Ritovir
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RITOVIR (RITOVIR)
Composition:
Active substance: ritonavir;
One tablet contains 100 mg of ritonavir;
Excipients: copovidone, sorbitan laurate, silicon dioxide colloidal anhydrous, calcium hydrogen phosphate, sodium stearyl fumarate, Opadry White 20C58634 (hypromellose (E464), titanium dioxide (E171), polyethylene glycol (E1521), hydroxypropyl cellulose (E463), talc (E553b), silicon dioxide colloidal anhydrous (E551), polysorbate 80 (E433)).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties: film-coated tablets, white or almost white, capsule-shaped, with the inscription “H” on one side and “R9” on the other.
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 co-administered protease inhibitor on ritonavir metabolism. Maximum inhibition of the metabolism of the concomitantly administered protease inhibitor is generally achieved at ritonavir doses ranging from 100 mg once daily to 200 mg twice daily, depending on the specific protease inhibitor used.
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 incapable of initiating new infection cycles. Ritonavir has selective affinity for HIV protease and exhibits low inhibitory activity against human aspartyl proteases.
Resistance
Ritonavir-resistant HIV-1 isolates 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 mutations associated with resistance to ritonavir accumulate, susceptibility to other protease inhibitors 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
An intravenous formulation of ritonavir is not available; 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 administered under non-fasting conditions. With repeated administration, ritonavir accumulation is slightly less than predicted based on single-dose administration, due to time- and dose-dependent increases in apparent oral clearance (Cl/F). Ritonavir concentrations declined over time, possibly due to enzyme induction, but likely stabilized by the end of the second week. Time to peak concentration (Tmax) remained constant with increasing dose and was approximately 4 hours. Mean renal clearance was less than 0.1 L/hr and remained relatively constant across the entire dose range.
Pharmacokinetic parameters observed under various dosing regimens of ritonavir as monotherapy are presented in the table below.
| Ritonavir dosing regimens |
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| Parameter |
100 mg once daily |
100 mg twice daily1 |
200 mg once daily |
200 mg twice daily |
600 mg twice daily |
| Cmax (µg/mL) |
0.84 ± 0.39 |
0.89 |
3.4 ± 1.3 |
4.5 ± 1.3 |
11.2 ± 3.6 |
| Ctrough (µg/mL) |
0.08 ± 0.04 |
0.22 |
0.16 ± 0.10 |
0.6 ± 0.2 |
3.7 ± 2.6 |
| AUC12 or 24 (µg•h/mL) |
6.6 ± 2.4 |
6.2 |
20.0 ± 5.6 |
21.92 ± 6.48 |
77.5 ± 31.5 |
| t½ (hours) |
~5 |
~5 |
~4 |
~8 |
~3–5 |
| Cl/F (L/h) |
17.2 ± 6.6 |
16.1 |
10.8 ± 3.1 |
10.0 ± 3.2 |
8.8 ± 3.2 |
1 Values expressed as geometric mean. Note: Ritonavir was administered with food in all listed regimens.
Effect of food on absorption following oral administration
Food reduces the bioavailability of ritonavir in the tablet formulation. 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) reduces the AUC and Cmax of ritonavir by approximately 20–23%.
Distribution
The apparent volume of distribution (VB/F) of ritonavir is approximately 20–40 L after 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. Studies in animals and in vitro experiments with human liver microsomes have shown that ritonavir is predominantly metabolized via oxidation. In humans, four metabolites of ritonavir have been identified. 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 compound.
Low doses of ritonavir have shown 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 "Interaction with other medicinal products and other forms of interaction").
Elimination
Studies with radiolabeled ritonavir have shown that elimination of ritonavir in humans occurs primarily via the hepatobiliary system; approximately 86% of the radioactive label was recovered in feces, with some of the drug excreted unchanged. These studies have demonstrated 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
After multiple dosing 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.
Patients with renal impairment
The pharmacokinetics of ritonavir have not been studied in patients with renal impairment. However, since renal clearance of ritonavir is negligible, changes in total clearance in patients with renal impairment are not expected.
Children
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 observed 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 1.5–1.7 times higher 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 this study were highly variable and somewhat lower than those in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Regardless of dose, oral clearance of ritonavir (CL/F/m²) decreased with increasing patient 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.
Used 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 enhancer of another protease inhibitor, contraindications to the use of that protease inhibitor specified in its medical instructions must be taken into account.
Ritonavir should not be administered to patients with decompensated liver disease, either as a pharmacokinetic enhancer 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. These contraindications are based on the potential of ritonavir to inhibit the metabolism of co-administered drugs, resulting in enhanced effects and increased risk of clinically significant adverse reactions.
The enzyme-modifying effect of ritonavir may be dose-dependent. For certain drugs, contraindications may be more significant when ritonavir is used as an antiretroviral agent than when used as a pharmacokinetic enhancer (e.g., rifabutin and voriconazole).
Increased or decreased levels of concomitant medicinal products
α1-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, piroxicam, propoxyphene. Increased plasma concentrations of norpethidine, piroxicam, and propoxyphene. Consequently, increased risk of serious respiratory depression or hematological disorders, or other serious adverse effects of these drugs.
Anti-anginal agents
Ranolazine. Increased plasma concentration of ranolazine, which may increase the likelihood of serious and/or life-threatening reactions (see section "Interaction with other medicinal products and other forms of interaction").
Anticancer agents
Neratinib. Increased plasma concentration of neratinib, which may increase the likelihood of serious and/or life-threatening reactions, including hepatotoxicity (see section "Interaction with other medicinal products and other forms of interaction").
Venetoclax. Increased plasma concentration of venetoclax. Increased risk of tumor lysis syndrome at the beginning of dosing and during the dose titration phase (see section "Interaction with other medicinal products and other forms of interaction").
Antiarrhythmic agents
Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine. Increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and quinidine. As a result, increased risk of arrhythmias or other serious adverse effects of these drugs.
Antibiotics
Fusidic acid. Increased 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 concentration of voriconazole and potential loss of efficacy (see section "Interaction with other medicinal products and other forms of interaction").
Antihistamines
Astemizole, terfenadine. Increased plasma concentrations of astemizole and terfenadine. Consequently, increased risk of serious arrhythmias associated with the use of these drugs.
Antigout agents
Colchicine. Risk of developing 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", "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 (see section "Special precautions for use"). Recommendations for 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 interaction".
Antipsychotics/neuroleptics
Lurasidone. Increased 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, pimozide. Increased plasma concentrations of clozapine and pimozide. Consequently, increased risk of serious hematological disorders or other serious adverse effects caused by these substances.
Quetiapine. Increased plasma concentration of quetiapine, which may lead to coma. Concomitant use with quetiapine is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").
Ergot alkaloids
Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Increased plasma concentrations of ergot derivatives, leading to acute ergot toxicity, including vasospasm and ischemia.
Agents for treatment of gastrointestinal (GI) motility disorders
Cisapride. Increased plasma concentration of cisapride. Consequently, increased risk of serious arrhythmias caused by this substance.
Lipid-lowering agents
HMG-CoA reductase inhibitors: lovastatin, simvastatin. Increased plasma concentrations of lovastatin and simvastatin. Consequently, increased risk of myopathy, including rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").
Inhibitor of microsomal triglyceride transfer protein
Lomitapide. Increased plasma concentration of lomitapide. Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure to lomitapide up to 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated.
Phosphodiesterase-5 (PDE5) inhibitor
Sildenafil. Contraindicated only when used for the treatment of pulmonary arterial hypertension. Increased plasma concentration of sildenafil, thereby increasing the risk of adverse reactions associated with sildenafil use (including arterial hypotension and vasovagal syncope). Information on concomitant use with sildenafil in patients with erectile dysfunction is provided in sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
Avanafil, vardenafil. Increased plasma concentrations of avanafil and vardenafil (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use").
Sedatives/hypnotics
Chlordiazepoxide, diazepam, estazolam, flurazepam, oral midazolam, triazolam. Increased plasma concentrations of chlordiazepoxide, diazepam, estazolam, 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".
Decreased ritonavir levels
Herbal products
St. John’s wort (Hypericum perforatum). Herbal products containing St. John’s wort (Hypericum perforatum) reduce the concentrations and clinical effect of ritonavir (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Ritonavir as a pharmacokinetic enhancer or antiretroviral agent
Ritonavir has a high affinity for certain cytochrome P450 (CYP) isoenzymes and can inhibit oxidative metabolism in the following order of intensity: CYP3A4 > CYP2D6. Administration of ritonavir in combination with drugs primarily metabolized by the CYP3A isoenzyme may result in increased plasma concentrations 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 high affinity for P-glycoprotein and thus can inhibit this transporter. Inhibition of P-gp by ritonavir (with or without other protease inhibitors) may diminish over time (e.g., with digoxin and fexofenadine – see below "Interaction of ritonavir with non-antiretroviral medicinal products"). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9, and CYP2C19 isoenzymes, thereby stimulating biotransformation of certain drugs undergoing these metabolic pathways. This may lead to reduced systemic exposure to such drugs and decreased or shortened therapeutic effect.
Important information on drug interactions with ritonavir as a pharmacokinetic enhancer is included in the medical instructions for the protease inhibitor intended for concomitant use.
MEDICINAL PRODUCTS AFFECTING RITONAVIR CONCENTRATION
The 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 must not be used concurrently with ritonavir. If a patient is already taking St. John’s wort, treatment should be discontinued and, if possible, viral load levels should be monitored. After discontinuation of St. John’s wort, ritonavir concentrations may increase, requiring dose adjustments. The inducing effect of St. John’s wort persists for at least 2 weeks after stopping the herbal product.
Other medicinal products that may affect ritonavir plasma concentrations include delavirdine, efavirenz, phenytoin, and rifampicin.
MEDICINAL PRODUCTS AFFECTED BY RITONAVIR ADMINISTRATION
Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are presented in the tables below. This list is not exhaustive. Individual product information leaflets should be consulted.
| Interaction of Ritonavir with Protease Inhibitors |
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| Drug |
Dose of Drug (mg) |
Dose of Ritonavir (mg) |
Evaluated Drug |
AUC |
Cmin |
|||||||
| Amprénavir |
600, twice daily |
100, twice daily |
Amprénavir1 |
↑ 64% |
↑ 5-fold |
|||||||
| Ritonavir increases plasma concentrations of amprénavir due to inhibition of the CYP3A4 enzyme. Clinical studies have confirmed the safety and efficacy of administering 600 mg amprénavir twice daily together with 100 mg ritonavir twice daily. |
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| Atazanavir |
300, once daily |
100, once daily |
Atazanavir |
↑ 86% |
↑ 11-fold |
|||||||
| Atazanavir2 |
↑ 2-fold |
↑ 3–7-fold |
||||||||||
| Ritonavir increases plasma concentrations of atazanavir 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. |
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| Darunavir |
600, single dose |
100, twice daily |
Darunavir |
↑ 14-fold |
||||||||
| Ritonavir increases plasma concentrations of darunavir due to inhibition of the CYP3A4 isoenzyme. Darunavir should be co-administered with ritonavir to ensure its therapeutic effect. The interaction of ritonavir at doses higher than 100 mg twice daily with concomitantly administered darunavir has not been studied. |
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| Fosamprenavir |
700, twice daily |
100, twice daily |
Amprénavir |
↑ 2.4-fold |
↑ 11-fold |
|||||||
| Ritonavir increases plasma concentrations of amprénavir (from fosamprenavir) due to inhibition of the CYP3A4 isoenzyme. Fosamprenavir should be administered with ritonavir to ensure therapeutic effect. 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 higher than 100 mg twice daily with concomitantly administered fosamprenavir has not been studied. |
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| Indinavir |
800, twice daily |
100, twice daily |
Indinavir3 |
↑ 178% |
ND |
|||||||
| Ritonavir |
↑ 72% |
ND |
||||||||||
| 400, twice daily |
400, twice daily |
Indinavir3 |
↔ |
↑ 4-fold |
||||||||
| Ritonavir |
↔ |
↔ |
||||||||||
| Ritonavir increases plasma concentrations of indinavir due to inhibition of the CYP3A4 isoenzyme. Appropriate doses regarding the efficacy and safety of this combination have not been established. The minimal benefit of ritonavir-mediated pharmacokinetic boosting is achieved after administration of a dose greater than 100 mg twice daily. Caution should be exercised when co-administering ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) due to the risk of exacerbation of nephrolithiasis. |
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| Nelfinavir |
1250, twice daily |
100, twice daily |
Nelfinavir |
↑ 20–39% |
ND |
|||||||
| 750, single dose |
500, twice daily |
Nelfinavir |
↑ 152% |
ND |
||||||||
| Ritonavir |
↔ |
↔ |
||||||||||
| Ritonavir increases plasma concentrations of nelfinavir due to inhibition of the CYP3A4 isoenzyme. Appropriate doses regarding the efficacy and safety of this combination have not been established. The minimal benefit of ritonavir-mediated pharmacokinetic boosting is achieved after administration of a dose greater than 100 mg twice daily. |
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| Saquinavir |
1000, twice daily |
100, twice daily |
Saquinavir4 |
↑ 15-fold |
↑ 5-fold |
|||||||
| Ritonavir |
↔ |
↔ |
||||||||||
| 400, twice daily |
400, twice daily |
Saquinavir4 |
↑ 17-fold |
ND |
||||||||
| Ritonavir |
↔ |
↔ |
||||||||||
| Ritonavir increases plasma concentrations of saquinavir due to inhibition of the CYP3A4 isoenzyme. Saquinavir should only be taken in combination with ritonavir. 100 mg ritonavir twice daily and 1000 mg saquinavir twice daily provide systemic exposure of saquinavir over 24 hours, which can otherwise be achieved by administering 1200 mg saquinavir alone three times daily. In a clinical study, acute hepatocellular toxicity with transaminase elevations >20 times the upper limit of normal was observed within 1–5 days after co-administration of rifampicin (600 mg once daily), saquinavir (1000 mg twice daily), and ritonavir (100 mg twice daily). Due to the risk of severe hepatotoxicity, saquinavir/ritonavir should not be used concomitantly with rifampicin. |
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| Tipranavir |
500, twice daily |
200, twice daily |
Tipranavir |
↑ 11-fold |
↑ 29-fold |
|||||||
| Ritonavir |
↓ 40% |
ND |
||||||||||
| Ritonavir increases plasma concentrations of tipranavir due to inhibition of the CYP3A4 isoenzyme. Tipranavir should be administered with low-dose 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. |
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| ND: Not determined.
|
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| Interaction of Ritonavir with Non-Protease Inhibitor Antiretrovirals |
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| Didanosine |
200, twice daily |
600, twice daily, 2 hours apart |
Didanosine |
↓ 13% |
↔ |
|||||||
| 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 fasting, these drugs should be administered with a 2.5-hour interval. AUC ↓ 64%. No dose adjustment is necessary. |
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| Delavirdine |
400, three times daily |
600, twice daily |
Delavirdine1 |
↔ |
↔ |
|||||||
| Ritonavir |
↑ 50% |
↑ 75% |
||||||||||
| 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 dose of ritonavir. |
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| Efavirenz |
600, once daily |
500, twice daily |
Efavirenz |
↑ 21% |
||||||||
| Ritonavir |
↑ 17% |
|||||||||||
| 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 with ritonavir as an antiretroviral agent. |
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| Maraviroc |
100, twice daily |
100, twice daily |
Maraviroc |
↑ 161% |
↑ 28% |
|||||||
| Ritonavir increases plasma concentrations of maraviroc due to inhibition of the CYP3A4 isoenzyme. Maraviroc may be used together with ritonavir to enhance maraviroc's effect. |
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| Nevaripine |
200, twice daily |
600, twice daily |
Nevaripine |
↔ |
↔ |
|||||||
| Ritonavir |
↔ |
↔ |
||||||||||
| Concomitant administration of ritonavir with nevirapine does not result in clinically significant changes in the pharmacokinetics of either nevirapine or ritonavir. |
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| Raltegravir |
400, single dose |
100, twice daily |
Raltegravir |
↓ 16% |
↓ 1% |
|||||||
| Concomitant administration of ritonavir and raltegravir results in a minor reduction in raltegravir levels. |
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| Zidovudine |
200, three times daily |
300, four times daily |
Zidovudine |
↓ 25% |
ND |
|||||||
| Ritonavir may induce glucuronidation of zidovudine, leading to a minor reduction in zidovudine levels. No dose adjustment is necessary. |
||||||||||||
| ND: Not determined.
|
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| Interaction of ritonavir with non-antiretroviral medicinal products |
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| Concomitantly administered medicinal product |
Dose of medicinal product (mg) |
Dose of ritonavir (mg) |
Effect on concomitantly administered medicinal products, AUC |
Effect on concomitantly administered medicinal products, Cmax |
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| α1-adrenoreceptor antagonists |
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| Alfuzosin |
Combination of ritonavir with alfuzosin may lead to increased plasma concentrations of alfuzosin and is therefore contraindicated (see section "Contraindications"). |
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| Amphetamine derivatives |
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| Amphetamine |
Ritonavir as an antiretroviral agent is capable of inhibiting CYP2D6 and, as a result, increases concentrations of amphetamine and its derivatives. When these drugs are used concomitantly (with the ritonavir dose for antiretroviral therapy), careful monitoring for therapeutic and adverse reactions is recommended (see section "Special warnings and precautions for use"). |
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| Analgesics |
||||||||||||
| Buprenorphine |
16, once daily |
100, twice daily |
↑ 57 % |
↑ 77 % |
||||||||
| Norbuprenorphine |
↑ 33 % |
↑ 108 % |
||||||||||
| Glucuronide metabolites |
↔ |
↔ |
||||||||||
| Increased plasma concentrations of buprenorphine and its active metabolite do not lead to clinically significant pharmacodynamic changes in opioid-tolerant patients. Therefore, dose adjustment is not required when buprenorphine is used concomitantly with ritonavir. If ritonavir is used in combination with other protease inhibitors and buprenorphine, the prescribing information for the concomitantly administered protease inhibitor should be reviewed for specific dosing recommendations. |
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| Pethidine |
Concomitant administration of ritonavir may lead to increased plasma concentrations of pethidine, piroxicam, and propoxyphene, and is therefore contraindicated (see section "Contraindications"). |
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| Fentanyl |
Ritonavir, as a pharmacokinetic enhancer or antiretroviral agent, inhibits CYP3A4 and, as a result, increases plasma concentrations of fentanyl. When fentanyl is used concomitantly with ritonavir, careful monitoring for therapeutic and adverse reactions (including respiratory depression) is recommended. |
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| Methadone1 |
5, single dose |
500, twice daily |
↓ 36 % |
↓ 38 % |
||||||||
| When methadone and ritonavir (as a pharmacokinetic booster or antiretroviral agent) are used concomitantly, due to induction of glucuronidation, consideration may be given to increasing the methadone dose. Based on the patient's clinical response to methadone treatment, dose adjustment should also be considered. |
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| Morphine |
When morphine and ritonavir (as a pharmacokinetic booster or antiretroviral agent) are used concomitantly, plasma concentrations of morphine may decrease due to induction of glucuronidation. |
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| Anti-anginal agents |
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| Ranolazine |
Increased concentrations of ranolazine are expected due to inhibition of CYP3A by ritonavir. Concomitant administration of ritonavir with ranolazine is contraindicated (see section "Contraindications"). |
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| Antiarrhythmic agents |
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| Amiodarone |
Concomitant administration of ritonavir may lead to increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and is therefore contraindicated (see section "Contraindications"). |
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| Digoxin |
0.5 single intravenous dose |
300, twice daily, for 3 days |
↑ 86 % |
NC |
||||||||
| 0.4 single oral dose |
200, twice daily, for 13 days |
↑ 22 % |
↔ |
|||||||||
| This interaction may occur due to P-glycoprotein-mediated efflux of digoxin induced by ritonavir administered as a pharmacokinetic booster or antiretroviral agent. Elevated digoxin concentrations observed in patients receiving ritonavir may decrease over time due to induction (see section "Special warnings and precautions for use"). |
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| Anti-asthmatic agents |
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| Theophylline1 |
3 mg/kg, three times daily |
500, twice daily |
↓ 43 % |
↓ 32 % |
||||||||
| An increased dose of theophylline may be required when used concomitantly with ritonavir due to induction of CYP1A2. |
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| Anticancer agents and kinase inhibitors |
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| Afatinib |
20 mg, single dose |
200, twice daily / 1 hour before |
↑ 48 % |
↑ 39 % |
||||||||
| 40 mg, single dose |
200, twice daily / simultaneously |
↑ 19 % |
↑ 4 % |
|||||||||
| 40 mg, single dose |
200, twice daily / 6 hours after |
↑ 11 % |
↑ 5 % |
|||||||||
| Serum concentrations may increase due to inhibition of breast cancer resistance protein and acute inhibition of P-glycoprotein by ritonavir. The extent of increase in AUC and Cmax depends on the timing of ritonavir administration. Caution should be exercised when prescribing afatinib in combination with ritonavir. Monitoring for possible adverse reactions associated with afatinib is required. |
||||||||||||
| 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 prescribing information for abemaciclib should be consulted. 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 exposure to 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. Monitoring for possible adverse reactions associated with ceritinib is required. |
|||||||||||
| Dasatinib |
When used concomitantly with ritonavir, serum concentrations of these drugs may increase, leading to an increased frequency of adverse reactions. |
|||||||||||
| Encorafenib |
Serum concentration may increase when used concomitantly with ritonavir, which may increase the risk of toxicity, including risk of serious adverse events such as QT interval prolongation. Concomitant use of encorafenib and ritonavir should be avoided. If benefit outweighs risk and ritonavir must be used, patients should be closely monitored for safety. |
|||||||||||
| Fostamatinib |
Concomitant use of fostamatinib with ritonavir may increase exposure to the metabolite R406 of fostamatinib, causing dose-dependent adverse effects such as hepatotoxicity, neutropenia, arterial hypertension, or diarrhea. The prescribing information for fostamatinib should be consulted for dose reduction recommendations if such events occur. |
|||||||||||
| Ibrutinib |
Serum concentrations of ibrutinib may increase due to inhibition of CYP3A by ritonavir, leading to increased risk of toxicity, including risk of tumor lysis syndrome. Concomitant use of ibrutinib and ritonavir should be avoided. If benefit outweighs risk and ritonavir must be used, the dose of ibrutinib should be reduced to 140 mg and the patient should be closely monitored for toxicity. |
|||||||||||
| Neratinib |
Serum concentrations may increase due to inhibition of CYP3A4 by ritonavir. |
|||||||||||
| Venetoclax |
Serum concentrations may increase due to inhibition of CYP3A by ritonavir, leading to increased risk of tumor lysis syndrome at the beginning of dose initiation and during the ramp-up phase (see section "Contraindications" and the prescribing information for venetoclax). |
|||||||||||
| Anticoagulants |
||||||||||||
| Rivaroxaban |
10, single dose |
600, twice daily |
↑ 153 % |
↑ 55 % |
||||||||
| Inhibition of CYP3A and P-glycoprotein leads to increased plasma levels and pharmacodynamic effects of rivaroxaban, which may increase the risk of bleeding. Therefore, use of ritonavir in patients receiving rivaroxaban is not recommended. |
||||||||||||
| Vorapaxar |
Serum concentrations may increase due to inhibition of CYP3A by ritonavir. Concomitant use of vorapaxar with ritonavir is not recommended (see section "Special warnings and precautions for use" and the prescribing information for vorapaxar). |
|||||||||||
| Warfarin |
5, single dose |
400, twice daily |
||||||||||
| S-Warfarin |
↑ 9 % |
↓ 9 % |
||||||||||
| R-Warfarin |
↓ 33 % |
↔ |
||||||||||
| Induction of CYP1A2 and CYP2C9 leads to decreased levels of R-warfarin, while having a negligible pharmacokinetic effect on S-warfarin when used concomitantly with ritonavir. Decreased levels of R-warfarin may lead to reduced anticoagulant effect; therefore, monitoring of anticoagulation parameters is recommended when warfarin is used concomitantly with ritonavir as an antiretroviral agent or as a pharmacokinetic booster. |
||||||||||||
| Anticonvulsants |
||||||||||||
| Carbamazepine |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentration of carbamazepine. Careful monitoring for therapeutic and adverse reactions is recommended when carbamazepine and ritonavir are used concomitantly. |
|||||||||||
| Divalproex |
Ritonavir as a pharmacokinetic booster or antiretroviral agent causes oxidation by CYP2C9 isoenzyme and glucuronidation and, as a result, increases plasma concentrations of anticonvulsants. Careful monitoring of anticonvulsant serum concentrations and therapeutic effect is recommended when these drugs are used concomitantly with ritonavir. Phenytoin may reduce serum levels of ritonavir. |
|||||||||||
| Antidepressants |
||||||||||||
| Amitriptyline |
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 these drugs are used concomitantly with ritonavir at doses indicated for antiretroviral therapy, careful monitoring for therapeutic and adverse reactions is recommended. |
|||||||||||
| Desipramine |
100, single oral dose |
500, twice daily |
↑ 145 % |
↑ 22 % |
||||||||
| AUC and Cmax of the 2-hydroxy metabolite decrease by 15% and 67%, respectively. Desipramine dose reduction is recommended when used concomitantly with ritonavir dosed as an antiretroviral agent. |
||||||||||||
| Trazodone |
50, single dose |
200, twice daily |
↑ 2.4 times |
↑ 34 % |
||||||||
| Increased frequency of adverse reactions associated with trazodone use is observed when this drug is used concomitantly with ritonavir used as a pharmacokinetic booster or antiretroviral agent. If trazodone is used concomitantly with ritonavir, the combination should be used with caution, starting trazodone at the lowest dose and monitoring clinical response and tolerability. |
||||||||||||
| Antigout agents |
||||||||||||
| Colchicine |
Increased colchicine concentrations are expected when colchicine is used concomitantly with ritonavir. |
|||||||||||
| Antihistamines |
||||||||||||
| Astemizole |
Concomitant administration of ritonavir with astemizole and terfenadine may lead to increased plasma concentrations of the latter and is therefore contraindicated (see section "Contraindications"). |
|||||||||||
| Fexofenadine |
Ritonavir (as a pharmacokinetic booster 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 booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of loratadine. Careful monitoring for therapeutic and adverse reactions is required when loratadine and ritonavir are used concomitantly. |
|||||||||||
| Antibacterial agents |
||||||||||||
| Fusidic acid |
Concomitant administration of ritonavir with fusidic acid may lead to increased plasma concentrations of both fusidic acid and ritonavir, and this interaction is therefore contraindicated (see section "Contraindications"). |
|||||||||||
| Rifabutin1 |
150 daily |
500, twice daily |
↑ 4 times |
↑ 2.5 times |
||||||||
| 25-O-desacetyl metabolite of rifabutin |
↑ 38 times |
↑ 16 times |
||||||||||
| Due to the significant increase in rifabutin AUC, concomitant use of rifabutin with ritonavir as an antiretroviral agent is contraindicated (see section "Contraindications"). Dose reduction of rifabutin to 150 mg three times weekly may be indicated for certain protease inhibitors when used concomitantly with ritonavir as a pharmacokinetic booster. For specific recommendations, consult the prescribing information for the concomitantly administered protease inhibitor. Attention should be paid to official guidelines for appropriate tuberculosis treatment in HIV-infected patients. |
||||||||||||
| Rifampicin |
Although rifampicin may cause metabolism of ritonavir, some data suggest that when high-dose ritonavir (600 mg twice daily) is used concomitantly with rifampicin, the additional stimulating effect of ritonavir is negligible or may have a clinically insignificant impact on ritonavir concentrations during high-dose treatment. The effect of ritonavir on rifampicin is unknown. |
|||||||||||
| Voriconazole |
200, twice daily |
400, twice daily |
↓ 82 % |
↓ 66 % |
||||||||
| 200, twice daily |
100, twice daily |
↓ 39 % |
↓ 24 % |
|||||||||
| Concomitant use of ritonavir as an antiretroviral agent with voriconazole is contraindicated due to decreased voriconazole concentrations (see section "Contraindications"). 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, reduces plasma concentrations of atovaquone. When atovaquone is used concomitantly 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 single-dose bedaquiline and multiple-dose 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 concomitant use. Due to the risk of bedaquiline-related adverse events, combinations of bedaquiline and ritonavir should be avoided. If benefit outweighs risk, extreme caution is required when using bedaquiline concomitantly with ritonavir. More frequent monitoring of ECG and transaminase levels is recommended (see section "Special warnings and precautions for use" and the prescribing information for bedaquiline). |
|||||||||||
| Clarithromycin |
500, twice daily |
200, three times daily |
↑ 77 % |
↑ 31 % |
||||||||
| 14-hydroxy metabolite of clarithromycin |
↓ 100 % |
↓ 99 % |
||||||||||
| 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 above 1 g daily with ritonavir dosed as an antiretroviral agent or pharmacokinetic booster should be avoided. 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 100 mg twice daily and lopinavir/ritonavir 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 (see section "Special warnings and precautions for use" and the prescribing information for delamanid). |
|||||||||||
| Erythromycin |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of erythromycin and itraconazole. Careful monitoring for therapeutic and adverse reactions is required when ritonavir is used concomitantly with erythromycin or itraconazole. |
|||||||||||
| Ketoconazole |
200 daily |
500, twice daily |
↑ 3.4 times |
↑ 55 % |
||||||||
| Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due to the high frequency of gastrointestinal and hepatic adverse reactions, consideration should be given to reducing the ketoconazole dose when used concomitantly with ritonavir dosed as an antiretroviral agent or pharmacokinetic booster. |
||||||||||||
| Sulfamethoxazole/trimethoprim2 |
800/160, single dose |
500, twice daily |
↓ 20 % / ↑ 20 % |
↔ |
||||||||
| Do not adjust the dose of sulfamethoxazole/trimethoprim when used concomitantly with ritonavir. |
||||||||||||
| Antipsychotic/neuroleptic agents |
||||||||||||
| Clozapine |
Concomitant use of ritonavir with clozapine and pimozide may lead to increased plasma concentrations of the latter and is therefore contraindicated |
|||||||||||
| Haloperidol |
Ritonavir as an antiretroviral agent is capable of inhibiting CYP2D6 and, as a result, reduces plasma concentrations of haloperidol, risperidone, and thioridazine. Careful monitoring for therapeutic and adverse reactions is required when ritonavir is used concomitantly with these drugs. |
|||||||||||
| Lurasidone |
Increased concentrations of lurasidone are expected due to inhibition of CYP3A by ritonavir. Concomitant use with lurasidone is contraindicated. |
|||||||||||
| Quetiapine |
It is expected that concentrations of quetiapine will increase due to inhibition of CYP3A by ritonavir. Concomitant use of ritonavir and quetiapine is contraindicated, as it may increase quetiapine-related toxicity (see section "Contraindications"). |
|||||||||||
| Long-acting β2-agonist |
||||||||||||
| Salmeterol |
Ritonavir inhibits CYP3A4 and, as a result, is expected to markedly increase plasma concentrations of salmeterol. Therefore, concomitant use is not recommended. |
|||||||||||
| Calcium channel blockers |
||||||||||||
| Amlodipine |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of calcium channel blockers. Careful monitoring for therapeutic and adverse reactions is required when ritonavir is used concomitantly with these drugs. |
|||||||||||
| Endothelin receptor antagonists |
||||||||||||
| Bosentan |
Concomitant use of bosentan and ritonavir may increase steady-state 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, ergonovine, ergotamine, methylergonovine |
Concomitant use of ritonavir with ergot derivatives may lead to increased plasma concentrations of the latter, and is therefore contraindicated (see section "Contraindications"). |
|||||||||||
| Agents for treatment of gastrointestinal motility |
||||||||||||
| Cisapride |
Concomitant use of ritonavir and cisapride may lead to increased plasma concentrations of the latter, and is therefore contraindicated (see section "Contraindications"). |
|||||||||||
| Direct-acting antiviral agent against hepatitis C virus (HCV) |
||||||||||||
| Glecaprevir/pibrentasvir |
Serum concentrations may increase due to inhibition of P-glycoprotein, BCRP, and OATP1B by ritonavir. |
|||||||||||
| HCV protease inhibitor |
||||||||||||
| Simeprevir |
200 daily |
100, twice daily |
↑ 7.2 times |
↑ 4.7 times |
||||||||
| Ritonavir increases plasma concentrations of simeprevir due to inhibition of CYP3A4. Concomitant use of ritonavir and simeprevir is not recommended. |
||||||||||||
| HMG-CoA reductase inhibitors |
||||||||||||
| Atorvastatin |
HMG-CoA reductase inhibitors that are highly dependent on CYP3A metabolism (e.g., lovastatin and simvastatin) have markedly increased plasma concentrations when used concomitantly with ritonavir as a pharmacokinetic booster or antiretroviral agent. Since increased concentrations of lovastatin and simvastatin may provoke myopathy, including rhabdomyolysis, in patients, combination of these drugs with ritonavir is contraindicated. Atorvastatin is less dependent on CYP3A. Although rosuvastatin elimination does not depend on CYP3A, increased duration of action of rosuvastatin has been observed when used concomitantly with ritonavir. |
|||||||||||
| Hormonal contraceptives |
||||||||||||
| Ethinylestradiol |
50 µg, single dose |
500, twice daily |
↓ 40 % |
↓ 32 % |
||||||||
| Due to decreased ethinylestradiol concentrations, consideration should be given to using barrier or other non-hormonal contraceptive methods when ritonavir is used concomitantly as an antiretroviral agent or as a pharmacokinetic booster. Ritonavir may alter uterine bleeding patterns and reduce the effectiveness of contraceptives containing estradiol (see section "Special warnings and precautions for use"). |
||||||||||||
| Immunosuppressants |
||||||||||||
| Cyclosporine |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A4 and, as a result, increases plasma concentrations of cyclosporine, tacrolimus, and everolimus. Careful monitoring for therapeutic and adverse reactions is required when ritonavir is used concomitantly with these drugs. |
|||||||||||
| Lipid-modifying agents |
||||||||||||
| Lomitapide |
CYP3A4 inhibitors increase lomitapide exposure, and strong inhibitors increase exposure by approximately 27 times. Increased lomitapide concentrations are expected due to inhibition of CYP3A by ritonavir. Concomitant use of ritonavir with lomitapide is contraindicated (see section "Contraindications" and the prescribing information for lomitapide). |
|||||||||||
| Phosphodiesterase inhibitors |
||||||||||||
| Avanafil |
50, single dose |
600, twice daily |
↑ 13 times |
↑ 2.4 times |
||||||||
| Concomitant use of avanafil with ritonavir is contraindicated (see section "Contraindications"). |
||||||||||||
| Sildenafil |
100, single dose |
500, twice daily |
↑ 11 times |
↑ 4 times |
||||||||
| Concomitant use of sildenafil for treatment of erectile dysfunction with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic booster should be done with caution, and sildenafil doses should not exceed 25 mg every 48 hours (see also section "Special warnings and precautions for use"). Concomitant use of sildenafil with ritonavir is contraindicated in patients with pulmonary arterial hypertension (see section "Contraindications"). |
||||||||||||
| Tadalafil |
20, single dose |
200, twice daily |
↑ 124 % |
↔ |
||||||||
| Concomitant use of tadalafil for treatment of erectile dysfunction with ritonavir, dosed as an antiretroviral agent or as a pharmacokinetic booster, should be used with caution, and reduced doses of no more than 10 mg tadalafil every 72 hours are recommended, with enhanced monitoring for adverse reactions (see section "Special warnings and precautions for use"). |
||||||||||||
| Vardenafil |
5, single dose |
600, twice daily |
↑ 49 times |
↑ 13 times |
||||||||
| Concomitant use of vardenafil with ritonavir is contraindicated (see section "Contraindications"). |
||||||||||||
| Sedatives/hypnotics |
||||||||||||
| Clorazepate |
Concomitant use of ritonavir may lead to increased plasma concentrations of clorazepate, diazepam, estazolam, and flurazepam, and is therefore contraindicated (see section "Contraindications"). |
|||||||||||
| Triazolam |
0.125, single dose |
200, 4 doses |
↑ > 20 times |
↑ 87 % |
||||||||
| Concomitant use of ritonavir may lead to increased plasma concentrations of triazolam, and is therefore contraindicated (see section "Contraindications"). |
||||||||||||
| Pethidine |
50, single dose |
500, twice daily |
↓ 62 % |
↓ 59 % |
||||||||
| Norpethidine metabolite |
↑ 47 % |
↑ 87 % |
||||||||||
| Due to the risk of increased concentrations of the norpethidine metabolite, which has both analgesic and CNS-stimulating activity, concomitant use of pethidine and ritonavir is contraindicated. Increased norpethidine concentrations increase the risk of central nervous system adverse reactions (e.g., seizures) (see section "Contraindications"). |
||||||||||||
| Alprazolam |
1, single dose |
200, twice daily, for 2 days |
↑ 2.5 times |
↔ |
||||||||
| 500, twice daily, for 10 days |
↓ 12 % |
↓ 16 % |
||||||||||
| After administration of ritonavir, metabolism of alprazolam is inhibited. After 10 days of ritonavir administration, no inhibitory effect of ritonavir was observed. Caution is required during the first few days of concomitant use of alprazolam with ritonavir as an antiretroviral agent or as a pharmacokinetic booster until induction of alprazolam metabolism develops. |
||||||||||||
| Buspirone |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of buspirone. Careful monitoring for therapeutic effects and adverse reactions is required when ritonavir is used concomitantly with buspirone. |
|||||||||||
| Hypnotics |
||||||||||||
| Zolpidem |
5 |
200, 4 doses |
↑ 28 % |
↑ 22 % |
||||||||
| Combination of zolpidem and ritonavir should be used with caution and the patient should be carefully monitored for excessive sedative effect. |
||||||||||||
| Smoking cessation |
||||||||||||
| Bupropion |
150 |
100, twice daily |
↓ 22 % |
↓ 21 % |
||||||||
| 150 |
600, twice daily |
↓ 66 % |
↓ 62 % |
|||||||||
| Bupropion is primarily metabolized by CYP2B6. Concomitant use of bupropion with repeated doses of ritonavir is expected to reduce bupropion levels. These effects are believed to represent induction of bupropion metabolism. However, since ritonavir has demonstrated inhibition of CYP2B6 in vitro, the recommended dose of bupropion should not be exceeded. No significant interaction with bupropion was observed after short-term (as opposed to long-term) use of low-dose ritonavir (200 mg twice daily for two days). Based on this observation, it can be assumed that decreased bupropion concentrations begin a few days after initiation of ritonavir administration. |
||||||||||||
| Steroids |
||||||||||||
| Fluticasone propionate (inhaled, intranasal, or injectable), budesonide, triamcinolone |
Systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression (during studies, plasma cortisol levels decreased by 86%), have been observed in patients receiving ritonavir and inhaled or intranasal fluticasone propionate. Similar effects may also occur with other corticosteroids metabolized by CYP3A enzyme, such as budesonide and triamcinolone. Therefore, concomitant use of glucocorticoids and ritonavir as an antiretroviral agent or pharmacokinetic booster is not recommended unless potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section "Special warnings and precautions for use"). Consideration should be given to reducing the glucocorticoid dose, while ensuring careful monitoring of local and systemic effects of glucocorticoids or switching to a glucocorticoid that is not a CYP3A4 substrate (e.g., beclomethasone). Additionally, when discontinuing glucocorticoids, a gradual dose reduction over a prolonged period is necessary. |
|||||||||||
| Dexamethasone |
Ritonavir as a pharmacokinetic booster or antiretroviral agent inhibits CYP3A and, as a result, increases plasma concentrations of dexamethasone. Careful monitoring for therapeutic effects and adverse reactions is required when ritonavir is used concomitantly with dexamethasone. |
|||||||||||
| Prednisolone |
20 |
200, twice daily |
↑ 28 % |
↑ 9 % |
||||||||
| When ritonavir is used concomitantly with prednisolone, 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. |
||||||||||||
| Hormone replacement therapy of the thyroid gland |
||||||||||||
| Levothyroxine |
Interactions between ritonavir-containing medicinal products and levothyroxine have been reported. Patients receiving levothyroxine should have thyroid-stimulating hormone (TSH) levels monitored for at least one month after initiation and/or discontinuation of ritonavir treatment. |
|||||||||||
| NC: Not calculated.
|
||||||||||||
When ritonavir is used concomitantly with other medicinal products, the respective product information leaflets must be consulted.
Cardiovascular and CNS adverse reactions have been reported during combined therapy with ritonavir and disopyramide, mexiletine, or nefazodone. The possibility of drug interactions cannot be excluded.
Since ritonavir is highly protein-bound, the potential for increased therapeutic and toxic effects due to displacement of co-administered drugs from protein binding sites should be considered.
Ritonavir dosed as a pharmacokinetic enhancer
Important information regarding drug interactions with ritonavir used as a pharmacokinetic booster is provided in the product information leaflet of the concomitantly administered protease inhibitor.
Proton pump inhibitors and H2-receptor antagonists. Proton pump inhibitors and H2-receptor antagonists (e.g., omeprazole or ranitidine) may reduce the concentrations of concomitantly administered protease inhibitors. For detailed information on the effect of co-administration of acid-reducing agents, refer to the product information leaflet of the protease inhibitor. Based on drug interaction studies with ritonavir-boosted protease inhibitors (lopinavir/ritonavir, atazanavir), co-administration of omeprazole or ranitidine had minimal impact on the boosting effect of ritonavir, despite minor changes in drug exposure (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 and other complications of HIV-1 infection may continue to occur.
Although effective viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, residual transmission risk cannot be excluded. Preventive measures should be taken in accordance with guidance from national competent authorities to avoid transmission of infection.
When ritonavir is used as a pharmacokinetic enhancer in combination with another protease inhibitor, all specific characteristics and warnings related to the use of that protease inhibitor should be considered; therefore, the full 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 efficacy (due to poor adherence) of ritonavir or concomitant medications. Severe vomiting and/or diarrhoea induced by ritonavir may also affect renal function. In patients with renal impairment, regular monitoring of kidney function is advisable.
Haemophilia. Increased bleeding, including spontaneous skin haematomas and haemarthrosis, has been reported in patients with haemophilia A and B receiving protease inhibitors. Some patients required additional factor VIII. If protease inhibitor therapy was discontinued, in more than half of the reported cases, treatment was either continued or restarted. 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 partly related to disease control and lifestyle. Regarding lipids, there is evidence that in some cases these changes are treatment-related, while no convincing evidence links 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 managed according to clinical practice.
Diabetes mellitus and hyperglycaemia. Cases of newly diagnosed diabetes mellitus, hyperglycaemia, and exacerbation of pre-existing diabetes have been reported during treatment with protease inhibitors. In some cases, hyperglycaemia was severe and associated with ketoacidosis. A significant proportion of these patients had predisposing conditions requiring medication known to be associated with the development of diabetes or hyperglycaemia. Glucose levels should be monitored.
Lipodystrophy. Combined antiretroviral therapy is associated with HIV-related redistribution of adipose tissue (lipodystrophy). The long-term consequences of this phenomenon are currently unknown. Data on its mechanism are incomplete. Visceral lipomatosis is currently thought to be associated with protease inhibitors, while lipoatrophy is linked 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 examination should include assessment for signs of fat redistribution. Serum lipid and fasting blood glucose levels should also be monitored. Abnormal lipid values 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, treatment with Ritonavir should be discontinued.
Immune reconstitution syndrome. In HIV-infected patients with severe immune deficiency, initiation of combination antiretroviral therapy (cART) may lead to an inflammatory response to asymptomatic or residual opportunistic pathogens, resulting in serious clinical conditions or worsening of symptoms. These reactions are typically observed within the first few weeks or months of 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, autoimmune hepatitis) have also been reported during immune recovery; however, the timing of such adverse reactions may vary, and they may manifest many months after initiation of therapy.
Hepatic disease. Ritonavir should not be used in patients with decompensated liver disease. In patients with chronic hepatitis B or C receiving combination antiretroviral therapy, the risk of severe and potentially life-threatening hepatic adverse reactions is significantly increased. When administering combination antiretroviral therapy to patients with hepatitis B or C, refer to the respective prescribing information for these medications.
In patients with pre-existing liver function abnormalities, including active chronic hepatitis, the frequency of liver function disturbances may increase during combination antiretroviral therapy. Close monitoring of such patients should be performed according to standard practice. If symptoms of worsening liver disease occur in these patients, interruption or discontinuation of treatment should be considered.
Renal disease. Since renal clearance of ritonavir is minimal, a reduction in total clearance in patients with renal impairment is unlikely.
Cases of renal failure, renal dysfunction, increased creatinine levels, hypophosphataemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil fumarate in clinical practice.
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 HIV disease and/or long-term combination antiretroviral therapy. Patients experiencing joint pain, stiffness, or difficulty moving should be 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 conduction disorders, or in patients receiving drugs 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 observed. 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 data listed below, refer to the prescribing information for the specific protease inhibitor.
Phosphodiesterase inhibitors (PDE5). Sildenafil, tadalafil, or vardenafil should be prescribed with particular caution for the treatment of erectile dysfunction in patients receiving ritonavir. Concomitant use of ritonavir with these agents is expected to significantly increase their concentrations and may lead to associated adverse effects such as 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 (statins). 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 ritonavir is used concomitantly with atorvastatin, which is less dependent on CYP3A metabolism. Rosuvastatin elimination does not depend on CYP3A, but increased rosuvastatin exposure has been reported with concomitant use of ritonavir. The mechanism of this interaction is not fully understood, but it is hypothetically attributed to transporter inhibition. Lower doses of atorvastatin and rosuvastatin should be used when co-administered with ritonavir. Pravastatin and fluvastatin metabolism does not depend on CYP3A, so no significant interactions with ritonavir are expected. If reductase inhibitor therapy is required, 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 in patients taking digoxin, as concomitant use is expected to increase digoxin concentrations. Elevated digoxin concentrations tend to decrease over time.
Patients already taking digoxin should have their digoxin dose reduced to half the usual dose upon initiation of ritonavir therapy and should remain under close medical supervision for several weeks after starting concomitant treatment.
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. When using barrier or other non-hormonal contraceptive methods, it should be noted that 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.
Tramadol. Ritonavir should be prescribed with particular caution in patients receiving tramadol. Tramadol is a CYP3A4 substrate; therefore, it is expected that concomitant use of ritonavir increases tramadol concentrations. In a study of single-dose interactions involving healthy volunteers, adverse reactions such as nausea, dizziness, hypotension, and syncope were observed.
Rivaroxaban. Use of ritonavir in patients receiving rivaroxaban is not recommended due to the risk of increased bleeding.
Riociguat. Concomitant use of ritonavir is not recommended due to the potential for increased riociguat concentrations.
Vorapaxar. Concomitant use of ritonavir is not recommended due to the potential for increased vorapaxar concentrations.
Bedaquiline. Potent inhibitors of the CYP3A isoenzyme, such as protease inhibitors, may enhance the effect of bedaquiline, increasing the risk of bedaquiline-related adverse reactions. Therefore, concomitant use of bedaquiline and ritonavir should be avoided. However, if benefit outweighs risk, concomitant use may be permitted with caution. More frequent ECG monitoring and transaminase level checks are recommended.
Delamanid. Concomitant use of delamanid with another potent CYP3A inhibitor (ritonavir) may increase the formation of delamanid metabolites associated with QTc interval prolongation. Therefore, if concomitant use of delamanid and 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 depends entirely 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. Ritonavir dose should not exceed 100 mg twice daily. Increased ritonavir doses have 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 transaminases) when all three drugs are taken together.
Tipranavir. Clinical hepatitis and hepatic decompensation, including several fatal cases, have been reported with tipranavir in combination with 200 mg ritonavir. Patients with chronic hepatitis B or C co-infection 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. Clinical evaluation of the combined use of fosamprenavir with ritonavir doses higher than 100 mg twice daily has not been conducted. 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 exceeding 100 mg once daily has not been clinically evaluated. Increasing the ritonavir dose may alter the safety profile of atazanavir (cardiovascular effects, hyperbilirubinaemia) and is therefore not recommended. 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 with this regimen should be conducted under continuous clinical supervision. For more detailed information, refer to the atazanavir prescribing information.
Use during pregnancy or breastfeeding.
Ritonavir has been used in >6100 pregnant women and <2800 women during the first trimester of pregnancy. 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 general population. Animal studies have demonstrated toxic effects on reproductive function. Ritonavir may be used during pregnancy only if the benefit to the mother outweighs the potential 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 effect of ritonavir on breastfed infants or on lactation. Due to the potential for transmission of HIV infection (to HIV-negative infants), the potential for development of viral resistance (in HIV-positive infants), and the risk of serious adverse reactions in infants, HIV-infected women should under no circumstances breastfeed their infants while taking ritonavir.
Fertility.
There are no data on the effect of ritonavir on human fertility. Animal studies have not demonstrated any harmful effects of ritonavir on fertility.
Ability to affect reaction speed when driving or operating machinery.
No studies have been conducted on the ability of ritonavir to affect reaction speed when driving or operating machinery. 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 Rytovir must be carried out by a physician experienced in the management of HIV infection.
Rytovir film-coated tablets are administered orally with food.
Rytovir film-coated tablets should be swallowed whole, without chewing, breaking, or crushing.
Dosing of Ritonavir as a Pharmacokinetic Enhancer
When using ritonavir as a pharmacokinetic enhancer in combination with other protease inhibitors, refer to the medical instructions for the protease inhibitor prescribed concomitantly with ritonavir.
Concomitant administration of ritonavir as a pharmacokinetic enhancer is recommended for the following HIV-1 protease inhibitors at the specified doses.
Adults.
Atazanavir 300 mg once daily with ritonavir 100 mg once daily.
Darunavir 600 mg twice daily with ritonavir 100 mg twice daily for patients previously treated with antiretroviral therapy.
Darunavir 800 mg once daily with ritonavir 100 mg once daily for patients who have not previously received antiretroviral therapy.
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 previously treated with antiretroviral therapy.
At initiation of saquinavir therapy at a dose of 500 mg twice daily, ritonavir 100 mg twice daily should be administered for the first 7 days, followed by saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily for treatment-naïve patients.
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.
Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.
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 concomitant use with ritonavir.
Patients with Renal Impairment. Since ritonavir is primarily metabolized in the liver, it may be cautiously used in patients with renal impairment, taking into account the specific protease inhibitor used concomitantly as a pharmacokinetic booster. However, since renal clearance of ritonavir is negligible, a reduction in total clearance in patients with renal impairment is unlikely. Prior to administration of ritonavir in patients with renal impairment, the physician should consult 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 prescribed concomitantly. 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 Rytovir film-coated tablets is 600 mg (6 tablets) twice daily (total daily dose – 1200 mg).
Gradual dose escalation of ritonavir 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 of up to 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 Rytovir is 350 mg/m² orally twice daily, but not exceeding 600 mg twice daily. Administration of Rytovir should begin at 250 mg/m², increasing by 50 mg/m² twice daily every 2–3 days.
Rytovir 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. Specific data on the use of the drug in such patients are currently lacking; therefore, no specific dosage recommendations are available. Renal clearance of ritonavir is negligible, so a reduction in total clearance in patients with renal impairment is unlikely. Since ritonavir is highly protein-bound, 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.
Rytovir is recommended for use in children aged 2 years and older. Rytovir 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.
Toxicity signs 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. Given the drug's solubility and potential for 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 a significant amount 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 administered concomitantly with ritonavir. Information on adverse reactions of the respective protease inhibitor used in combination with ritonavir can be found in the package insert for that protease inhibitor.
Ritonavir dosed as an antiretroviral agent
Adverse reactions reported during clinical trials and post-marketing use 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), and fatigue/asthenia.
Adverse reactions are listed by organ system and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (frequency cannot be estimated from the available data).
| From the blood and lymphatic system |
|
| Common |
Decreased levels of leukocytes, hemoglobin, neutrophils; increased levels of eosinophils, thrombocytopenia |
| Uncommon |
Increased levels of neutrophils |
| From the immune system |
|
| Common |
Hypersensitivity, including urticaria and facial swelling |
| Rare |
Anaphylaxis |
| Metabolism and nutrition disorders |
|
| Common |
Hypercholesterolemia, hypertriglyceridemia, gout, edema and peripheral edema, dehydration (usually associated with gastrointestinal symptoms) |
| Uncommon |
Diabetes mellitus |
| Rare |
Hyperglycemia |
| From the nervous system |
|
| Very common |
Dysgeusia, oral mucosal and peripheral paresthesia, dizziness, peripheral neuropathy, headache |
| Common |
Insomnia, anxiety, confusion, inattention, syncope, seizures |
| From the eye |
|
| Common |
Blurred vision |
| From the heart |
|
| Uncommon |
Myocardial infarction |
| From the vascular system |
|
| Common |
Arterial hypertension, arterial hypotension including orthostatic hypotension, sensation of cold in the extremities |
| From the respiratory system, thoracic organs and mediastinum |
|
| Very common |
Pharyngitis, sore throat, cough |
| From the gastrointestinal tract |
|
| Very common |
Abdominal pain (upper and lower), nausea, diarrhea (including severe with electrolyte imbalance), vomiting, dyspepsia |
| Common |
Anorexia, flatulence, oral ulcers, gastrointestinal bleeding, gastroesophageal reflux disease, pancreatitis |
| From the liver and biliary system |
|
| Common |
Hepatitis (including elevated AST, ALT, GGT), increased blood bilirubin (including jaundice) |
| From the skin and subcutaneous tissue |
|
| Very common |
Itching, rash (including erythematous and maculopapular) |
| Common |
Acne |
| Rare |
Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) |
| From the musculoskeletal and connective tissue system |
|
| Very common |
Arthralgia and back pain |
| Common |
Myositis, rhabdomyolysis, myalgia, myopathy/elevated creatine phosphokinase |
| From the kidneys and urinary system |
|
| Common |
Increased frequency of urination, renal failure (e.g., oliguria, elevated blood creatinine) |
| Uncommon |
Acute renal failure |
| Frequency unknown |
Nephrolithiasis |
| Uncommon |
Acute renal failure |
| From the reproductive system and breast |
|
| Common |
Menorrhagia |
| General disorders and administration site conditions |
|
| Very common |
Fatigue, including asthenia, hot flushes, sensation of heat |
| Common |
Fever, weight loss |
| Laboratory investigations |
|
| Common |
Elevated blood amylase, decreased levels of free and total thyroxine |
| Uncommon |
Elevated glucose levels, elevated magnesium levels, elevated alkaline phosphatase |
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 increases in blood lipid and glucose levels may occur.
In HIV-infected patients with severe immune deficiency, initiation of combination antiretroviral therapy (cART) may lead to an inflammatory response against asymptomatic or residual opportunistic pathogens. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the time to onset of these adverse reactions may vary, and they may manifest many months after initiation of treatment.
Pancreatitis, including cases in patients who developed hypertriglyceridemia, has been reported in patients receiving ritonavir. 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 increased.
Cases of osteonecrosis have been reported, particularly in patients with generally recognized risk factors, those at late stages of HIV disease, or those receiving long-term combination antiretroviral therapy. The frequency of such events is unknown.
Children
In children aged 2 years and older, the safety profile of ritonavir is similar to that observed in adult patients.
Shelf life. 2 years.
Storage conditions. Store in the original container at a temperature not exceeding 25°C, in a place inaccessible to children.
Packaging. 30 tablets in a container, 1 container in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Hetero Labs Limited, India.
Manufacturer's address and site of operations.
Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.