use of atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir with ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir with ritonavir should not be used in patients with moderate or severe hepatic impairment.

Elderly Patients

Appropriate precautions and careful monitoring are advised when prescribing the drug to elderly patients due to increased frequency of impaired liver, kidney, and cardiovascular function, as well as potential comorbidities or drug interactions.

Pregnancy and Postpartum Period

Second and Third Trimesters of Pregnancy

Atazanavir with ritonavir may not provide sufficient atazanavir exposure, especially if atazanavir activity or the entire treatment regimen may be compromised due to drug resistance. Given the limited available data and inter-patient variability during pregnancy, therapeutic drug monitoring (TDM) may be considered to ensure adequate efficacy.

There is a potential risk of further decreased atazanavir exposure if atazanavir is co-administered with drugs known to reduce its exposure (e.g., tenofovir disoproxil fumarate or H2-receptor antagonists).

• If concomitant use of tenofovir disoproxil fumarate or H2-receptor antagonists is necessary, increasing the atazanavir dose to 400 mg with ritonavir 100 mg with TDM should be considered.
• Concomitant use of atazanavir with ritonavir is not recommended in pregnant women receiving both tenofovir disoproxil fumarate and H2-receptor antagonists.

Postpartum Period

Following the potential reduction in atazanavir exposure during the second and third trimesters, exposure may increase during the first 2 months postpartum. Therefore, postpartum patients should be closely monitored for adverse reactions.

• During this period, postpartum patients should follow the same dosing recommendations as non-pregnant patients, including recommendations regarding concomitant administration of drugs known to affect atazanavir exposure.

Method of Administration

Atazor-R is recommended for oral administration with food.

Pediatric Use

The drug is not administered to children.

Overdose

Experience with acute atazanavir overdose in humans is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic adverse effects. At high doses leading to high drug exposure, jaundice due to indirect (unconjugated) hyperbilirubinemia (without corresponding changes in liver function tests) or prolonged PR interval may occur.

Experience with acute ritonavir overdose in humans is limited. In clinical trials, one patient received 1500 mg ritonavir daily for two days and reported paresthesia, which resolved after dose reduction. A case of renal failure with eosinophilia has been reported.

Toxicity signs observed in animals (mice and rats) included decreased activity, ataxia, dyspnea, and tremor.

Treatment

In case of overdose, the following measures should be taken: monitoring of vital physiological parameters and ECG, gastric lavage, induction of emesis to remove unabsorbed drug, administration of activated charcoal, and observation of the patient's general condition. Since atazanavir is extensively metabolized in the liver and highly protein-bound, dialysis is ineffective in removing the drug from the body.

There is no specific antidote for ritonavir overdose. Management should include general supportive measures, including monitoring of vital functions and clinical status. Due to the drug's solubility and potential for transintestinal elimination, gastric lavage and administration of activated charcoal should be included in overdose management. Because ritonavir is extensively metabolized by the liver and highly protein-bound, dialysis is unlikely to be beneficial in removing a significant amount of the drug.

Adverse Reactions

The most commonly reported adverse reactions in patients receiving ritonavir alone or in combination with other antiretroviral agents were gastrointestinal disorders (including diarrhea, nausea, vomiting, and upper and lower abdominal pain), neurological disturbances (including paresthesia and oral mucosal paresthesia), and fatigue/asthenia.

Chronic kidney disease has been reported in HIV-infected patients receiving atazanavir with or without ritonavir during post-marketing surveillance. A large observational study showed an association between increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimens in HIV-infected patients with normal baseline estimated glomerular filtration rate. This association was observed independently of the effect of tenofovir disoproxil. Regular monitoring of renal function should be maintained throughout treatment (see section "Special Warnings and Precautions for Use").

The adverse reactions listed below have been observed with the use of atazanavir and ritonavir based on clinical trial and post-marketing data. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), and very rare (< 1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing occurrence.

Haematological and lymphatic system disorders
Common	Decreased levels of leukocytes, hemoglobin, neutrophils; increased levels of eosinophils; thrombocytopenia
Uncommon	Increased levels of neutrophils
Immune system disorders
Common	Increased sensitivity, including urticaria and facial swelling
Rare	Anaphylaxis, hypersensitivity
Metabolism and nutrition disorders
Common	Hypercholesterolemia, hypertriglyceridemia, gout, edema and peripheral edema, dehydration (usually associated with gastrointestinal symptoms)
Uncommon	Decreased or increased body weight, anorexia, increased appetite, diabetes mellitus
Rare	Hypoglycemia
Psychiatric disorders
Uncommon	Depression, confusion, restlessness, insomnia, sleep disorders, abnormal dreams
Nervous system disorders
Very common	Dysgeusia, oral mucosal and peripheral paresthesia, dizziness, peripheral neuropathy, headache
Common	Insomnia, anxiety, confusion, inattention, syncope, seizures
Uncommon	Amnesia, somnolence
Eye disorders
Common	Scleral icterus, blurred vision
Cardiac disorders
Uncommon	Myocardial infarction, torsades de pointes ventricular tachycardia
Rare	QT interval prolongation, edema, palpitations
Vascular disorders
Common	Arterial hypertension, arterial hypotension including orthostatic hypotension, sensation of cold in extremities
Respiratory, thoracic and mediastinal disorders
Very common	Pharyngitis, oropharyngeal pain, cough
Uncommon	Dyspnea
Gastrointestinal disorders
Very common	Abdominal pain (upper and lower), nausea, diarrhea (including severe diarrhea with electrolyte imbalance), vomiting, dyspepsia
Common	Anorexia, flatulence, oral ulcers, gastrointestinal hemorrhage, gastroesophageal reflux disease, pancreatitis
Uncommon	Pancreatitis, gastritis, abdominal distension, aphthous stomatitis, flatulence, dry mouth
Hepatobiliary disorders
Common	Jaundice, hepatitis (including elevated AST, ALT, GGT), increased blood bilirubin (including jaundice)
Uncommon	Hepatitis, cholelithiasis, cholestasis
Rare	Hepatosplenomegaly, cholecystitis
Skin and subcutaneous tissue disorders
Very common	Pruritus, rash (including erythematous and maculopapular)
Common	Acne
Uncommon	Multiform erythema, drug rash with eosinophilia, toxic skin reactions (DRESS), alopecia, pruritus, urticaria, Quincke's edema
Rare	Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), vesiculobullous rash, eczema, vasodilation
Musculoskeletal and connective tissue disorders
Very common	Arthralgia and back pain
Common	Myositis, rhabdomyolysis, myalgia, myopathy/increased creatine phosphokinase
Uncommon	Muscle atrophy, arthralgia
Rare	Myopathy
Renal and urinary disorders
Common	Increased frequency of urination, renal failure (e.g., oliguria, elevated blood creatinine)
Uncommon	Nephrolithiasis, hematuria, proteinuria, pollakiuria, interstitial nephritis, acute renal failure
Rare	Renal pain
Reproductive system and breast disorders
Common	Menorrhagia
Uncommon	Gynecomastia
General disorders
Very common	Fatigue, including asthenia, hot flushes, sensation of heat
Common	Fever, weight loss, lipodystrophy
Uncommon	Chest pain, fever, malaise, asthenia
Rare	Walking disturbances
Investigations
Common	Elevated blood amylase levels, decreased levels of free and total thyroxine
Uncommon	Elevated blood glucose, elevated magnesium levels, elevated alkaline phosphatase

Description of individual adverse reactions

Metabolic parameters

During antiretroviral therapy, body weight, as well as blood lipid and glucose levels, may increase.

In HIV-infected patients with severe immune deficiency, inflammatory reactions to asymptomatic or residual opportunistic microorganisms may occur at the initiation of combination antiretroviral therapy (cART). Autoimmune disorders (e.g., Graves' disease) have also been reported; however, the onset of such adverse reactions may be variable, and they may manifest many months after initiation of treatment.

Pancreatitis, including fatal cases, has been reported in patients receiving ritonavir, including in patients who developed hypertriglyceridemia. In patients with advanced HIV disease, the risk of elevated triglyceride concentrations and pancreatitis may be increased.

Cases of osteonecrosis have been reported, particularly in patients with generally recognized risk factors, at late stages of HIV disease, or with long-term combination antiretroviral therapy. The frequency of such events is unknown.

Combination antiretroviral therapy in HIV-infected patients is associated with redistribution of subcutaneous fat (lipodystrophy), including loss of peripheral and subcutaneous fat in the face, increased intra-abdominal and visceral fat, breast enlargement, and accumulation of fat in the upper back and neck region ("buffalo hump").

Combination antiretroviral therapy is associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging.

30 tablets in a bottle. 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Emcure Pharmaceuticals Ltd.

Manufacturer's address and location of business operation.

Plot No. P-1 and P-2, ITBT Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.