Ritonavir

Mechanism

Dual mechanism: ritonavir strongly inhibits CYP3A4, the partial clearance route of amiodarone, raising amiodarone levels. Both drugs also prolong QT. The FDA lists the combination as an absolute contraindication.

Symptoms

QT prolongation on ECG, dizziness, syncope, palpitations. Severe cases progress to torsades de pointes with risk of ventricular fibrillation and sudden cardiac death.

Management

The combination is not prescribed. For HIV-positive patients with atrial fibrillation, use a beta-blocker for rate control or catheter ablation for rhythm control. Where possible, switch antiretroviral therapy to a ritonavir-free regimen.

Mechanism

Ritonavir strongly inhibits the liver enzyme CYP3A4 and slows the breakdown of drugs that depend on it. The US ritonavir label lists cisapride among drugs whose clearance depends heavily on CYP3A and whose raised plasma levels are linked to serious or life-threatening reactions. When the two are taken together, cisapride levels in the blood rise, but the documents give no study with numbers for this pair. With clarithromycin, another strong CYP3A4 inhibitor, the prescribing information reports raised cisapride levels in patients taking both drugs. This can prolong the QT interval on the electrocardiogram and cause ventricular arrhythmias.

Symptoms

The danger of the combination is serious heart rhythm disorders (ritonavir labels). They include QT interval prolongation on the electrocardiogram, ventricular tachycardia, ventricular fibrillation and torsade de pointes (clarithromycin prescribing information on its combination with cisapride). An attack shows as sudden strong palpitations, dizziness or fainting. Prolonged torsade de pointes can turn into ventricular fibrillation and cardiac arrest. Ritonavir itself causes a moderate, symptom-free prolongation of the PR interval in some healthy people. Rare cases of second- or third-degree atrioventricular block have been reported in people with structural heart disease and conduction abnormalities (ritonavir label, European Medicines Agency, EMA).

Management

The combination is contraindicated (ritonavir label, European Medicines Agency, EMA; ritonavir label, US Food and Drug Administration, FDA). The same contraindication appears in the generic ritonavir label (Spanish Agency of Medicines and Medical Devices, AEMPS) and in the label of Paxlovid, where ritonavir is combined with nirmatrelvir (EMA). These documents set no dose condition for cisapride, so the contraindication also covers the low ritonavir doses used to boost other antiviral drugs, including in Paxlovid. When ritonavir boosts another protease inhibitor, also check the contraindications in that drug's label (ritonavir labels, EMA and FDA).

Mechanism

Colchicine is a CYP3A4 and P-glycoprotein substrate with narrow therapeutic window. Ritonavir is the strongest CYP3A4 inhibitor and a notable P-glycoprotein inhibitor. Colchicine levels rise 4-fold or more. FDA carries a boxed warning.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

The combination is not prescribed. For acute gout in a patient on ritonavir, use glucocorticoids (intra-articular or short systemic) or NSAIDs. For long-term prophylaxis, allopurinol.

Mechanism

Ritonavir is the strongest ARV CYP3A4 inhibitor. Fatal ergotism.

Symptoms

Digital ischaemia, stroke.

Management

Combination contraindicated.

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available. Dronedarone plasma levels may rise 25-fold or more, plus both drugs prolong QT. FDA Multaq Section 4.3 specifically lists ritonavir.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk rises with hypokalaemia and hypomagnesaemia.

Management

The combination is not prescribed. For HIV-positive patients with atrial fibrillation, use a beta-blocker (rate control) or catheter ablation (rhythm control). Ritonavir-free antiretroviral regimens are discussed with the infectious diseases team.

Mechanism

The liver breaks down eletriptan mainly through the enzyme CYP3A4, and ritonavir strongly inhibits this enzyme. The labels give no study of this exact pair. The closest guide is data on other strong CYP3A4 inhibitors. Ketoconazole 400 mg raised the eletriptan area under the curve (AUC) 5.9-fold and lengthened its half-life from 4.8 to 8.3 hours. Erythromycin 1000 mg raised the AUC 3.6-fold. Like other triptans, eletriptan can cause coronary artery spasm. The Paxlovid (nirmatrelvir with ritonavir) labels explain the contraindication by the risk of serious adverse reactions, including cardiovascular and cerebrovascular events.

Symptoms

Tightness, pain or pressure in the chest, throat, neck and jaw is common after eletriptan. It is usually not cardiac but can be a sign of coronary artery spasm. Myocardial infarction, ventricular tachycardia and ventricular fibrillation have been reported within a few hours of triptan use, sometimes in people without known heart disease. Rarely, blood pressure rises sharply, even to a hypertensive crisis. Spasm of other arteries can cause Raynaud's syndrome or bowel ischaemia with abdominal pain and bloody diarrhoea. Stroke and brain haemorrhage have occurred after triptans.

Management

The combination is contraindicated (eletriptan label, US Food and Drug Administration, FDA). The Paxlovid labels, where ritonavir is combined with nirmatrelvir, also contraindicate it (European Medicines Agency, EMA, and FDA). The eletriptan summary of product characteristics (SmPC) says not to use eletriptan with ritonavir or other strong inhibitors of the enzyme CYP3A4 (Spanish Agency of Medicines and Medical Devices, AEMPS). Wait at least 72 hours after the last dose of ritonavir before giving eletriptan (eletriptan label, FDA; Paxlovid labels, EMA and FDA). The documents set no dose condition, so the contraindication also covers the low ritonavir doses used to boost other antiviral drugs, including in Paxlovid. If eletriptan has been taken during ritonavir treatment and chest pain or tightness suggesting cardiac ischaemia appears, give no further doses and evaluate the heart (eletriptan SmPC, AEMPS). Stop eletriptan if arrhythmias occur and monitor blood pressure during treatment (eletriptan label, FDA). If signs of spasm in other arteries appear, such as abdominal pain with blood in the stool or white, cold fingers, rule out vasospasm before the next dose (eletriptan label, FDA).

Mechanism

According to the Inspra summary of product characteristics (SmPC) from the Spanish Agency of Medicines and Medical Devices (AEMPS), eplerenone is cleared mainly through the enzyme CYP3A4 (section 5.2). Ritonavir strongly inhibits this enzyme (Norvir SmPC, European Medicines Agency, EMA, section 4.3). The labels give no eplerenone data with ritonavir itself. The closest guide is ketoconazole, another strong CYP3A4 inhibitor. At 200 mg twice daily, it raised the eplerenone area under the curve (AUC) by 441%, or 5.4-fold (Inspra SmPC, AEMPS, section 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 12.3). Eplerenone blocks mineralocorticoid receptors, so excess drug increases potassium retention and lowers blood pressure further. The SmPC names hypotension and hyperkalaemia as the most likely signs of overdose (Inspra SmPC, AEMPS, section 4.9). The Paxlovid labels, where ritonavir 100 mg is combined with nirmatrelvir, contraindicate eplerenone because of the potential for hyperkalaemia (EMA, section 4.5; FDA, section 7.3). Eplerenone does not affect ritonavir: it inhibits neither the main cytochrome P450 (CYP) enzymes nor P-glycoprotein (Inspra SmPC, AEMPS, section 4.5).

Symptoms

The main danger is hyperkalaemia. The Paxlovid labels, where ritonavir is combined with nirmatrelvir, contraindicate eplerenone for exactly this reason (European Medicines Agency, EMA; US Food and Drug Administration, FDA). High potassium causes muscle weakness, bradycardia and arrhythmias up to cardiac arrest, with peaked T waves and a widened QRS complex on the electrocardiogram (ECG). Low blood pressure causes dizziness and fainting, especially on standing (Inspra summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.8 and 4.9). The risk of hyperkalaemia is higher in older people, in reduced kidney function or diabetes, and with concurrent angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (Inspra SmPC, AEMPS, section 4.4).

Management

The combination is contraindicated. The Inspra summary of product characteristics (SmPC) and prescribing information bar eplerenone in patients taking strong inhibitors of the enzyme CYP3A4 and name ritonavir explicitly (Inspra SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.3 and 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 4). These documents set no dose condition, so the ban also covers the low ritonavir doses added to other antiviral drugs to raise their blood levels. Paxlovid is ritonavir 100 mg taken with nirmatrelvir every 12 hours for 5 days. Its labels contraindicate eplerenone because of the risk of hyperkalaemia (Paxlovid SmPC, European Medicines Agency, EMA, sections 4.2, 4.3 and 4.5; FDA, section 4). The eplerenone ceiling of 25 mg daily applies only to weak and moderate CYP3A4 inhibitors, so a lower dose does not make the combination with ritonavir acceptable (Inspra SmPC, AEMPS, sections 4.2 and 4.5). If the two drugs have already been taken together, stop one of them and check potassium and creatinine at once. The eplerenone labels require a potassium check at any dose change, and a potassium and creatinine check within 3–7 days of adding even a moderate CYP3A4 inhibitor (Inspra SmPC, AEMPS, section 4.4; FDA, section 2.3). Stop eplerenone if serum potassium reaches 6.0 mmol/L or higher (Inspra SmPC, AEMPS, section 4.2).

Mechanism

Ritonavir is the strongest CYP3A4 inhibitor. Fatal ergotism. FDA Ergomar Section 4.

Symptoms

Digital ischaemia, MI, stroke.

Management

Combination contraindicated.

Mechanism

The enzyme CYP2D6 breaks down a large part of flecainide. Ritonavir inhibits this enzyme and, even more strongly, the CYP3A enzymes. According to the ritonavir documents, flecainide blood levels rise, and with them the risk of arrhythmias and other serious adverse reactions. The documents give no figures for this pair. The US ritonavir label only says that the area under the curve (AUC) of drugs broken down by CYP2D6 can rise up to 2-fold. Flecainide lengthens the PR and QRS intervals on the electrocardiogram in a dose-related way. Ritonavir prolongs the PR interval on its own, and rare cases of second- or third-degree atrioventricular block have been reported with it.

Symptoms

When flecainide levels rise above the therapeutic range, adverse reactions become more likely, mainly cardiac ones. The electrocardiogram (ECG) shows a wider QRS complex and longer PR and QT intervals. Atrioventricular block, a slow heart rate, ventricular tachycardia or ventricular fibrillation can develop. The person may notice palpitations, dizziness, or double or blurred vision. Low blood pressure, fainting, and new or worsening heart failure with breathlessness and swelling can occur. In severe flecainide toxicity, seizures, cardiac arrest and death have been reported.

Management

The combination is contraindicated (ritonavir prescribing information from the European Medicines Agency, EMA, and the US Food and Drug Administration, FDA). These documents set no dose condition for flecainide, so the contraindication also covers the low ritonavir doses used to boost other human immunodeficiency virus (HIV) protease inhibitors. When ritonavir boosts another protease inhibitor, check that drug's prescribing information for contraindications as well (ritonavir summary of product characteristics, EMA; ritonavir label, FDA). The flecainide prescribing information also says to avoid this combination (Spanish Agency of Medicines and Medical Devices, AEMPS). If a patient has taken both drugs, flecainide blood levels can be measured. Trough levels are usually 0.2–1.0 µg/mL, and adverse reactions, especially cardiac ones, become more likely above 0.7–1.0 µg/mL (flecainide prescribing information, AEMPS). Flecainide overdose is life-threatening. There is no specific antidote, and dialysis does not help. Treatment is supportive, and temporary transvenous pacing is considered for conduction block (flecainide prescribing information, AEMPS). Flecainide has a half-life of about 20 hours, so this treatment may be needed for a long time (flecainide prescribing information, AEMPS).

Mechanism

Ritonavir inhibits CYP3A4 (meperidine metabolism) while inducing formation of neurotoxic normeperidine. Seizure risk.

Symptoms

Seizures, delirium.

Management

Combination contraindicated. Alternative – fentanyl.

Mechanism

Ritonavir is the strongest ARV CYP3A4 inhibitor. Pimozide concentration rises 15-fold. FDA Orap Section 4 strict contraindication.

Symptoms

QT prolongation, syncope, torsades de pointes.

Management

Combination contraindicated. For HIV in a pimozide patient, switch ARV to a regimen without ritonavir or cobicistat (e.g., dolutegravir + 2 NRTIs).

Mechanism

Quetiapine is cleared via hepatic CYP3A4. Ritonavir is the strongest available CYP3A4 inhibitor. Quetiapine plasma levels rise 6- to 10-fold.

Symptoms

Marked sedation, orthostatic hypotension with syncope, tachycardia, QT prolongation on ECG. Hyperglycaemia and metabolic disturbance worsen. Older patients face higher fall and fracture risk.

Management

The combination is not prescribed. Alternative antipsychotics on ritonavir: paliperidone (minimal CYP3A4 metabolism) or aripiprazole with caution and a 50% dose cut.

Mechanism

The liver breaks down ranolazine mainly through the enzyme CYP3A4, and ritonavir strongly inhibits this enzyme. The labels give no figures for this exact pair. The closest guide is ketoconazole, another strong CYP3A4 inhibitor, which raised the ranolazine area under the curve 3.0–3.9-fold. As ranolazine levels rise, so do its dose-dependent adverse effects and QT interval prolongation.

Symptoms

Excess ranolazine causes dizziness, nausea and vomiting. At high concentrations, double vision, lethargy and fainting are possible. In ranolazine overdose, low blood pressure, slow heart rate, QT prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations have been reported.

Management

The combination is contraindicated (ritonavir and ranolazine SmPCs, European Medicines Agency, EMA; US labels of both drugs, US Food and Drug Administration, FDA). The contraindication includes low-dose ritonavir used to boost other human immunodeficiency virus (HIV) protease inhibitors. All HIV protease inhibitors are on the ranolazine contraindication list (ranolazine SmPC, EMA), and the ritonavir documents contraindicate ranolazine at any ritonavir dose (ritonavir SmPC, EMA; ritonavir label, FDA). When ritonavir boosts another protease inhibitor, check that drug's prescribing information for contraindications as well (ritonavir SmPC, EMA). If a patient has taken both and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).

Mechanism

Strong CYP3A4 inducer. Ritonavir falls 35%, darunavir/atazanavir within regimen fall 80%. ART failure.

Symptoms

Rising viral load.

Management

Combination contraindicated. Alternatively for TB – switch rifampicin to rifabutin (weaker induction).

Mechanism

Simvastatin is cleared via hepatic CYP3A4. Ritonavir is the strongest available CYP3A4 inhibitor. Simvastatin plasma levels rise 30-fold or more. The FDA lists the combination as an absolute contraindication.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–2 weeks of co-prescription.

Management

The combination is not prescribed. For HIV patients on ritonavir-boosted therapy who need a statin, use low-dose pravastatin or rosuvastatin. Cap rosuvastatin at 10 mg/day with ritonavir.

Mechanism

Ritonavir is the strongest CYP3A4 inhibitor. Sirolimus rises 15-fold.

Symptoms

Acute nephrotoxicity, thrombotic microangiopathy.

Management

Combination contraindicated. For HIV in transplant patient – ARV regimen without ritonavir or cobicistat.

Mechanism

Strongest CYP3A4 inhibitor. Ticagrelor rises 10+ fold.

Symptoms

Severe bleeding.

Management

Combination contraindicated.

Mechanism

Ritonavir – CYP3A4 inhibitor. Vardenafil rises 13-fold.

Symptoms

Severe hypotension, QT prolongation.

Management

Combination contraindicated.

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available – the main alprazolam metabolic route. Alprazolam plasma levels rise 4-fold. Marked sedation, ataxia, and respiratory depression risk emerge.

Symptoms

Deep sedation, drowsiness, marked ataxia. Older patients: fall and fracture risk. With high alprazolam doses and high ritonavir doses: respiratory depression risk.

Management

Avoid the combination. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam (metabolised by glucuronidation, weakly affected by ritonavir). If alprazolam is needed, reduce the dose 4-fold.

Mechanism

Ritonavir strongly inhibits CYP3A4 and P-glycoprotein, which is why it is used as a pharmacokinetic booster in HIV regimens. Apixaban is cleared through both routes. According to the apixaban SmPC, strong CYP3A4 and P-gp inhibitors may double apixaban exposure, or raise it further in severe renal impairment. No label lists the pair as a contraindication: the EMA advises against it, and the FDA asks for a dose cut or avoidance.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not recommended. If a person with HIV on ritonavir needs anticoagulation, a drug without this interaction is chosen: a low-molecular-weight heparin for short courses, or warfarin. With warfarin, the FDA ritonavir label recommends frequent INR checks at the start of co-administration, because ritonavir can shift warfarin levels either way. The FDA also allows apixaban: a dose of 5 or 10 mg twice daily is halved, and at 2.5 mg twice daily the combination is avoided. The patient is told the signs of bleeding: black stools, blood in the urine, bruising without injury.

Mechanism

Ritonavir inhibits CYP3A4 (and weakly CYP2D6). Aripiprazole rises 2-3 fold. Enhanced extrapyramidal effects and sedation.

Symptoms

Sedation, akathisia, dyskinesia.

Management

Halve aripiprazole dose.

Mechanism

Atorvastatin is broken down in the liver by CYP3A4, and ritonavir inhibits this enzyme. In studies of ritonavir-containing regimens, atorvastatin area under the curve (AUC) rose 2.5- to 9.4-fold depending on the partner protease inhibitor: 5.9-fold with lopinavir/ritonavir and 9.4-fold with tipranavir/ritonavir. Higher atorvastatin levels raise the risk of muscle damage.

Symptoms

Muscle pain, cramps or weakness, sometimes with fever and malaise, dark urine, raised creatine kinase in the blood. Severe cases progress to rhabdomyolysis with kidney injury.

Management

Avoid the combination where possible and consider non-interacting alternatives (atorvastatin label). If atorvastatin is still needed, start with a lower dose, use a lower maximum dose and monitor the patient (atorvastatin label). The European Medicines Agency (EMA) advises the lowest possible atorvastatin dose and, if a statin is needed, pravastatin or fluvastatin (ritonavir label, EMA). The dose cap depends on the other drug in the regimen. The US Food and Drug Administration (FDA) does not recommend atorvastatin with tipranavir plus ritonavir and limits it to 20 mg a day with ritonavir-boosted darunavir, saquinavir or fosamprenavir (atorvastatin FDA label). Ask the patient to report muscle pain, cramps or weakness right away. If these occur, check creatine kinase and stop atorvastatin if it is more than 5 times the upper limit of normal (atorvastatin label).

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available. Systemic budesonide exposure (inhaled or oral) rises 8- to 10-fold. High risk of iatrogenic Cushing's syndrome, especially during long-term inhaled therapy for asthma or COPD.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia. With prolonged combination and abrupt withdrawal: adrenal insufficiency risk.

Management

Avoid the combination. Alternative inhaled corticosteroid: beclomethasone (less CYP3A4-dependent) or short-acting β2-agonists with inhaled anticholinergics. If replacement is impossible: minimum effective budesonide dose with glucose and blood pressure monitoring.

Mechanism

Ritonavir strongly inhibits CYP3A4, which is why it is used as a pharmacokinetic booster in HIV regimens. Cyclosporine is cleared through CYP3A4 and P-glycoprotein, so its blood level rises on ritonavir. Both labels expect the rise: the ritonavir SmPC names cyclosporine, and the cyclosporine SmPC lists protease inhibitors among drugs that raise its levels. The size of the rise is not known in advance: the FDA cyclosporine label notes that no formal studies of this pair are available. Excess cyclosporine damages the kidneys and raises blood pressure.

Symptoms

Sharp creatinine rise, hypertension.

Management

The combination is possible only with cyclosporine level monitoring: the FDA ritonavir label recommends therapeutic concentration monitoring of the immunosuppressant, and the ritonavir SmPC asks for careful monitoring of effect and adverse reactions. Cyclosporine trough levels are measured before ritonavir starts, frequently in the first days and after any change of the antiretroviral regimen, and the cyclosporine dose follows the result. Creatinine, potassium and blood pressure are watched in parallel. When ritonavir stops, cyclosporine levels fall and the dose is reviewed again by level. The transplant team and the HIV specialist agree on the plan together.

Mechanism

Dual CYP3A4 inhibition (clarithromycin + ritonavir). Plasma levels of both drugs rise, plus additive QT prolongation.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antibiotics without CYP3A4 inhibition: azithromycin or doxycycline. If clarithromycin is needed: ECG before start and every 3 days during therapy; do not increase clarithromycin dose.

Mechanism

Ritonavir blocks CYP3A4 and CYP2C19, through which clopidogrel becomes its active metabolite. The active metabolite is not formed – antiplatelet effect is lost. Ritonavir also induces glucuronidation, further reducing clopidogrel activity.

Symptoms

The patient feels no symptoms – the weakened antiplatelet effect is silent. In patients with a coronary stent or after acute coronary syndrome: risk of recurrent myocardial infarction, stent thrombosis, and ischaemic stroke.

Management

Avoid the combination. Alternative antiplatelet: ticagrelor (no CYP2C19 activation needed). If ticagrelor is impossible: prasugrel (requires activation but via a different route) with caution.

Mechanism

Ritonavir is one of the strongest CYP3A4 inhibitors, and CYP3A4 clears everolimus. With ketoconazole, an inhibitor of the same strength, everolimus AUC rises 15-fold.

Symptoms

Acute nephrotoxicity, pneumonitis.

Management

The combination is not recommended. The European everolimus SmPCs for cancer and tuberous sclerosis (EMA) name ritonavir among strong CYP3A4 inhibitors and advise against the pair, as there are no data to guide dosing. The US cancer label (FDA) says to avoid it. After organ transplantation, the Spanish everolimus SmPC allows the pair only if the benefit outweighs the risk, and the US transplant label only with close monitoring of everolimus trough levels. In that case, adjust the dose to trough levels measured at least 4–5 days after the previous dose change (everolimus SmPC). The ritonavir label calls for careful monitoring of everolimus effect and adverse reactions.

Mechanism

Dual potent CYP3A4 inhibition. Ketoconazole plasma levels may rise 3-fold. Hepatotoxicity and adrenal cortex suppression intensify.

Symptoms

Nausea, vomiting, abdominal pain and rising liver enzymes (ALT, AST); in severe cases jaundice and dark urine. Signs of adrenal insufficiency: weakness, fatigue, loss of appetite and weight, low blood pressure, low sodium and high potassium, low blood sugar. Ketoconazole itself prolongs the QT interval on the ECG.

Management

Ketoconazole tablets authorised by the European Medicines Agency (EMA) are indicated for Cushing's syndrome. With ritonavir alone the combination is not contraindicated, but the ketoconazole dose is kept lower than usual. The US ritonavir label (FDA) does not recommend ketoconazole doses above 200 mg a day, and the European ritonavir and ketoconazole SmPCs advise considering a dose reduction. While both drugs are taken, watch closely for signs of adrenal insufficiency and adjust the ketoconazole dose to cortisol levels (ketoconazole SmPC, EMA). Check liver enzymes and bilirubin before starting, weekly in the first month, then monthly for six months, and weekly for a month after each dose increase. Record an ECG before ketoconazole starts and within the first week (ketoconazole SmPC, EMA). If ritonavir boosts saquinavir or is part of paritaprevir/ombitasvir, ketoconazole is contraindicated with that regimen (ketoconazole SmPC, EMA).

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 5- to 10-fold. High risk of iatrogenic Cushing's syndrome and severe adrenal insufficiency on withdrawal.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.

Management

Avoid the combination. Alternative glucocorticoid: hydrocortisone (less CYP3A4-dependent) or inhaled/topical routes (no systemic effect). If methylprednisolone is needed, reduce 5-fold and keep the course as short as possible. Taper over several weeks on withdrawal because of suppressed adrenal cortex.

Mechanism

Ritonavir inhibits CYP3A4. Rifabutin rises 4-fold – severe neutropenia and uveitis risk. WHO 2024 recommends reducing rifabutin to 150 mg three times weekly.

Symptoms

Neutropenia, uveitis within 2-4 weeks.

Management

Reduce rifabutin to 150 mg three times weekly. Weekly CBC for first month.

Mechanism

Ritonavir strongly inhibits CYP3A4 and P-glycoprotein, both clearance routes of rivaroxaban. Ritonavir 600 mg twice daily raised rivaroxaban AUC 2.5-fold and peak concentration 1.6-fold. The EU SmPCs of rivaroxaban and ritonavir do not recommend the combination, and the FDA labels say to avoid it. None of these labels lists the pair as a contraindication.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

Avoid the combination. In a patient with HIV, choose a ritonavir-free antiretroviral regimen where possible or switch the anticoagulant. Warfarin is an option with frequent INR checks: ritonavir lowers R-warfarin levels, and the ritonavir SmPC advises INR monitoring. Another option is a short course of low molecular weight heparin. Nirmatrelvir with ritonavir for COVID-19 also contains ritonavir, and its SmPC does not recommend use with rivaroxaban.

Mechanism

Rosuvastatin barely uses CYP3A4 but is a substrate of OATP1B1 and BCRP transporters, both inhibited by ritonavir. Rosuvastatin plasma levels rise 2- to 4-fold.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

On ritonavir-boosted antiretroviral therapy, cap rosuvastatin at 10 mg/day. Check creatine kinase at 4–6 weeks and on muscle symptoms.

Mechanism

Sildenafil is broken down in the liver by CYP3A4, and ritonavir strongly inhibits this enzyme. With ritonavir 500 mg twice daily, sildenafil area under the curve (AUC) rose 11-fold and peak concentration 4-fold; 24 hours after the dose, sildenafil levels were still about 200 ng/mL compared with about 5 ng/mL without ritonavir. This raises the risk of sildenafil side effects.

Symptoms

A sharp drop in blood pressure with dizziness and fainting, prolonged erection, visual disturbances. An erection lasting more than 4 hours needs urgent medical care.

Management

The European Medicines Agency (EMA) contraindicates the combination in pulmonary arterial hypertension (ritonavir label and pulmonary hypertension sildenafil label, EMA). During a nirmatrelvir/ritonavir course for COVID-19, sildenafil is contraindicated for any indication (nirmatrelvir/ritonavir label, EMA). For erectile dysfunction in a patient on long-term ritonavir, the combination is not recommended (sildenafil label). If sildenafil is still needed, use a single 25 mg dose and no more than 25 mg in 48 hours (ritonavir and sildenafil labels). The US Food and Drug Administration (FDA) sets the same limit and advises closer monitoring for side effects: low blood pressure, fainting, prolonged erection (ritonavir and sildenafil FDA labels).

Mechanism

Tacrolimus is almost entirely cleared via hepatic CYP3A4. Ritonavir is the strongest CYP3A4 inhibitor available. Tacrolimus plasma levels can rise 50-fold or more. Acute nephrotoxicity and neurotoxicity with encephalopathy have been reported.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients, accelerated graft function decline.

Management

Avoid the combination where possible, as the tacrolimus SmPC states. If ritonavir cannot be avoided, the SmPC advises considering omitting the tacrolimus dose on the day ritonavir starts. Tacrolimus is restarted the next day at a reduced dose guided by blood levels. Trough levels (C0) are checked often from the first days and again after ritonavir is stopped, and the dose follows them. Renal function and the QT interval on ECG are monitored as well. Transplant patients are managed jointly by transplant and infectious diseases teams. Where possible, switch to a ritonavir-free antiretroviral regimen, for example one based on dolutegravir or bictegravir.

Mechanism

Ritonavir inhibits CYP3A4, the enzyme that clears tadalafil. Ritonavir 200 mg twice daily doubled tadalafil exposure (AUC) after a single 20 mg dose, and 500–600 mg twice daily raised it by 32% (tadalafil and ritonavir SmPCs). Later ritonavir also induces the same enzyme, and after about one week tadalafil exposure is close to normal (US tadalafil label for pulmonary arterial hypertension, FDA).

Symptoms

Hypotension, headache, priapism.

Management

The combination is not contraindicated, but the tadalafil dose is limited and the plan depends on the indication. For erectile dysfunction taken as needed, use no more than 10 mg of tadalafil once every 72 hours and watch more closely for adverse reactions (ritonavir SmPC). For once-daily use in erectile dysfunction or benign prostatic hyperplasia, the maximum is 2.5 mg a day (US tadalafil label, FDA). In pulmonary arterial hypertension, the European tadalafil SmPC (EMA) does not recommend use with ritonavir. If the pair cannot be avoided, the US label gives this plan: in a patient on ritonavir for at least one week, start tadalafil at 20 mg once daily and increase to 40 mg as tolerated; when ritonavir is added to tadalafil, stop tadalafil at least 24 hours before ritonavir starts and resume at 20 mg after at least one week (US tadalafil label, FDA).

Mechanism

Tamsulosin is a CYP3A4 substrate. Ritonavir is a potent CYP3A4 inhibitor. Tamsulosin plasma levels rise 5-fold or more; orthostatic hypotension and syncope emerge.

Symptoms

Sudden blood pressure drop on standing, syncope, dizziness. Older patients: fall and fracture risk.

Management

Avoid the combination. Alternative for benign prostatic hyperplasia on ritonavir: a 5α-reductase inhibitor (finasteride, dutasteride; minimal CYP3A4 dependence) or an α1-blocker with less CYP3A4 dependence (alfuzosin with caution).

Mechanism

Ritonavir is a strong CYP3A4 inhibitor, but it also induces CYP2C19 and CYP2C9, the main enzymes that clear voriconazole. Induction wins, and voriconazole exposure falls. With ritonavir 400 mg twice daily, voriconazole AUC drops by 82% and Cmax by 66%; with 100 mg twice daily, by 39% and 24% (Vfend SmPC, EMA). Voriconazole inhibits CYP3A4, but this barely affects ritonavir: its exposure is unchanged with the high dose and falls by 13% (AUC) with the low dose.

Symptoms

The main risk is loss of antifungal effect: invasive aspergillosis, candidiasis or another fungal infection treated with voriconazole fails to respond or progresses. The voriconazole and ritonavir labels (EMA and FDA) warn of a possible loss of effect. On the ritonavir side there is little to see: its concentration changes little, and the labels describe no added ritonavir toxicity.

Management

Do not combine voriconazole with ritonavir at 400 mg twice daily or higher, the dose at which ritonavir is an antiretroviral in its own right: both labels list this as a contraindication (Vfend SmPC, EMA, section 4.3; Norvir SmPC, EMA, section 4.3; Vfend and Norvir prescribing information, FDA, sections 4 and 7). Also avoid voriconazole with ritonavir 100 mg twice daily, the booster dose for another protease inhibitor, unless an assessment of benefit and risk for the patient justifies voriconazole (Vfend SmPC, EMA, sections 4.4 and 4.5; Norvir SmPC, EMA, section 4.5). The labels give no voriconazole dose adjustment for this case. When keeping both drugs, expect voriconazole exposure to fall by about 39% (Vfend SmPC, EMA) and watch the response of the fungal infection. When ritonavir is used as a booster, look up the contraindications of the boosted protease inhibitor in its own label (Norvir SmPC, EMA, section 4.3).

Mechanism

Ritonavir strongly inhibits CYP3A4, and at full antiretroviral doses it probably inhibits CYP2D6 as well (ritonavir SmPC). The liver breaks down amitriptyline mainly through CYP2D6 and CYP2C19, and to a lesser degree through CYP3A4 (amitriptyline SmPC). The ritonavir SmPC expects higher amitriptyline levels, and the amitriptyline SmPC expects a clinically relevant interaction with strong CYP3A4 inhibitors, naming ritonavir. Neither document gives the size of the rise.

Symptoms

Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. QT prolongation with torsades risk.

Management

The combination is allowed but needs monitoring. With ritonavir at full antiretroviral doses, watch the therapeutic and adverse effects of amitriptyline closely (ritonavir SmPC). The amitriptyline dose may need to be lowered (US Food and Drug Administration (FDA) ritonavir label). When a tricyclic antidepressant is combined with a strong CYP2D6 inhibitor, the amitriptyline SmPC advises considering plasma level monitoring and adjusting the dose if needed. Use amitriptyline with caution in significant bradycardia, decompensated heart failure and with other drugs that prolong the QT interval (amitriptyline SmPC). After ritonavir is stopped, amitriptyline levels may fall and a higher antidepressant dose may be needed (FDA amitriptyline label).

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available – the main amlodipine metabolic route. Amlodipine plasma levels rise 2- to 3-fold, with hypotension and peripheral oedema.

Symptoms

Lower blood pressure, postural dizziness, marked lower-leg oedema. Older patients: fall risk.

Management

Halve amlodipine when combined (starting 2.5 mg/day) and monitor blood pressure 1–2 weeks after. Alternative antihypertensive on ritonavir: ACE-I or ARB (no CYP3A4 dependence).

Mechanism

Ritonavir inhibits CYP3A4 but at the same time speeds up other methadone elimination pathways, including glucuronidation. The net result is lower methadone exposure: in a study, methadone AUC fell by 36% (ritonavir label). This can bring on withdrawal symptoms.

Symptoms

Methadone levels usually fall, and a patient on maintenance therapy develops withdrawal signs: watery eyes, runny nose, sneezing, yawning. If the methadone dose was raised and ritonavir is later stopped, methadone levels can rise: drowsiness, slow shallow breathing. Methadone prolongs the QT interval on the ECG; marked prolongation can cause fainting and torsades de pointes.

Management

The combination can be used with monitoring. After ritonavir is started, watch a patient on methadone closely for withdrawal signs and raise the methadone dose if needed, guided by clinical response (ritonavir and methadone labels). If ritonavir is stopped, watch for drowsiness and slowed breathing and consider lowering the methadone dose: the US methadone label (FDA) asks for this with any change in concomitant drugs that can raise methadone levels. The Spanish methadone SmPC lists CYP3A4 inhibitors, ritonavir among them, as a risk factor for QT prolongation. Record an ECG before methadone starts, two weeks later and before each dose increase. Low potassium, calcium or magnesium also raise the risk, so these patients need closer monitoring (methadone SmPC).

Mechanism

Complex mechanism. Ritonavir inhibits CYP3A4 but simultaneously induces CYP1A2, CYP2C9, and CYP2C19 (long-term effect). The net effect on warfarin varies: in some patients INR rises, in others it falls.

Symptoms

If INR rises: gum bleeding, epistaxis, bruising without trauma, blood in urine or stool. If INR drops: thromboembolic risk (deep vein thrombosis, stroke in atrial fibrillation).

Management

The combination can be used with closer coagulation monitoring. The US ritonavir label (FDA) recommends frequent INR checks at the start of co-administration. The European ritonavir SmPC asks for monitoring of anticoagulation parameters both at antiretroviral doses and at the low dose used to boost other protease inhibitors. Adjust the warfarin dose to the INR. The Spanish warfarin SmPC requires close coagulation control whenever a concomitant medicine is added or stopped, so check the INR more often after ritonavir is stopped as well (warfarin SmPC).