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 is the most potent CYP3A4 and P-glycoprotein inhibitor in clinical use (a pharmacokinetic booster in HIV regimens). Apixaban plasma levels roughly double. The FDA lists the combination as an absolute 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

The combination is not prescribed. For HIV patients on ritonavir-boosted regimens, anticoagulate with warfarin under INR control. Alternative: low molecular weight heparin for short courses.

Mechanism

Atorvastatin uses hepatic CYP3A4 for ~70% of its clearance. Ritonavir is the strongest available CYP3A4 inhibitor. Atorvastatin plasma levels rise 5- to 7-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 1–2 weeks of co-prescription.

Management

Cap atorvastatin at 10 mg/day. Preferable strategy: switch to pravastatin or rosuvastatin (cap rosuvastatin at 10 mg/day on ritonavir). Check creatine kinase at 4–6 weeks and on muscle symptoms.

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 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

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

Ritonavir strongly inhibits CYP3A4 and P-glycoprotein – the clearance routes of rivaroxaban. Rivaroxaban plasma levels rise several-fold. The FDA lists the combination as an absolute 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

The combination is not prescribed. For HIV patients, anticoagulate with warfarin under INR control or short-course low molecular weight heparin.

Mechanism

Sildenafil is cleared via hepatic CYP3A4. Ritonavir is the strongest CYP3A4 inhibitor available. Sildenafil levels rise 11-fold. The risk of severe hypotension and priapism rises sharply.

Symptoms

Sudden blood pressure drop: dizziness, syncope. Priapism – painful erection lasting more than 4 hours, requiring emergency care. Visual and auditory disturbances are amplified.

Management

For erectile dysfunction on ritonavir, sildenafil is capped at 25 mg no more than once every 48 hours. For pulmonary arterial hypertension (which needs regular high doses), the combination is contraindicated. Alternatives: inhaled iloprost or bosentan with dose adjustment.

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

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

Reduce tacrolimus dose 10- to 20-fold from day 1 and check daily trough (C0) levels. Post-transplant patients require joint management by transplant and infectious diseases teams. Where possible, switch antiretroviral therapy to a ritonavir-free regimen (dolutegravir + bictegravir-based).