Norvir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORTHERN® (NORVIR®)

Composition:

Active substance: 1 tablet contains 100 mg of ritonavir;

Excipients: copovidone, sorbitan laurate, colloidal anhydrous silicon dioxide, sodium stearyl fumarate, anhydrous calcium hydrogen phosphate, hypromellose, titanium dioxide (E 171), macrogol, hydroxypropyl cellulose, talc, polysorbate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or practically white oval film-coated tablets, embossed with "NK" on one side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Protease inhibitors. ATC code J05AE03.

Pharmacological properties.

Pharmacodynamics.

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 concomitantly administered protease inhibitor, as well as the effect of the concomitant protease inhibitor on ritonavir metabolism. Maximal inhibition of the metabolism of the concomitantly administered protease inhibitor is generally achieved with ritonavir doses ranging from 100 mg once daily to 200 mg twice daily, and depends on the specific concomitant protease inhibitor.

Ritonavir dosed as an antiretroviral agent.

Ritonavir is a peptidomimetic inhibitor of HIV-1 and HIV-2 aspartyl protease for oral administration. Inhibition of HIV protease renders this enzyme unable to process the gag-pol polyprotein precursor, resulting in the formation of morphologically immature HIV particles that are unable to initiate new cycles of infection. 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. Overall, as resistance-associated mutations accumulate, susceptibility to other PIs may decrease due to cross-resistance. For specific information regarding protease mutations associated with reduced response to these agents, refer to the Summary of Product Characteristics for other protease inhibitors or to official data included in updated medical prescribing information.

Pharmacokinetics.

Absorption.

Ritonavir is not available in a parenteral formulation; therefore, the extent of absorption and absolute bioavailability of this formulation have not been studied. The pharmacokinetics of ritonavir after multiple dosing have been investigated in HIV-positive adult volunteers under non-fasting conditions. Following multiple doses, ritonavir accumulation was slightly less than predicted based on single-dose data, due to time- and dose-dependent increases in apparent clearance (Cl/F). Ritonavir concentrations declined over time, possibly due to enzyme induction, although they likely stabilized by the end of the second week. Time to reach 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 the dose range.

Pharmacokinetic parameters observed with different dosing regimens of ritonavir as monotherapy are presented in the table below.

1 Values are expressed as geometric mean values. Note: Ritonavir was administered after food for all the regimens listed.

Effect of food on oral absorption.

Food reduces the bioavailability of Norvir® tablets to some extent. Administration of a single 100 mg dose of ritonavir tablets with a moderate-fat meal (857 kcal, 31% of calories from fat) or a high-fat meal (907 kcal, 52% of calories from fat) results in a mean reduction of ritonavir AUC and Cmax by 20–23%.

Distribution.

The apparent volume of distribution (VB/F) of ritonavir is approximately 20–40 L following a single 600 mg dose. The extent of binding of ritonavir 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.

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 predominantly metabolized via oxidation. Four metabolites of ritonavir have been identified in humans. The major metabolite is the isopropylthiazole oxidative 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 AUC of the parent drug.

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 (see section 4.5).

Elimination.

Studies with radiolabeled ritonavir have shown that elimination of ritonavir in humans occurs predominantly via the hepatobiliary system; approximately 86% of the radioactive label 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. These findings are consistent with observations made in animal studies.

Special patient groups.

Clinically significant differences in AUC and Cmax between men and women were not observed. Pharmacokinetic parameters of ritonavir were not statistically significantly correlated with body weight or lean body mass. Plasma concentrations of ritonavir in patients aged 50 to 70 years receiving a 100 mg dose in combination with lopinavir or higher doses in the absence of other protease inhibitors are similar to those observed in younger patients.

Patients with hepatic impairment.

Following multiple doses of ritonavir in healthy volunteers (500 mg twice daily) and in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B, 400 mg twice daily), ritonavir exposure, after dose normalization, did not differ significantly between these two groups.

Patients with renal impairment.

The pharmacokinetics of ritonavir have not been studied in patients with renal impairment. However, since renal clearance of ritonavir is minimal, changes in total clearance in patients with renal impairment are not expected.

Paediatric population.

Steady-state pharmacokinetics of ritonavir were evaluated in HIV-infected patients aged 2 years and older receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Ritonavir concentrations achieved in children receiving doses of 350 to 400 mg/m² twice daily were similar to those achieved in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Regardless of dose, oral clearance of ritonavir (CL/F/m²) in children aged 2 years and older was approximately 1.5 to 1.7 times faster than in adults.

Steady-state pharmacokinetics of ritonavir were also evaluated in HIV-infected patients under 2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations observed in children in this study were highly variable and somewhat lower than those achieved in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Regardless of dose, oral clearance of ritonavir (CL/F/m²) decreased with age, with mean values of 9.0 L/h/m² in children under 3 months, 7.8 L/h/m² in children aged 3 to 6 months, and 4.4 L/h/m² in children aged 6 to 24 months.

Clinical characteristics.

Indications.

In combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children aged 2 years and older).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

When ritonavir is used as a pharmacokinetic booster of another protease inhibitor, contraindications to the use of this protease inhibitor specified in the instructions for medical use must be taken into account.

Ritonavir should not be used in patients with decompensated liver disease either as a pharmacokinetic booster or as an antiretroviral agent.

In vitro and in vivo studies have shown that ritonavir is a potent inhibitor of biotransformation mediated by CYP3A and CYP2D6 isoenzymes. Unless otherwise specified, the following drugs are contraindicated for concomitant use with ritonavir. The contraindication is based on the potential ability of ritonavir to inhibit the metabolism of drugs administered together with it, thereby enhancing their effect and increasing the risk of clinically significant adverse effects.

The enzyme-modifying effect of ritonavir may be dose-dependent. For some drugs, contraindications may be more significant when ritonavir is used as an antiretroviral agent than when it is used as a pharmacokinetic booster (e.g., rifabutin and voriconazole).

Increase or decrease in levels of concomitant medicinal products.

Alpha1-adrenoreceptor antagonists.

Alfuzosin. Increased plasma concentration of alfuzosin may cause severe arterial hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Analgesics.

Pethidine, propoxyphene. Increased plasma concentration of norpethidine and propoxyphene. Consequently, increased risk of developing serious respiratory depression or hematological disorders or other serious adverse effects of these drugs.

Anti-anginal agents.

Ranolazine. Increases ranolazine plasma concentration, which may lead to serious and/or life-threatening reactions (see section "Interaction with other medicinal products and other forms of interaction").

Antiarrhythmic agents.

Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine. Increased plasma concentration of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine. As a result, increased risk of arrhythmia or other serious adverse effects of these drugs.

Antibiotics.

Fusidic acid. Increased plasma concentration of fusidic acid and ritonavir.

Anticancer agents.

Apalutamide. Apalutamide is a moderate to strong CYP3A4 inducer and may lead to decreased exposure of lopinavir/ritonavir and potential loss of virological response. In addition, increased plasma concentration of apalutamide may lead to serious adverse events, including seizures.

Neratinib. Increased plasma concentration of neratinib may increase the occurrence of serious and/or life-threatening reactions, including hepatotoxicity (see section "Interaction with other medicinal products and other forms of interaction").

Venetoclax. Increases plasma concentration of venetoclax. Increased risk of tumor lysis syndrome at initiation and during the dose escalation phase (see section "Interaction with other medicinal products and other forms of interaction").

Antifungal agents.

Voriconazole. Concomitant use of ritonavir (400 mg twice daily or more) and voriconazole is contraindicated due to decreased plasma concentration of voriconazole and possible lack of effect (see section "Interaction with other medicinal products and other forms of interaction").

Antihistamines.

Astemizole, terfenadine. Increased plasma concentration of astemizole and terfenadine. As a result, increased risk of developing serious arrhythmia associated with the use of these drugs.

Antigout agents.

Colchicine. Possible development of serious and/or life-threatening reactions in patients with impaired renal and/or hepatic function (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

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 concentration of rifabutin and risk of adverse reactions, including uveitis. Recommendations for the use of ritonavir as a pharmacokinetic booster in combination with rifabutin are given in the section "Interaction with other medicinal products and other forms of interaction".

Antipsychotic agents/neuroleptics

Lurasidone. Increases plasma concentration of lurasidone, which may lead to serious and/or life-threatening reactions (see section "Interaction with other medicinal products and other forms of interaction").

Clozapine, blonanserin, pimozide. Increased plasma concentration of clozapine, blonanserin, and pimozide. As a result, increased risk of serious hematological disorders or other serious adverse events caused by these substances.

Quetiapine. Increased plasma concentration of quetiapine, which may lead to coma (see section "Interaction with other medicinal products and other forms of interaction").

Ergot alkaloids.

Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Increased plasma concentration of ergot derivatives, causing acute ergot toxicity, including vascular spasm and ischemia.

Agents for gastrointestinal (GI) motility.

Cisapride. Increased plasma concentration of cisapride. As a result, increased risk of developing serious arrhythmias caused by this substance.

Lipid-lowering agents.

HMG-CoA reductase inhibitors.

Lovastatin, simvastatin. Increased plasma concentration of lovastatin and simvastatin. As a result, increased risk of myopathy, including rhabdomyolysis.

Inhibitor of microsomal triglyceride transfer protein.

Lomitapide. Increases plasma concentration of lomitapide (see section "Interaction with other medicinal products and other forms of interaction").

Long-acting beta-adrenergic agonists.

Salmetrol. May lead to potential increase in cardiovascular adverse reactions associated with salmeterol. Therefore, concomitant use is not recommended.

Phosphodiesterase 5 (PDE5) inhibitor

Sildenafil. Contraindicated only when used for the treatment of pulmonary arterial hypertension (PAH). Increased plasma concentration of sildenafil, consequently, increased risk of adverse reactions from sildenafil (including arterial hypotension and vasovagal syncope). Information on concomitant use with sildenafil in patients with erectile dysfunction is provided in the section "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".

Avanafil, vardenafil. Increased plasma concentration of avanafil and vardenafil (see section "Interaction with other medicinal products and other forms of interaction").

Sedatives/hypnotics.

Clorazepate, diazepam, etizolam, flurazepam, oral midazolam, triazolam. Increased plasma concentration of clorazepate, diazepam, etizolam, flurazepam, oral midazolam, and triazolam. As a result, risk of excessive sedative effect and respiratory depression. Warnings regarding parenteral administration of midazolam are provided in the section "Interaction with other medicinal products and other forms of interaction".

Decrease in ritonavir drug levels.

Herbal products.

St. John's wort. Herbal products containing St. John's wort (Hypericum perforatum) reduce concentrations and clinical effect of ritonavir.

Interaction with other medicinal products and other forms of interaction.

Ritonavir as a pharmacokinetic booster or antiretroviral agent.

Ritonavir has a high degree of similarity to certain cytochrome P450 (CYP) isoenzymes and can inhibit oxidation with the following intensity: CYP3A4 > CYP2D6. The use of ritonavir in combination with drugs that are primarily metabolized by the CYP3A isoenzyme may lead to increased plasma concentration of these drugs, thereby enhancing and prolonging their therapeutic and adverse effects. For certain drugs (e.g., alprazolam), the inhibitory effect of ritonavir on CYP3A4 may diminish over time. Ritonavir also has a high degree of similarity to P-glycoprotein and thus can inhibit this transporter. Inhibition of P-gp activity by ritonavir (with or without other protease inhibitors) may diminish over time (e.g., with digoxin and fexofenadine – see table "Interaction of ritonavir with non-antiretroviral drugs"). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9, and CYP2C19 isoenzymes, thus stimulating biotransformation of certain drugs undergoing these metabolic pathways. This may lead to decreased systemic exposure of these drugs and reduced or shortened therapeutic effect.

Important information on drug interactions with ritonavir used as a pharmacokinetic booster is contained in the instructions for medical use of the protease inhibitor intended for concomitant use.

Medicinal products affecting ritonavir concentration.

Plasma concentration of ritonavir may be reduced by concomitant use of herbal products containing St. John's wort (Hypericum perforatum). This is due to induction of enzymes involved in drug metabolism. Herbal products containing St. John's wort should not be used concurrently 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 concentration may increase, requiring dose adjustments. The inducing effect of St. John's wort persists for at least 2 weeks after discontinuation of herbal treatment.

Plasma concentration of ritonavir may also be affected by drugs such as delavirdine, efavirenz, phenytoin, and rifampicin.

Medicinal products affected by ritonavir use.

Interaction of ritonavir with protease inhibitors, antiretroviral drugs, and other non-antiretroviral drugs is specified in the table below.

Interaction of ritonavir with protease inhibitors.

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

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

Darunavir. Ritonavir increases plasma concentrations of darunavir (AUC ↑14 times) due to inhibition of CYP3A4 isoenzyme. A single dose of darunavir 600 mg should be used concomitantly with ritonavir 100 mg twice daily to ensure its therapeutic effect. Interaction of ritonavir doses higher than 100 mg twice daily with darunavir has not been studied.

Fosamprenavir. Ritonavir increases plasma concentrations of ampranavir (from fosamprenavir) (AUC ↑2.4 times, Cmin ↑11 times) due to inhibition of CYP3A4 isoenzyme. Fosamprenavir should be used with ritonavir to ensure therapeutic effect. Clinical studies have confirmed the safety and efficacy of 700 mg fosamprenavir twice daily together with 100 mg ritonavir twice daily. Interaction of ritonavir at doses higher than 100 mg twice daily with fosamprenavir has not been studied.

Indinavir. Ritonavir increases plasma concentrations of indinavir (AUC indinavir ↑178 %, AUC ritonavir ↑72 %) due to inhibition of CYP3A4 isoenzyme. Appropriate doses for efficacy and safety of this combination have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic boosting is achieved after administration of doses greater than 100 mg twice daily. In case of concomitant administration of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily), caution is required due to risk of exacerbation of nephrolithiasis.

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

Saqunavir. Ritonavir increases plasma concentrations of saquinavir (AUC ↑15 times, Cmin ↑5 times) due to inhibition of CYP3A4 isoenzyme. Saquinavir should be taken only in combination with ritonavir. 100 mg ritonavir twice daily and 1000 mg saquinavir twice daily provide systemic action of saquinavir for more than 24 hours, which can be achieved by using 1200 mg saquinavir alone three times daily.

In a clinical study investigating the interaction of rifampicin (600 mg once daily) with saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily), acute hepatocellular toxicity with transaminase elevation >20 times the upper limit of normal was observed 1-5 days after concomitant administration of the drugs. Due to the risk of severe hepatotoxicity, saquinavir/ritonavir should not be used concomitantly with rifampicin.

Symeprevir. Concomitant use of symeprevir 200 mg once daily with ritonavir 100 mg may lead to increased plasma concentration of symeprevir. Concomitant use of symeprevir and ritonavir is not recommended.

Tipranavir. Ritonavir increases plasma concentrations of tipranavir (AUC tipranavir ↑11 times, Cmin ↑29 times, AUC ritonavir ↓40 %) due to inhibition of CYP3A4 isoenzyme. Tipranavir should be used 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 efficacy of the combination may change.

Interaction of ritonavir with antiretroviral drugs other than protease inhibitors.

Didanosine. Since ritonavir 600 mg twice daily is recommended to be taken with food, and didanosine 200 mg twice daily – on an empty stomach, doses of these drugs should be administered with a 2.5-hour interval. AUC ↓ 64 %. No need to change doses.

Delavirdine. Based on recent data comparison, pharmacokinetics of delavirdine 400 mg three times daily was not affected by ritonavir 600 mg twice daily. In case of concomitant use of the drugs, consideration may be given to reducing the dose of ritonavir (AUC ritonavir ↑50 %, Cmin ritonavir ↑75 %).

Efavirenz. Higher frequency of adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory parameter deviations from normal (e.g., elevated liver enzyme levels) were observed during concomitant use of efavirenz (600 mg once daily) with ritonavir (500 mg twice daily) as an antiretroviral agent. (AUC efavirenz ↑21 %, AUC ritonavir ↑17 %)

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

Nevirapine. Concomitant use of ritonavir 600 mg twice daily with nevirapine 200 mg twice daily does not lead to clinically significant changes in pharmacokinetics of either nevirapine or ritonavir.

Raltegravir. Concomitant use of ritonavir 100 mg twice daily and raltegravir 400 mg single dose leads to insignificant decrease in raltegravir levels (AUC ↓16 %, Cmin ↓1 %).

Zidovudine. Ritonavir 300 mg four times daily may cause glucuronidation of zidovudine 200 mg three times daily, leading to insignificant decrease in zidovudine levels (AUC ↓25 %). No need to change dose.

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

Alpha1-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 may inhibit CYP2D6 and, as a result, increase concentrations of amphetamine and its derivatives. When these drugs are used concomitantly (with ritonavir dose for antiretroviral therapy), careful monitoring of therapeutic and adverse reactions is recommended.

Interaction of ritonavir with non-antiretroviral medicinal products used 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, in case of concomitant use of buprenorphine 16 mg once daily with ritonavir 100 mg twice daily, dose adjustment is not required. If ritonavir is used in combination with other protease inhibitors and buprenorphine, the instructions for medical use of the concomitantly administered protease inhibitor should be reviewed for special dosing.

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

Fentanyl. Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of fentanyl. When fentanyl and ritonavir are used concomitantly, careful monitoring of therapeutic and adverse reactions (including respiratory depression) is recommended.

Methadone. In case of concomitant use of methadone 5 mg single dose and ritonavir 500 mg twice daily (as a pharmacokinetic booster or antiretroviral agent), due to induction of glucuronidation, consideration may be given to increasing the dose of methadone. AUC ↓36 %, Cmax ↓38 %. Considering the patient's clinical response to methadone treatment, dose adjustment should also be considered.

Morphine. In case of concomitant use of morphine and ritonavir (as a pharmacokinetic booster 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 concentrations of ranolazine are expected. Concomitant administration of ritonavir with ranolazine is contraindicated.

Antiarrhythmic agents.

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

Digoxin. This interaction is possible due to P-glycoprotein-mediated efflux of digoxin caused by ritonavir dosed as a pharmacokinetic booster or antiretroviral agent. Increased digoxin concentrations (AUC ↑86%) observed in patients receiving ritonavir may decrease over time due to induction.

Antiasthmatic agents.

Theophylline. Increased dose of theophylline (3 mg/kg three times daily) may be necessary in case of concomitant use with ritonavir 500 mg twice daily due to induction of CYP1A2 (AUC ↓43 %, Cmax ↓32 %).

Anticancer agents and kinase inhibitors.

Dasatinib, nilotinib, vincristine, vinblastine. In case of concomitant use with ritonavir, serum concentrations of these drugs may be increased, leading to increased frequency of adverse reactions.

Afatinib. Serum concentrations may increase due to inhibition of BCRP (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) - AUC ↑48 %, Cmax ↑39 %; 40 mg afatinib single dose and 200 mg ritonavir twice daily (concomitant use) - AUC ↑19 %, Cmax ↑4 %; 40 mg afatinib single dose and 200 mg ritonavir twice daily (6 hours after) - AUC ↑11 %, Cmax ↑5 %. Caution should be exercised when prescribing afatinib in combination with ritonavir. Possible adverse reactions to afatinib should be monitored.

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

Apalutamide. Apalutamide is a moderate to strong CYP3A4 inducer and may lead to decreased exposure of ritonavir and potential loss of virological response. Serum concentration of apalutamide may increase due to inhibition of CYP3A by ritonavir, which may cause serious adverse events, including seizures. Concomitant use of ritonavir and apalutamide is not recommended.

Ceritinib. Serum concentrations may increase due to inhibition of CYP3A and P-glycoprotein by ritonavir. Caution should be exercised when prescribing ceritinib in combination with ritonavir. Possible adverse reactions to ceritinib should be monitored.

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

Encorafenib and ivosidenib. Serum concentration 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.

Fostamatinib. Concomitant use of fostamatinib with ritonavir may increase exposure of R406 metabolite of fostamatinib, leading to dose-dependent adverse reactions such as hepatotoxicity and neutropenia, hypertension or diarrhea. In case of such reactions, recommendations for dose reduction are provided in the instructions for medical use of fostamatinib.

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

Venetoclax. Concomitant administration of venetoclax and ritonavir may increase the risk of tumor lysis syndrome at initiation and during the dose escalation phase. For patients who have completed the dose escalation phase and are on maintenance daily dose of venetoclax, the dose of venetoclax should be reduced by at least 75% when used with strong CYP3A inhibitors (see instructions for medical use of venetoclax).

Anticoagulants.

Warfarin, S-Warfarin, R-Warfarin. When warfarin 5 mg single dose is used with ritonavir 400 mg twice daily, induction of CYP1A2 and CYP2C9 leads to decreased concentrations of S-Warfarin (AUC ↑9%, Cmax ↓9%), while having little effect on pharmacokinetics of R-Warfarin (AUC ↓33%). Decreased R-Warfarin levels lead to reduced anticoagulation; therefore, in case of concomitant use with ritonavir (dosed as antiretroviral agent or pharmacokinetic booster), anticoagulation parameters should be monitored.

Dabigatran etexilate, edoxaban. Serum concentration may increase due to inhibition of P-glycoprotein by ritonavir. When ritonavir is used concomitantly with direct oral anticoagulants (DOACs) transported by P-glycoprotein but not metabolized by CYP3A4, including dabigatran etexilate and edoxaban, consideration should be given to clinical monitoring and/or dose reduction of DOAC.

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. Thus, use of ritonavir 600 mg twice daily is not recommended in patients receiving rivaroxaban 10 mg single dose.

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 booster or antiretroviral agent inhibits CYP3A4 and, as a result, decreases plasma concentration of carbamazepine. When carbamazepine and ritonavir are used concomitantly, careful monitoring of therapeutic and adverse reactions is recommended.

Divalproex, lamotrigine, phenytoin. Ritonavir as a pharmacokinetic booster or antiretroviral agent causes oxidation by CYP2C9 isoenzyme and glucuronidation, and, as a result, increases plasma concentrations of anticonvulsants. When these drugs are used concomitantly with ritonavir, careful monitoring of anticonvulsant serum concentration and therapeutic effect is recommended. Phenytoin may decrease ritonavir levels in serum.

Antidepressants.

Amtriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline. Ritonavir as an antiretroviral agent may inhibit CYP2D6 and, as a result, may increase plasma concentrations of amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, or sertraline. In case of concomitant use of these drugs with ritonavir at doses intended for antiretroviral therapy, careful monitoring of therapeutic and adverse reactions is recommended.

Desipramine. AUC and Cmax of 2-hydroxy metabolite decrease by 15% and 67%, respectively. In case of concomitant use of desipramine 100 mg single dose and ritonavir 500 mg twice daily, consideration should be given to reducing the dose of desipramine.

Trazodone. Increased frequency of adverse reactions associated with trazodone 50 mg single dose is observed when used concomitantly with ritonavir 200 mg twice daily used as a pharmacokinetic booster or antiretroviral agent (AUC ↑2.4 times, Cmax ↑34%). This combination should be used with caution. Trazodone therapy should be initiated with the lowest dose. Clinical response and tolerability of the combination should be monitored.

Antigout agents.

Colchicine. Increased concentration of colchicine is expected when used concomitantly with ritonavir. Life-threatening drug interactions and drug interactions with fatal outcomes have been reported in patients with impaired renal and/or hepatic function who received colchicine and ritonavir (inhibition of CYP3A4 and P-glycoprotein).

Antihistamines.

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

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

Loratadine. Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of loratadine. When loratadine and ritonavir are used concomitantly, careful monitoring of therapeutic and adverse reactions is recommended.

Antibacterial agents.

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

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

Due to significant increase in AUC of rifabutin, its concomitant use with ritonavir as an antiretroviral agent is contraindicated. Reducing the dose of rifabutin to 150 mg three times daily may be indicated for certain protease inhibitors when used concomitantly with ritonavir as a pharmacokinetic booster.

Rifampicin. Although rifampicin may cause metabolism of ritonavir, some data suggest that concomitant use of ritonavir at high doses (600 mg twice daily) with rifampicin additional stimulatory effect of ritonavir is insignificant or may have clinically insignificant effect on ritonavir concentrations during treatment with high doses. The effect of ritonavir on rifampicin is unknown.

Voriconazole. Concomitant use of ritonavir 400 or 100 mg twice daily as an antiretroviral agent with voriconazole 200 mg twice daily is contraindicated due to decreased concentration of voriconazole (AUC ↓82% or 39%, Cmax ↓66% or 24%, respectively). Concomitant use of voriconazole with ritonavir as a pharmacokinetic booster should be avoided until benefit/risk assessment for the patient justifies the use of voriconazole.

Atovaquone. Ritonavir as a pharmacokinetic booster or antiretroviral agent causes glucuronidation and, as a result, decreases plasma concentrations of atovaquone. When atovaquone is used concomitantly with ritonavir, serum levels of both drugs and their therapeutic effects should be carefully monitored.

Bedaquiline. Drug interaction with ritonavir alone has not been studied. In a study of interaction of single dose of bedaquiline and multiple doses of lopinavir/ritonavir, AUC of bedaquiline increased by 22%. This increase is likely related to ritonavir, and more pronounced effect may be observed during prolonged concomitant use. Due to the risk of bedaquiline-related adverse events, combination of bedaquiline and ritonavir should be avoided. If benefit outweighs risk, extreme caution should be exercised when using bedaquiline with ritonavir. More frequent monitoring of ECG and transaminase levels is recommended.

Clarithromycin, 14-hydroxy metabolite of clarithromycin. Due to the large therapeutic window of clarithromycin, there is no need to reduce dose in patients with normal renal function. Concomitant use of clarithromycin at doses higher than 1 g with ritonavir 200 mg three times daily dosed as antiretroviral agent or pharmacokinetic booster should not be used (clarithromycin AUC ↑77%, Cmax ↑31%, 14-hydroxy metabolite of clarithromycin AUC ↓100%, Cmax ↓99%). In case of renal impairment in patients, consideration should be given to reducing the dose of clarithromycin: for patients with creatinine clearance of 30-60 ml/min, dose should be reduced by 50%; for patients with creatinine clearance below 30 ml/min, dose should be reduced by 75%.

Delamanid. Drug interaction with ritonavir alone has not been studied. In a drug interaction study with delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days in healthy volunteers, concentration of 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 booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of erythromycin and itraconazole. When ritonavir is used concomitantly with erythromycin or itraconazole, therapeutic and adverse reactions of the drugs should be carefully monitored.

Ketoconazole. Ritonavir 500 mg twice daily inhibits CYP3A-mediated metabolism of ketoconazole 200 mg daily. AUC ↑3.4 times, Cmax ↑55%. Due to high frequency of gastrointestinal and liver adverse reactions, consideration should be given to reducing the dose of ketoconazole when used concomitantly with ritonavir dosed as antiretroviral agent or pharmacokinetic booster.

Sulfamethoxazole/trimethoprim. Dose of sulfamethoxazole/trimethoprim (800 mg/160 mg single dose) should not be changed during concomitant use with ritonavir (500 mg twice daily). AUC ↓20%/↑20%.

Antipsychotic/neuroleptic agents.

Clozapine, pimozide. Concomitant use 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 may inhibit CYP2D6 and, as a result, increases plasma concentrations of haloperidol, risperidone, and thioridazine. When ritonavir is used concomitantly with these drugs, therapeutic and adverse reactions of the drugs should be carefully monitored.

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

Quetiapine. Caution should be exercised when using ritonavir concomitantly with quetiapine. It is expected that due to inhibition of CYP3A isoenzyme by ritonavir, quetiapine concentration will increase, which may lead to toxicity associated with quetiapine use.

Long-acting beta2-agonist.

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

Calcium channel blockers.

Amlodipine, diltiazem, nifedipine. Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of calcium channel blockers. When ritonavir is used concomitantly with these drugs, therapeutic and adverse reactions of the drugs should be carefully monitored.

Endothelin receptor antagonists.

• Bosentan.* Concomitant use of bosentan and ritonavir may increase equilibrium maximum concentrations (Cmax) of bosentan and increase 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 use of ritonavir with ergot derivatives may lead to increased plasma concentrations of the latter, therefore such use is contraindicated.

Agents for gastrointestinal (GI) motility.

• Cisapride.* Concomitant use of ritonavir and cisapride may lead to increased plasma concentrations of the latter, therefore such use is contraindicated.

Direct-acting antiviral agents (HCV).

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

Protease inhibitor (HCV).

• Simeprevir.* Ritonavir increases plasma concentrations of simeprevir due to inhibition of CYP3A4 (AUC ↑7.2 times, Cmax ↑4.7 times). Concomitant use of ritonavir 100 mg twice daily and simeprevir 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 these drugs are combined with ritonavir as a pharmacokinetic booster or antiretroviral agent. Since increased concentrations of lovastatin and simvastatin may provoke development of myopathy, including rhabdomyolysis, combination of these drugs with ritonavir is contraindicated. Atorvastatin is less dependent on CYP3A. While elimination of rosuvastatin does not depend on CYP3A, increased duration of action of rosuvastatin has been noted when used concomitantly with ritonavir.

The mechanism of this interaction is not clear, but may lead to inhibition of transporter. If atorvastatin and rosuvastatin are used concomitantly with ritonavir as a pharmacokinetic booster or antiretroviral agent, doses of atorvastatin and rosuvastatin should be as low as possible. Metabolism of pravastatin and fluvastatin 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 the effect of lomitapide up to 27 times. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated.

Hormonal contraceptives.

• Ethinylestradiol.* When ritonavir 500 mg twice daily is used concomitantly with ethinylestradiol 50 mcg single dose, concentrations of ethinylestradiol may decrease (AUC ↓40%, Cmax ↓32%), consideration should be given to using barrier or other methods of non-hormonal contraception concomitantly with ritonavir (as a pharmacokinetic booster or antiretroviral agent). Ritonavir may change the profile of uterine bleeding and reduce the effectiveness of contraceptives containing estradiol.

Immunosuppressants.

• Cyclosporine, tacrolimus, everolimus.* Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of cyclosporine, tacrolimus, and everolimus. When ritonavir is used concomitantly with these drugs, therapeutic effect and adverse reactions of the drugs should be carefully monitored.

Phosphodiesterase inhibitors.

• Avanafil.* Use of avanafil 50 mg single dose with ritonavir 600 mg twice daily is contraindicated. AUC ↑13 times, Cmax ↑2.4 times.

• Sildenafil.* Combination of sildenafil (for treatment of erectile dysfunction) 100 mg single dose with ritonavir 500 mg twice daily as a pharmacokinetic booster or antiretroviral agent should be used with caution, and doses of sildenafil should not exceed 25 mg within 48 hours. AUC ↑11 times, Cmax ↑4 times. Concomitant use of sildenafil and ritonavir is contraindicated in patients with pulmonary arterial hypertension.

• Tadalafil.* Combination of tadalafil (for treatment of erectile dysfunction) 20 mg single dose with ritonavir 200 mg twice daily as a pharmacokinetic booster or antiretroviral agent should be used 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 instructions for medical use of tadalafil.

• Vardenafil.* Use of vardenafil 5 mg single dose with ritonavir 600 mg twice daily is contraindicated. AUC ↑49 times, Cmax ↑13 times.

Gonadotropin-releasing hormone receptor antagonists.

• Elagolix.* Concomitant use of elagolix with ritonavir may increase exposure of elagolix due to inhibition of OATP, CYP3A, and P-gp. Serious adverse reactions with elagolix use are known, such as suicidal ideation and increased liver transaminases. In addition, elagolix is a weak/moderate inducer of CYP3A, which may cause decreased exposure of ritonavir. Refer to the instructions for medical use of elagolix for dosing when used with strong CYP3A4 inhibitors.

Kinase inhibitors (also see Antineoplastic agents above).

• Fostamatinib.* Concomitant use of fostamatinib with ritonavir may increase exposure of R406 metabolite of fostamatinib, leading to dose-dependent adverse reactions such as hepatotoxicity and neutropenia, hypertension or diarrhea. In case of such reactions, recommendations for dose reduction are provided in the instructions for medical use of fostamatinib.

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 times, Cmax 2.04 times, Cmin 2.36 times. Exposure to paritaprevir may increase when used concomitantly with ritonavir. Concomitant use is not recommended.

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

Sedatives/hypnotics.

• Clorazepate, diazepam, estazolam, flurazepam, oral and parenteral midazolam.* Ritonavir in combination with clorazepate, diazepam, estazolam, and flurazepam may increase plasma concentrations of the latter, and therefore such combination is contraindicated.

Midazolam is extensively metabolized by CYP3A4 enzyme. Concomitant use with ritonavir may lead to significant increase in concentration of this benzodiazepine. Interaction of Norvir® with benzodiazepines when used concomitantly has not been studied. Based on data for other CYP3A4 inhibitors, plasma concentrations are expected to be significantly higher when oral midazolam is used. Therefore, Norvir® should not be combined with oral midazolam, and caution is required when using Norvir® concomitantly with parenteral midazolam.

Based on data obtained after concomitant use of parenteral midazolam with other protease inhibitors, plasma concentration may increase by 3-4 times. If Norvir® is used concomitantly with parenteral midazolam, such treatment should be carried out in an intensive care unit or similar facility where careful clinical monitoring and appropriate medical care are ensured in case of respiratory depression and/or prolonged sedation. Consideration should be given to adjusting the dose of midazolam, especially if more than one dose of the drug is administered.

• Triazolam.* Concomitant use of ritonavir 200 mg four doses and triazolam 0.125 mg single dose may lead to increased plasma concentrations of the latter (AUC ↑>20 times, Cmax ↑87%), therefore such use is contraindicated.

• Pethidine (metabolite – norpethidine).* Due to risk of increased metabolite concentration (AUC norpethidine ↑47%, Cmax ↑87%), which has both analgesic and CNS-stimulating activity, concomitant use of pethidine 50 mg orally single dose and ritonavir 500 mg twice daily is contraindicated. Increased concentrations of norpethidine increase the risk of adverse reactions from the central nervous system (e.g., seizures).

• Alprazolam.* Ritonavir inhibits metabolism of alprazolam (AUC ↑2.5 times). Inhibitory effect of ritonavir 500 mg twice daily disappears after its use for 10 days (AUC ↓12%, Cmax ↓16%). Caution should be exercised in the first days of concomitant use of alprazolam with ritonavir as a pharmacokinetic booster or antiretroviral agent, before alprazolam metabolism begins.

• Buspirone.* Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of buspirone. When ritonavir is used concomitantly with buspirone, therapeutic effects and adverse reactions of the drugs should be carefully monitored.

Hypnotics.

• Zolpidem.* Combination of zolpidem 5 mg and ritonavir 200 mg 43 doses should be used with caution and patient should be carefully monitored for excessive sedative effect (AUC ↑28%, Cmax ↑22%).

Smoking cessation.

• Bupropion.* Bupropion is mostly metabolized by CYP2B6. Concomitant use of bupropion 150 mg and ritonavir 100 mg or 600 mg twice daily reduces levels of the latter (AUC ↓22% or 66% respectively, Cmax ↓21% or 62% respectively). This effect is believed to be caused by bupropion metabolism. However, since ritonavir has demonstrated inhibition of CYP2B6 in vitro, recommended dose of bupropion should not be exceeded. No significant interaction with bupropion after short-term (as opposed to long-term) use of low doses of ritonavir (200 mg twice daily for two days) was observed. As a result of this observation, it can be assumed that decrease in bupropion concentrations begins several days after initiation of ritonavir administration.

Steroids.

• Fluticasone propionate (inhaled, intranasal or by injection), budesonide, triamcinolone.* Systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression (in studies, plasma cortisol levels decreased by 86%), have been observed in patients receiving ritonavir 100 mg twice daily and inhaled or intranasal fluticasone propionate 200 mcg once daily. AUC ↑350 times, Cmax ↑25 times); similar effects may also occur with other corticosteroids metabolized by CYP3A enzyme, e.g., budesonide. Therefore, concomitant use of glucocorticoid and ritonavir as an antiretroviral agent or pharmacokinetic booster is not recommended until potential benefit of treatment outweighs risk of systemic effects of corticosteroids. Consideration should be given to reducing the dose of glucocorticoid, while ensuring careful monitoring of local and systemic effects of glucocorticoid or switching to a glucocorticoid that is not a substrate for CYP3A4 (e.g., beclomethasone). In addition, in case of discontinuation of glucocorticoids for a long period, gradual dose reduction is required.

• Dexamethasone.* Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of dexamethasone. When ritonavir is used concomitantly with dexamethasone, therapeutic effects and adverse reactions of the drugs should be carefully monitored.

• Prednisolone.* When ritonavir 200 mg twice daily is used concomitantly with prednisolone 20 mg, therapeutic effects and adverse reactions of the drugs should be carefully monitored. AUC of metabolite and prednisolone increases by 37% and 28% after 4 and 14 days of ritonavir use, respectively.

Hormone replacement therapy of the thyroid gland.

• Levothyroxine.* Interaction between ritonavir-containing medicinal products and levothyroxine has been reported. Patients receiving levothyroxine should monitor thyroid-stimulating hormone (TSH) levels for at least one month after initiation and/or discontinuation of ritonavir treatment.

When ritonavir is used concomitantly with other medicinal products, the instructions for medical use of the latter should be consulted.

During combination therapy with ritonavir and disopyramide, mexiletine or nefazodone, adverse reactions from the cardiovascular system and CNS have been reported. Drug interaction cannot be excluded.

Since ritonavir binds well to proteins, possible increased therapeutic and toxic effects due to displacement of concomitant drugs from protein binding should be considered.

Ritonavir dosed as a pharmacokinetic booster

Important information on drug interactions with ritonavir used as a pharmacokinetic booster is contained in the instructions for medical use of the protease inhibitor used concomitantly.

Proton pump inhibitors and H2-receptor antagonists. Proton pump inhibitors and H2-receptor antagonists (e.g., omeprazole or ranitidine) may reduce concentration of concomitant protease inhibitors. For detailed information on the effect of concomitant use of acid-reducing agents, refer to the instructions for medical use of the protease inhibitor. Based on a drug interaction study using ritonavir-boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concomitant use of omeprazole or ranitidine slightly changed the effectiveness of ritonavir used as a pharmacokinetic booster, despite minor changes in drug action (approximately 6-18%).

Special precautions for use.

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

When ritonavir is used as a pharmacokinetic enhancer in combination with another protease inhibitor, all details regarding special precautions and warnings for the use of that protease inhibitor should be taken into account; therefore, the prescribing information for that specific drug should be carefully reviewed.

Ritonavir dosed as an antiretroviral agent or pharmacokinetic booster

Patients with chronic diarrhoea or malabsorption. If diarrhoea develops, additional evaluation is recommended. The relatively high incidence of diarrhoea during ritonavir treatment may affect absorption and the efficacy (due to poor adherence to the treatment regimen) of ritonavir or concomitant medications. Uncontrolled vomiting and/or severe diarrhoea induced by ritonavir may also affect renal function. In patients with renal impairment, regular monitoring of renal function is advisable.

Haemophilia. Increased bleeding, including spontaneous skin bruising and haemarthrosis, has been reported in patients with haemophilia A and B receiving protease inhibitors. Some patients required additional factor VIII. In more than half of the reported cases, protease inhibitor therapy was either continued or restarted after interruption. A causal relationship has been established, although the mechanism of action remains unclear. Therefore, patients with haemophilia should be warned about the possibility of increased bleeding.

Body weight and metabolic parameters. During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur. Such changes may be partially related to disease control and lifestyle. Regarding lipid levels, 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 blood lipid and glucose levels should be performed according to established guidelines for HIV infection management. Lipid abnormalities should be managed according to clinical practice.

Diabetes mellitus and hyperglycaemia. Cases of newly diagnosed diabetes mellitus, hyperglycaemia, and exacerbation of pre-existing diabetes mellitus have been reported during treatment with protease inhibitors. In some of these cases, hyperglycaemia was severe and associated with ketoacidosis. A significant proportion of such patients had predisposing conditions requiring medication associated with the development of diabetes or hyperglycaemia. 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. Data on its underlying mechanism are incomplete. Currently, visceral lipomatosis is thought to be associated with protease inhibitors, and lipoatrophy with 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. Fasting serum lipid and blood glucose levels should also be monitored. Abnormal lipid parameters require management according to accepted clinical practice.

Pancreatitis. Pancreatitis should be considered in the presence of clinical symptoms (nausea, vomiting, abdominal pain) or laboratory abnormalities (elevated serum lipase or amylase levels). Patients presenting with these signs or symptoms should be evaluated, and if pancreatitis is diagnosed, Norvir® therapy should be discontinued.

Immune reconstitution syndrome. In HIV-infected patients with advanced immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic microorganisms and severe clinical conditions or worsening of symptoms may occur during combined antiretroviral therapy (cART). Such reactions are usually observed within the first few weeks or months after initiation of 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 during immune reconstitution; however, the timing of adverse reactions may vary and may occur many months after initiation of treatment.

Hepatic disease. Ritonavir should not be used in patients with decompensated liver disease. In patients with chronic hepatitis B or C receiving combined antiretroviral therapy, the risk of severe and potentially life-threatening hepatic adverse reactions is significantly increased. When combined antiretroviral therapy is administered to patients with hepatitis B or C, reference should be made to the respective prescribing information for these medications.

In patients with pre-existing hepatic dysfunction, including active chronic hepatitis, an increased frequency of hepatic function abnormalities may occur during combined antiretroviral therapy. These patients should be closely monitored according to standard practice. If signs of worsening liver disease occur in such patients, consideration should be given to interrupting or discontinuing treatment.

Renal disease. Since renal clearance of ritonavir is negligible, a reduction in total clearance in patients with renal impairment is unlikely.

Cases of renal failure, renal dysfunction, increased creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the clinical use of tenofovir disoproxil fumarate.

Osteonecrosis. Although the aetiology 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 (cART). Patients experiencing joint pain, joint stiffness, or difficulty in movement are advised to consult a physician.

PR interval prolongation. Ritonavir has caused mild asymptomatic PR interval prolongation in several healthy adult volunteers. There have been isolated reports of second- or third-degree atrioventricular block in patients with a history of cardiac disease and pre-existing conduction abnormalities or in patients receiving medications known to prolong the PR interval (e.g., verapamil or atazanavir) when used concomitantly with ritonavir. Ritonavir should be used with caution in such patients.

Interactions with other medicinal products.

Ritonavir as an antiretroviral agent.

When ritonavir is used as an antiretroviral agent, the relevant warnings and precautions should be considered. The use of ritonavir as a pharmacokinetic booster at doses of 100 mg and 200 mg does not require adherence to the same warnings and precautions. When ritonavir is used as a pharmacokinetic booster, full information regarding warnings and precautions for the co-administered protease inhibitor must be taken into account. Therefore, to determine the applicability of the information below, reference should be made to the prescribing information for the specific protease inhibitor.

Phosphodiesterase inhibitors (PDE5). 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 agents is believed to significantly increase their concentrations and may lead to associated 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. The 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 be exercised or dose reduction considered when atorvastatin, which is less dependent on CYP3A metabolism, is used concomitantly with ritonavir. Rosuvastatin elimination 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 hypothetically may involve transporter inhibition. Lower doses of atorvastatin and rosuvastatin should be used when administered concomitantly with ritonavir. The metabolism of pravastatin and fluvastatin does not depend on CYP3A, and therefore no significant interactions with ritonavir are expected. If reductase inhibitor therapy is required, pravastatin or fluvastatin are 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 in 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 initiate digoxin therapy 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 concomitant use of ritonavir at therapeutic or lower doses with contraceptives containing ethinylestradiol 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 outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Trazodone. Ritonavir should be prescribed with particular caution in patients receiving trazodone. Trazodone is a CYP3A4 substrate, and concomitant use with ritonavir is expected to increase trazodone concentrations. In a study of single-dose interactions 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.

Bedaquiline. Potent CYP3A4 isoenzyme inhibitors, such as protease inhibitors, may enhance the effect of bedaquiline, increasing the risk of adverse reactions associated with bedaquiline. Therefore, concomitant use of bedaquiline and ritonavir should be avoided. However, if benefit outweighs risk, concomitant use of bedaquiline and ritonavir may be permitted with caution. More frequent monitoring of electrocardiograms and transaminase levels is recommended.

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

Ritonavir dosed as a pharmacokinetic booster.

The interaction profile of HIV protease inhibitors used in combination with low-dose ritonavir is entirely dependent on the specific protease inhibitor co-administered.

Descriptions of mechanisms and potential mechanisms affecting the interaction profile of protease inhibitors are provided in the prescribing information for the boosted protease inhibitor.

Saquinavir. The ritonavir dose should not exceed 100 mg twice daily. Increasing the ritonavir dose has been shown to increase the frequency of adverse reactions. Concomitant use of saquinavir and ritonavir has been associated with severe adverse effects, primarily diabetic ketoacidosis and hepatic dysfunction, especially in patients with pre-existing liver disease.

Saquinavir/ritonavir should not be co-administered with rifampicin due to the risk of severe hepatotoxicity (manifested by elevated liver transaminase levels) when all three drugs are taken simultaneously.

Tipranavir. Clinical hepatitis and hepatic decompensation, including several fatal cases, have been reported with tipranavir in combination with 200 mg ritonavir. Patients with co-infection, chronic hepatitis B or C require special attention, as their risk of hepatotoxicity is significantly higher.

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

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

Atazanavir. Combined use of atazanavir with ritonavir doses higher than 100 mg once daily has not been clinically evaluated. Increasing the ritonavir dose may alter the safety profile of atazanavir (cardiovascular effects, hyperbilirubinemia) and is therefore undesirable. Only when atazanavir and ritonavir are used concomitantly with efavirenz, may consideration be given to increasing the ritonavir dose to 200 mg once daily. Treatment under this regimen should be conducted under continuous clinical monitoring. For more detailed information, refer to the prescribing information for atazanavir.

Sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Ritonavir has been used in >6100 pregnant women, including <2800 during the first trimester of pregnancy. The available data largely relate to the use of ritonavir in combination therapy and at subtherapeutic, reduced doses as a pharmacokinetic booster for other protease inhibitors. These data indicate no increased incidence of congenital malformations compared to the rate observed in congenital malformation monitoring systems in the general population. Animal studies have demonstrated toxic effects on reproductive function. Norvir® may be used during pregnancy only if the benefit to the mother outweighs the risk to the fetus.

Ritonavir negatively interacts with oral contraceptives. Therefore, an alternative, effective, and safe method of contraception should be selected during treatment.

Limited published data indicate that ritonavir is excreted in breast milk.

There is no information on the effects of ritonavir on infants who are breastfed or on lactation. Due to the possibility of (1) transmission of HIV infection (to HIV-negative children), (2) development of viral resistance (in HIV-positive children), and (3) serious adverse reactions in breastfed infants, HIV-infected women taking Norvir® should not breastfeed their infants.

Fertility.

Data on the effect of ritonavir on human fertility are lacking. Animal studies did not demonstrate any harmful effects of ritonavir on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the ability of ritonavir to affect reaction speed when driving or operating machinery have not been conducted. Since drowsiness and dizziness are known adverse reactions associated with ritonavir use, this should be taken into account when driving or operating machinery.

Method of Administration and Dosage.

Prescription of Norvir® should be performed by a physician experienced in the management of HIV infection.

Norvir®, film-coated tablets, should be taken orally with food.

Norvir®, film-coated tablets, should be swallowed whole, without chewing, breaking, or crushing.

Dosing of Ritonavir as a Pharmacokinetic Enhancer

When ritonavir is used as a pharmacokinetic enhancer in combination with other protease inhibitors, refer to the full prescribing information of the co-administered protease inhibitor.

Concomitant use of ritonavir as a pharmacokinetic enhancer is recommended for the following HIV-1 protease inhibitors at the specified doses.

Adults.

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.

Atazanavir 300 mg once daily with ritonavir 100 mg once daily.

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Lopinavir in combination with ritonavir (lopinavir/ritonavir):
400 mg/100 mg or 800 mg/200 mg.

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily for patients who have previously received antiretroviral therapy.

For treatment-naïve patients, initiate saquinavir at 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, followed by saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. The combination of tipranavir and ritonavir should not be used in treatment-naïve patients.

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily for patients who have previously received antiretroviral therapy.

Darunavir 800 mg once daily with ritonavir 100 mg once daily for treatment-naïve patients.

Children. Ritonavir is recommended for use in children aged 2 years and older. Dosing should be determined according to the prescribing information of the protease inhibitor recommended for co-administration with ritonavir.

Patients with Renal Impairment. Since ritonavir is primarily metabolized in the liver, it may be used cautiously in patients with renal impairment, taking into account the specific protease inhibitor co-administered with ritonavir as a pharmacokinetic enhancer. However, as renal clearance of ritonavir is minimal, a significant reduction in total clearance in patients with renal impairment is unlikely. Before administering ritonavir to patients with renal impairment, the physician should review the dosing information provided in the prescribing information of the protease inhibitor co-administered with ritonavir.

Patients with Hepatic Impairment. Ritonavir should not be used as a pharmacokinetic enhancer in patients with decompensated liver disease. In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child-Pugh Class C) without decompensation, ritonavir as a pharmacokinetic enhancer should be used with particular caution, as increased concentrations of the co-administered protease inhibitor may occur. The specific considerations for using ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment depend on the protease inhibitor being co-administered. Refer to the dosing information in the prescribing information of the protease inhibitor co-administered with ritonavir.

Dosing of Ritonavir as an Antiretroviral Agent

Adults. The recommended oral dose of Norvir®, film-coated tablets, is 600 mg (6 tablets) twice daily (total daily dose – 1200 mg).

Gradual dose escalation at the beginning of treatment may improve tolerability. Treatment should be initiated at a dose of 300 mg (3 tablets) twice daily for 3 days, then gradually increased by 100 mg (1 tablet) twice daily every 2–3 days over a period not exceeding 14 days until reaching 600 mg twice daily. Ritonavir at a dose of 300 mg twice daily should not be administered for longer than 3 days.

Children (aged 2 years and older). The recommended pediatric dose of Norvir® is 350 mg/m² orally twice daily, but not exceeding 600 mg twice daily. Initiate Norvir® at 250 mg/m² and increase by 50 mg/m² twice daily every 2–3 days.

Norvir® is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy in this patient group.

Patients with Renal Impairment. Currently, specific data on the use of the drug in this patient group are lacking; therefore, no specific dosage recommendations are available. Since renal clearance of ritonavir is minimal, a significant reduction in total clearance in patients with renal impairment is unlikely. Due to the high protein binding of ritonavir, significant elimination via hemodialysis or peritoneal dialysis is unlikely.

Patients with Hepatic Impairment. Ritonavir is primarily metabolized and eliminated via the liver. Pharmacokinetic data indicate that dose adjustment is not required in patients with mild to moderate hepatic impairment. Ritonavir is not recommended for use in patients with severe hepatic impairment.

Elderly Patients. Pharmacokinetic data indicate that dosage adjustment is not required for elderly patients.

Children.

Norvir® is recommended for use in children aged 2 years and older. Norvir® is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy in this patient group.

Overdose.

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

Signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnea, and tremor.

There is no specific antidote for ritonavir overdose. Management of overdose should include general supportive measures, including monitoring of vital functions and clinical observation. Due to the solubility of the drug and the possibility of transintestinal elimination, treatment should include gastric lavage and administration of activated charcoal. Since ritonavir is extensively metabolized by the liver and highly protein-bound, dialysis is unlikely to be beneficial for removing significant amounts of the drug.

Adverse Reactions.

Ritonavir, dosed as a pharmacokinetic enhancer.

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer depend on the specific protease inhibitor used concomitantly with ritonavir. Information on adverse reactions of the corresponding protease inhibitor used in combination with ritonavir can be found in the package insert of that protease inhibitor.

Ritonavir, dosed as an antiretroviral agent.

Adverse reactions reported during clinical trials and from post-marketing experience observed in adult patients.

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 disorders (including paresthesia and oral mucosal paresthesia), fatigue/asthenia.

Adverse reactions are listed by organ systems and frequency of occurrence: very common – more than 10%, common – 1-10%, uncommon – 0.1-1%, rare – 0.01-0.1%, very rare – less than 0.01%, frequency not known – frequency cannot be estimated from the available data.

In patients receiving ritonavir alone or in combination with other antiretroviral agents, elevations in liver transaminases five times above the upper limit of normal, clinical signs of hepatitis, and jaundice have been observed.

During antiretroviral therapy, increases in body weight as well as in blood levels of lipids and glucose may occur.

In HIV-infected patients with severe immune deficiency, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur at the initiation of combination antiretroviral therapy (cART). Autoimmune disorders (e.g., Graves' disease) have also been reported; however, the time to onset of such adverse reactions may vary and may appear several months after the start of treatment.

Pancreatitis has been reported in patients receiving ritonavir, including in those who developed hypertriglyceridemia. In some cases, this led to fatal outcomes. In patients with progressive HIV infection, the risk of increased triglyceride concentrations and development of pancreatitis may be elevated.

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

Children

In children aged 2 years and older, the safety profile of Norvir® is similar to that observed in adult patients.

Reporting suspected adverse reactions after drug registration is of great importance. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Keep out of reach of children, at a temperature not exceeding 25°C.

Packaging. 30 or 60 tablets in a plastic bottle, one bottle packed in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Abbvie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.