Antiretroviral protease inhibitor (PI) — potent CYP3A4/P-gp inhibitor
Ritonavir is an antiretroviral medicine used to treat HIV infection, almost always at low doses to boost other antiretrovirals. It strongly blocks the elimination of many medicines, so interactions are frequent and require medical review.
Also known as: Norvir
Combining Praziquantel with Ritonavir increases Praziquantel concentrations, with an increased risk of adverse effects, especially of the central nervous system.
Praziquantel is rapidly metabolised by the cytochrome P450 enzyme system (CYP3A4) and undergoes first-pass effect; the praziquantel label explicitly states that "CYP450 inhibitors, for example cimetidine, ketoconazole, itraconazole, erythromycin and ritonavir, may increase praziquantel plasma concentrations". Raised levels potentiate the adverse effects (headache, dizziness, abdominal discomfort, nausea, urticaria and, in susceptible patients, seizures or arrhythmias — bradycardia, ventricular fibrillation and AV blocks have been observed). Monitor the patient during treatment (usually 1 day of therapy) and consider a lower dose in patients with liver disease, where exposure is already increased.
Praziquantel + ritonavir: ritonavir inhibits CYP3A4 and raises praziquantel levels. Watch for adverse effects (headache, dizziness, seizures).
As a CYP3A4 inhibitor, Ritonavir reduces Praziquantel metabolism, increasing its exposure and the risk of toxicity (headache, dizziness, seizures).
Watch for CNS adverse effects (headache, dizziness, drowsiness, seizures).
Seizures or severe neurological effects require discontinuation and evaluation.
Monitor adverse effects and consider reducing the Praziquantel dose if the combination is necessary.
DailyMed/FDA (NIH/NLM) — approved Praziquantel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34ce1cdd-648e-4f1e-8512-bf3d4cc22eb9 ; approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Corticosteroid + ritonavir: CYP3A4 inhibition markedly increases corticosteroid exposure.
Dexamethasone is metabolised by CYP3A4, and ritonavir is a potent inhibitor of this enzyme: the combination raises corticosteroid exposure, with a risk of corticosteroid excess — Cushing syndrome, adrenal suppression, hyperglycaemia, sodium and fluid retention, potassium loss and immunosuppression (the dexamethasone label lists potassium loss, hypokalaemic alkalosis and adrenal axis suppression among the adverse reactions). The combination occurs mainly in HIV patients needing corticosteroids; use the lowest effective dose, watch for signs of corticosteroid excess and adrenal function, and consider reducing the dexamethasone dose. Note: dexamethasone also induces CYP3A4 — in ritonavir-boosted regimens, evaluate the impact on the protease inhibitors.
Dexamethasone + ritonavir: ritonavir inhibits CYP3A4 and raises dexamethasone levels. Watch for corticosteroid excess (Cushing, adrenal suppression).
Ritonavir (potent CYP3A4 inhibitor) reduces dexamethasone metabolism, risking Cushing syndrome.
Blood glucose, blood pressure, signs of corticosteroid excess.
Cushing syndrome, hyperglycaemia, oedema.
Avoid the combination; if unavoidable, reduce dexamethasone dose and monitor.
DailyMed (FDA) — approved Dexamethasone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3 ; approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Levocetirizine + ritonavir: possible increased levocetirizine exposure.
Levocetirizine is predominantly eliminated renally (without significant hepatic metabolism), so the pharmacokinetic interaction with ritonavir is limited; the clinical risk is additive sedation — the levocetirizine label warns about drowsiness and the increased effect with alcohol, sedatives and tranquillisers, and ritonavir also causes fatigue and CNS symptoms. In patients with renal or hepatic impairment (in whom levocetirizine accumulates and the dose should be reduced) and in the elderly, the combination requires vigilance: monitor drowsiness, dizziness and driving ability, and use the lowest effective levocetirizine dose.
Levocetirizine + ritonavir: additive risk of sedation/drowsiness. Monitor, especially with renal or hepatic impairment.
Ritonavir may reduce levocetirizine clearance.
Sedative effects and tolerance.
Drowsiness, fatigue, dry mouth.
Watch for sedation and adverse effects.
DailyMed (FDA) — approved Levocetirizine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f722b84-08de-7e6a-41ac-2c9d9bb9fb43 ; approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Ritonavir with Carbamazepine increases Carbamazepine concentrations and toxicity, requiring dose adjustment and monitoring.
The interaction is bidirectional and complex: ritonavir (potent CYP3A4 inhibitor) can raise carbamazepine concentrations to toxic levels, while carbamazepine (CYP3A4 inducer) can lower ritonavir and boosted protease inhibitor levels, compromising viral suppression. Monitor carbamazepine levels (reduce the dose if needed) and the virological response; consider an alternative antiepileptic (e.g. levetiracetam) in patients on ritonavir-based antiretroviral therapy.
Ritonavir + carbamazepine: ritonavir inhibits CYP3A4 and raises carbamazepine levels, while carbamazepine lowers antiretroviral levels. Monitor both.
Ritonavir inhibits CYP3A4, the main metabolic pathway of Carbamazepine, lowering its clearance and increasing the risk of adverse effects (neurological, haematological).
Watch for signs of Carbamazepine toxicity: diplopia, ataxia, drowsiness, nausea, hyponatraemia.
Marked drowsiness, ataxia or diplopia require discontinuation and reassessment of the regimen.
Reduce the Carbamazepine dose as needed and, if available, monitor serum concentrations; consider an alternative antiepileptic.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Cetirizine + ritonavir: possible increased cetirizine exposure.
Cetirizine is predominantly eliminated renally, with minimal hepatic metabolism, so the pharmacokinetic interaction with ritonavir is limited; the clinical risk is additive sedation — the cetirizine label warns about drowsiness and the increased effect with alcohol, sedatives and tranquillisers, and ritonavir also causes fatigue and CNS symptoms. In patients with renal or hepatic impairment (in whom cetirizine accumulates and the dose should be reduced — the label recommends asking a doctor) and in the elderly, the combination requires vigilance: monitor drowsiness, dizziness and driving ability, and use the lowest effective cetirizine dose.
Cetirizine + ritonavir: additive risk of sedation/drowsiness. Monitor, especially with renal or hepatic impairment.
Ritonavir may raise cetirizine concentrations (pharmacokinetic interaction described in the label).
Sedative effects and tolerance to therapy.
Marked drowsiness, dry mouth, confusion.
Watch for excessive drowsiness and antihistamine adverse effects.
DailyMed (FDA) — approved Cetirizine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b92d959d-dd35-b2a3-e053-2995a90af3ff ; approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Ritonavir with Sildenafil markedly increases Sildenafil concentrations and effects, with an increased risk of hypotension and priapism.
Sildenafil is metabolised by CYP3A4, and ritonavir (a potent inhibitor) markedly raises its concentrations: the ritonavir label recommends for erectile dysfunction "sildenafil 25 mg every 48 hours" and contraindicates sildenafil (Revatio) in pulmonary hypertension; the label lists the sildenafil-associated adverse events — visual abnormalities, hypotension, prolonged erection and syncope. Raised sildenafil levels potentiate the risk of hypotension, headache, flushing, dyspepsia, priapism and visual disturbances. For erectile dysfunction, never exceed 25 mg every 48 hours; for pulmonary hypertension, the combination is contraindicated — seek an alternative.
Ritonavir + sildenafil: ritonavir inhibits CYP3A4 and greatly raises sildenafil levels. ED: 25 mg starting dose every 48h; PH: contraindicated.
Ritonavir (a CYP3A4 inhibitor) markedly reduces first-pass metabolism of Sildenafil, greatly increasing its systemic exposure.
Monitor blood pressure, orthostatic hypotension and abnormally prolonged erection.
Severe symptomatic hypotension or an erection lasting more than 4 hours requires urgent medical evaluation.
Sildenafil for erectile dysfunction should be started low (max 25 mg every 48 h) with Ritonavir; for pulmonary hypertension the combination is contraindicated in many regimens.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 ; approved Sildenafil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00ee09dd-2de0-4dc4-85f6-b51ed6eabd5b — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Ritonavir with Atorvastatin increases Atorvastatin concentrations, with an increased risk of myopathy and rhabdomyolysis.
Ritonavir (a protease inhibitor, often used as a pharmacokinetic booster) is a potent CYP3A4 inhibitor, and co-administration with atorvastatin raises statin concentrations and the risk of myopathy/rhabdomyolysis. The atorvastatin label specifies: with saquinavir+ritonavir, darunavir+ritonavir or fosamprenavir(+ritonavir), do not exceed 20 mg of atorvastatin per day; with tipranavir+ritonavir the combination is not recommended; with lopinavir+ritonavir consider the risk/benefit. In practice (HIV on antiretroviral therapy), use the lowest appropriate dose and titrate slowly with monitoring of lipids, muscle symptoms and CK; alternatively, consider a statin less dependent on CYP3A4. Instruct the patient about myopathy signs.
Atorvastatin + ritonavir: ritonavir strongly inhibits CYP3A4 and raises statin levels. Do not exceed 20 mg/day with the ritonavir regimens indicated in the label.
By inhibiting CYP3A4, Ritonavir reduces the metabolism of Atorvastatin (a CYP3A4 substrate), raising its exposure and the risk of muscular toxicity.
Watch for muscle symptoms (myalgia, weakness, dark urine) and, if symptomatic, check creatine kinase.
Severe myalgia, proximal weakness or brown urine require stopping the statin and medical evaluation.
Limit Atorvastatin to 20 mg/day during Ritonavir use, or choose a statin less dependent on CYP3A4 (e.g. pravastatin).
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 ; approved Atorvastatin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86841382-4229-4e03-958e-3ac22639efd4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Ritonavir with Warfarin can unpredictably alter the anticoagulant effect of Warfarin, posing a risk of bleeding or thrombotic events.
Ritonavir has a complex pharmacokinetic profile: it is a potent inhibitor of CYP3A4 and CYP2D6, but also an inducer of other enzymes and transporters. The net effect on warfarin is variable and unpredictable between patients — most reports show an INR increase, but cases of reduction exist. When ritonavir is used at low boosting doses (with other antiretrovirals), the effect is equally variable. The INR should be monitored frequently at initiation, during and after ritonavir discontinuation, adjusting the warfarin dose according to the result and alerting for bleeding and thrombosis signs.
Ritonavir inhibits and induces several CYP isoenzymes; the net effect on warfarin is unpredictable (usually an INR increase). Monitor the INR closely when starting and stopping.
Ritonavir is a potent inhibitor of CYP3A4 and P-glycoprotein; Warfarin is mainly metabolised by CYP2C9. The net effect on warfarin exposure is variable (increase or decrease) between patients, requiring monitoring.
Frequent INR at start and at each dose change; watch for bleeding signs (spontaneous bruising, gum bleeding, haematuria) and thrombotic symptoms.
INR above 3.5 or active bleeding requires immediate discontinuation or adjustment of the anticoagulant.
Maintain INR monitoring whenever Ritonavir is started, stopped or adjusted; titrate the Warfarin dose based on the INR. When possible, prefer anticoagulants with more predictable pharmacokinetics.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Alcohol adds hepatotoxicity to that of ritonavir, with increased risk in patients with hepatitis B or C.
Avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925
Taking ritonavir with food improves gastrointestinal tolerability (less nausea).
Take with food if nausea or gastric discomfort occurs.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925
Ritonavir can cause hyperglycaemia, glucose intolerance and new-onset diabetes; the risk is higher in diabetic patients or those with risk factors.
Monitor blood glucose in diabetic or at-risk patients; adjust antidiabetic therapy if needed.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925
Ritonavir is hepatotoxic, especially in hepatitis B or C coinfection; prior liver disease increases the risk of decompensation.
Monitor transaminases; consider alternatives in severe liver disease.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925
Ritonavir is used in pregnancy as a pharmacokinetic booster of HIV antiretroviral therapy.
Use in pregnancy as part of the antiretroviral regimen, under supervision.
Excreted into breast milk; in HIV infection breastfeeding is not recommended regardless of treatment.
Ritonavir reduces the efficacy of hormonal contraceptives — use an additional (barrier) method.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
HIV-1 protease inhibitor antiretroviral; used at low doses as a pharmacokinetic booster of other antiretrovirals. Slightly prolongs the QTcF interval (maximum Δ 5.5 ms) and the PR interval (22 ms) at 400 mg twice daily. Protein binding of 98 to 99% (albumin and alpha-1 acid glycoprotein); red blood cell/plasma ratio of 0.14.
Peptidomimetic inhibitor of HIV-1 protease: inhibition prevents the processing of the Gag-Pol polyprotein precursor, leading to the production of immature non-infectious viral particles. The M-2 metabolite (isopropylthiazole oxidation) has antiviral activity similar to the parent compound.
Absolute bioavailability not determined; peak plasma concentrations about 2 hours after dosing while fasting and about 4 hours after a meal (600 mg oral solution). Food reduces tablet Cmax and AUC by 21 to 23% relative to fasting.
Metabolised mainly by CYP3A, with contribution of CYP2D6; the main metabolite is M-2. Excretion: 86.4% in faeces (33.8% as unchanged drug) and 11.3% in urine. Potent inhibitor of CYP3A4 and P-glycoprotein — the basis of the pharmacokinetic boosting effect.
Half-life of 3 to 5 hours; oral clearance of 4.6 L/h (single 600 mg dose) and 8.8 L/h at steady state (600 mg every 12 hours). Accumulation with multiple dosing is less than predicted from a single dose, due to a time- and dose-related increase in clearance.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
