Rifampicin

Mechanism

Strong CYP3A4 induction – atazanavir falls 80%. ART failure.

Symptoms

Rising viral load.

Management

Combination contraindicated.

Mechanism

Strong CYP3A4 inducer. Cobicistat falls 80% – ART failure.

Symptoms

Rising viral load, resistance risk.

Management

Combination contraindicated. TB in HIV patient – dolutegravir-based ARV (double dose with rifampicin).

Mechanism

Strong CYP3A4 induction – darunavir falls 80%. ART failure.

Symptoms

Rising viral load.

Management

Combination contraindicated. Alternative – rifabutin.

Mechanism

Rifampicin is a strong CYP3A4 inducer. Isavuconazole falls 97% – antifungal effect lost.

Symptoms

Fungal infection progression.

Management

Combination contraindicated. EMA Cresemba Section 4.3.

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

Rifampicin strongly induces CYP3A4 – the main N-deethylation pathway of amiodarone. Amiodarone and N-desethyl-amiodarone plasma levels fall by about 50%; antiarrhythmic effect weakens.

Symptoms

Atrial fibrillation symptoms return: palpitations, irregular pulse, fatigue, dyspnoea. Rhythm breakthroughs may require admission.

Management

During anti-TB therapy, replace amiodarone with a beta-blocker for rate control or plan catheter ablation. Induction persists for 2 weeks after rifampicin stops – restart amiodarone gradually.

Mechanism

Rifampicin is the strongest clinical inducer of CYP3A4 and P-glycoprotein. Apixaban levels fall by 54%, anticoagulation lost. FDA recommends avoiding the combination.

Symptoms

Ischemic stroke or recurrent VTE on apparently active apixaban. Lab: low anti-Xa level.

Management

The combination is avoided. In a patient on rifampicin, the apixaban SmPC does not recommend apixaban for treating deep vein thrombosis or pulmonary embolism, because efficacy may be compromised. For stroke prevention in atrial fibrillation it allows use with caution, while the FDA label says to avoid the pair for any indication. Apixaban is usually replaced for the rifampicin course by a parenteral anticoagulant such as a low-molecular-weight heparin. Warfarin is awkward here: per the rifampicin SmPC, S-warfarin exposure falls by 74%. The warfarin dose is then titrated under frequent INR checks and reduced again after rifampicin stops.

Mechanism

Rifampicin strongly induces CYP3A4 and the OATP1B1 transporter – two atorvastatin clearance routes. Atorvastatin plasma levels fall by 80%; lipid-lowering effect weakens.

Symptoms

The patient feels nothing. Laboratory: LDL cholesterol and total cholesterol rise. In high cardiovascular risk patients, myocardial infarction and stroke risk increase.

Management

During anti-TB therapy, switch to pravastatin (less induction-sensitive metabolism) or temporarily stop the statin for a short course. Induction persists for 2 weeks after rifampicin stops.

Mechanism

Rifampicin is a strong inducer of CYP3A4 and P-glycoprotein, the pathways that clear cyclosporine. In healthy volunteers cyclosporine oral bioavailability fell from 33% to 9% with rifampicin, and in kidney transplant recipients cyclosporine AUC fell by about 60%. Levels drop below the therapeutic range and the risk of graft rejection rises.

Symptoms

Rejection signs within 1–2 weeks.

Management

Increase cyclosporine 3–5 fold with level monitoring. Alternative – rifabutin (weaker).

Mechanism

Rifampicin strongly induces P-glycoprotein, the main dabigatran clearance route. Dabigatran plasma levels fall by 66%; stroke prevention in atrial fibrillation or VTE treatment fails.

Symptoms

The patient feels nothing. Stroke risk in atrial fibrillation rises, as do deep vein thrombosis and pulmonary embolism risks.

Management

The combination is not prescribed. Alternative anticoagulants: warfarin with INR monitoring or low molecular weight heparin for short courses. Induction persists for 2 weeks after rifampicin stops.

Mechanism

Rifampicin is a potent inducer of drug-metabolizing enzymes and transporters, including CYP3A4 and P-glycoprotein (rifampicin label). Diltiazem is metabolized by CYP3A4 (diltiazem label). With rifampicin, diltiazem blood levels fell to undetectable (FDA diltiazem label), so its antianginal and blood pressure-lowering effect can be lost.

Symptoms

Return of hypertension, anginal episodes in ischaemic heart disease. Rate control in atrial fibrillation is lost.

Management

Avoid the combination and consider other treatment (FDA diltiazem labels). When choosing a replacement, note that nifedipine, nimodipine, nisoldipine and nitrendipine are contraindicated with rifampicin (rifampicin label). If diltiazem is kept, monitor the patient closely when rifampicin is started and after it is stopped, checking the effect of diltiazem (diltiazem labels). The diltiazem dose may need adjustment when rifampicin is started or stopped (rifampicin label).

Mechanism

Rifampicin is a strong CYP3A4 inducer. At 600 mg daily it lowered dronedarone levels by 80% without major change in the active metabolite, and the antiarrhythmic effect weakens. The EU SmPC of dronedarone does not recommend the combination, and the FDA label says to avoid it. Neither the dronedarone nor the rifampicin labels list the pair as a contraindication.

Symptoms

Recurrence of atrial fibrillation symptoms: palpitations, irregular pulse, fatigue, dyspnoea. Possible rhythm breakthroughs requiring admission.

Management

Avoid the combination. In a patient with atrial fibrillation who needs tuberculosis treatment, plan rhythm control with a cardiologist for the rifampicin course, including catheter ablation. Rifampicin is hard to replace because it is part of the standard first-line regimen. Other antiarrhythmics lose exposure too: the rifampicin SmPC reports falls of 80% for quinidine and 87% for propafenone. If the pair continues, watch for recurrent atrial fibrillation on ECG and by symptoms.

Mechanism

Rifampicin is the most potent CYP3A4 inducer in clinical practice. Ethinylestradiol plasma levels fall by 40–60% within the first week. Combined oral contraceptive efficacy drops to chance.

Symptoms

Breakthrough bleeding, missed periods, unplanned pregnancy. The patient feels no symptoms at the moment of dosing – the problem becomes apparent only later.

Management

Switch hormonal contraception to non-hormonal methods (copper IUD or barrier methods) for the duration of rifampicin and an additional 4 weeks after stopping. Alternatives: depot progesterone or a levonorgestrel IUD (minimal CYP3A4 effect).

Mechanism

Rifampicin is a strong CYP3A4 inducer. Everolimus falls 60% – transplant rejection risk.

Symptoms

Transplant rejection signs.

Management

Alternative TB regimen without rifampicin. If necessary – double everolimus with frequent blood level monitoring.

Mechanism

Rifampicin strongly induces CYP3A4, which partly metabolises fluconazole. Fluconazole plasma levels fall by 25%; antifungal efficacy decreases.

Symptoms

Recurrence of mycosis symptoms: ongoing fever, skin or mucosal lesions; in immunocompromised patients, risk of systemic mycosis progression.

Management

When combined, increase fluconazole by 50–100% with efficacy monitoring. Alternative antifungal during anti-TB therapy: echinocandins (micafungin, caspofungin; no CYP3A4 dependence).

Mechanism

Rifampicin strongly induces CYP3A4 – the main haloperidol metabolic route. Haloperidol plasma levels fall by 70%; antipsychotic effect weakens.

Symptoms

Return of positive symptoms: hallucinations, delusions, agitation. In schizophrenia: risk of acute relapse.

Management

During anti-TB therapy, increase haloperidol 2- to 3-fold with clinical monitoring. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

Dual mechanism. Rifampicin strongly induces CYP3A4, which partly metabolises ketoconazole. Ketoconazole plasma levels fall by 50–80%; antifungal efficacy is lost.

Symptoms

Recurrence of mycosis symptoms: ongoing fever, skin or mucosal lesions; in immunocompromised patients, risk of systemic mycosis progression.

Management

The combination is not prescribed. Alternative antifungal during anti-TB therapy: echinocandins (micafungin, caspofungin; resistant to CYP3A4 induction) or terbinafine for dermatophytosis.

Mechanism

Rifampicin induces UGT1A4. Lamotrigine falls 40%.

Symptoms

Seizure breakthrough.

Management

Increase lamotrigine by 50-100%.

Mechanism

Rifampicin is the most potent CYP3A4 inducer available. Quetiapine plasma levels fall 5- to 8-fold – clinical inefficacy of the antipsychotic.

Symptoms

Return of positive symptoms: hallucinations, delusions, agitation. In bipolar disorder: manic episode risk.

Management

During anti-TB therapy, increase quetiapine 5-fold with clinical monitoring. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole. Alternative anti-TB drug: rifabutin (weaker CYP3A4 induction).

Mechanism

Rifampicin is a strong CYP3A4 + P-gp inducer. Rivaroxaban falls 50% – anticoagulation lost.

Symptoms

Stroke or recurrent VTE.

Management

Avoid the combination unless the patient can be closely watched for signs of thrombosis, as the EU SmPC and the FDA label of rivaroxaban state. During the rifampicin course rivaroxaban can be replaced with low molecular weight heparin. Warfarin is affected too: the rifampicin SmPC reports a 74% fall in S-warfarin exposure, so the dose is titrated to INR, checked more often than usual, including after rifampicin is stopped.

Mechanism

Rifampicin strongly induces CYP3A4 and the OATP1B1 transporter – the routes of simvastatin activation and hepatocyte uptake. Simvastatin plasma levels fall by 87%; lipid-lowering effect practically disappears.

Symptoms

The patient feels nothing. Laboratory: LDL cholesterol and total cholesterol rise. In high cardiovascular risk patients, myocardial infarction and stroke risk increase.

Management

During anti-TB therapy, switch simvastatin to pravastatin (less induction-sensitive metabolism). Induction persists for 2 weeks after rifampicin stops – reintroduce simvastatin gradually.

Mechanism

Strong CYP3A4 + P-gp inducer. Sirolimus falls 70% – rejection risk.

Symptoms

Rejection signs.

Management

Alternative TB regimen. If rifampicin necessary – triple sirolimus dose.

Mechanism

Strong CYP3A4 inducer. Tacrolimus falls 3-fold – transplant rejection risk.

Symptoms

Rejection signs, rising creatinine.

Management

For TB in transplant patient – increase tacrolimus 3-5 fold with blood level monitoring. Alternative – rifabutin (weaker).

Mechanism

Rifampicin induces CYP1A2 and CYP3A4. Theophylline falls 50% – bronchoconstriction breakthrough risk.

Symptoms

Return of dyspnoea, bronchospasm.

Management

Double theophylline dose with blood level monitoring.

Mechanism

Strong CYP3A4 inducer – ticagrelor falls 86%. Antiplatelet effect lost – stent thrombosis risk.

Symptoms

Stent thrombosis, MI.

Management

Combination contraindicated. Alternative – clopidogrel or prasugrel.

Mechanism

Rifampicin induces CYP2C9, CYP3A4 and CYP1A2 – all main warfarin metabolism pathways. Warfarin requirement rises 2–3 fold. After rifampicin withdrawal sensitivity returns over 2–4 weeks, with bleeding risk if the dose is not titrated back down.

Symptoms

During use: subtherapeutic INR, thrombosis risk. After rifampicin withdrawal: sudden INR rise, bleeding risk.

Management

Monitor INR twice weekly for the first 4 weeks of rifampicin; increase warfarin by 25–100% as needed. After rifampicin withdrawal, frequent INR monitoring and downward titration.

Mechanism

Rifampicin is a strong inducer of CYP3A4 and other drug-metabolising enzymes (rifampicin SmPC). CYP3A4 takes part in amlodipine metabolism, so amlodipine levels may fall and its blood pressure effect may weaken (both SmPCs). The documents do not give the size of the fall for amlodipine. For other calcium channel blockers it has been measured: rifampicin reduced exposure to nifedipine by 64% and to verapamil by 93% (rifampicin SmPC).

Symptoms

Blood pressure returns to previous values or rises higher, and headache may appear. In angina, attacks may become more frequent.

Management

The combination is acceptable with blood pressure control. While rifampicin is taken and after it is stopped, measure blood pressure and consider adjusting the amlodipine dose (amlodipine labels). Doses of drugs affected by rifampicin may need adjustment both when it is started and when it is stopped (rifampicin SmPC). Nifedipine, nimodipine, nisoldipine and nitrendipine are contraindicated with rifampicin, so they cannot replace amlodipine (rifampicin SmPC). Rifampicin also reduces exposure to the active metabolite of enalapril, so if a patient is switched to it, the dose is set by clinical response (rifampicin SmPC).

Mechanism

Rifampicin induces CYP3A4, modestly lowering bisoprolol plasma levels (bisoprolol is metabolised 50% via CYP3A4 and 50% renally). The effect is weaker than for fully CYP-dependent beta-blockers.

Symptoms

Gradual blood pressure rise or return of anginal symptoms 2–3 weeks after starting rifampicin. In tachyarrhythmias: return of symptoms.

Management

During anti-TB therapy, increase bisoprolol by 50% with blood pressure and pulse monitoring. After rifampicin stops, taper back gradually (induction persists for 2 weeks).

Mechanism

Rifampicin induces enterocyte P-glycoprotein. Digoxin bioavailability falls by 30%, levels drop — risking loss of rate control in atrial fibrillation or worsening of chronic heart failure.

Symptoms

Return of underlying disease: tachycardia in atrial fibrillation, dyspnoea and oedema in chronic heart failure. After rifampicin stops, digoxin levels may rise sharply.

Management

On the combination, check digoxin levels at 2 and 4 weeks after rifampicin start and 2 weeks after rifampicin stops. Digoxin dose is usually raised by 25–50% during rifampicin and returned to baseline afterward. In atrial fibrillation, consider adding a beta-blocker (bisoprolol, metoprolol) for rate control.

Mechanism

Rifampicin strongly induces liver enzymes, including CYP3A4 and CYP2B6, which mainly clear methadone (rifampicin SmPC). Rifampicin 600 mg/day reduced the oral bioavailability of methadone from 70% to 50% (rifampicin SmPC), and in patients stable on methadone, serum levels fell markedly and withdrawal symptoms appeared (US Food and Drug Administration (FDA) methadone label). After rifampicin is stopped, the induction fades and methadone levels rise again (methadone FDA label).

Symptoms

Opioid withdrawal on the previous methadone dose: restlessness, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, and also irritability, anxiety, back and joint pain, abdominal cramps, insomnia, nausea, vomiting, diarrhoea, and increased blood pressure, respiratory rate or heart rate. After rifampicin is stopped, if the methadone dose is not reduced, sedation and respiratory depression can follow, up to a fatal overdose.

Management

The pair is not banned. While the patient takes rifampicin, a higher methadone dose may be needed (methadone and rifampicin SmPCs). The US Food and Drug Administration (FDA) methadone label advises, if the combination is necessary, to consider raising the methadone dose until stable effects are reached and to watch for withdrawal signs. After rifampicin is stopped, a lower methadone dose is considered and the patient is seen at frequent intervals to catch sedation and respiratory depression early (methadone FDA label). The rifampicin SmPC warns that doses of other drugs may need adjusting both when rifampicin is started and when it is stopped.