Carbamazepine

Mechanism

Carbamazepine is a strong CYP3A4 inducer. Isavuconazole falls significantly. EMA Cresemba Section 4.3.

Symptoms

Mycosis progression.

Management

Combination contraindicated.

Mechanism

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI) (linezolid SmPC), and the Spanish carbamazepine SmPC contraindicates carbamazepine with MAOIs; the US label does not recommend the combination and calls the grounds theoretical (US carbamazepine label). Both drugs suppress the bone marrow: linezolid causes anaemia, leukopenia, thrombocytopenia and pancytopenia, with risk rising with treatment length (linezolid SmPC), and carbamazepine lowers white cell and platelet counts and is rarely linked to agranulocytosis and aplastic anaemia (carbamazepine SmPC). As a strong inducer of liver enzymes, carbamazepine may lower linezolid exposure; the clinical significance is unknown (US linezolid label).

Symptoms

Weakness, pallor and breathlessness on exertion (anaemia), frequent infections and fever (leukopenia), bruising and bleeding (thrombocytopenia). Linezolid-related bone marrow suppression is more likely with courses longer than 10–14 days and in older patients (linezolid SmPC).

Management

The combination is contraindicated by the Spanish carbamazepine SmPC, which contraindicates carbamazepine with monoamine oxidase inhibitors (MAOIs) and requires MAOIs to be stopped at least 2 weeks before carbamazepine is started (carbamazepine SmPC). The linezolid SmPC describes linezolid as a reversible, non-selective MAOI (linezolid SmPC), while the linezolid labels do not mention carbamazepine. The FDA wording is softer: carbamazepine with MAOIs is not recommended on theoretical grounds (US carbamazepine label). If linezolid is still given to a patient on carbamazepine, check a full blood count with platelets weekly: the linezolid SmPC requires this for all patients and asks for especially close monitoring when other drugs that lower haemoglobin or platelets are taken (linezolid SmPC). If significant bone marrow suppression develops, stop linezolid unless continuing it is absolutely necessary (linezolid SmPC).

Mechanism

Carbamazepine induces CYP3A4; alprazolam plasma levels fall by 50%. Loss of anxiolytic effect and withdrawal symptoms (anxiety, insomnia, tremor) are possible.

Symptoms

Return of anxiety, insomnia, tremor, sweating, tachycardia (withdrawal). With high carbamazepine doses, full return of panic disorder symptoms is possible.

Management

During carbamazepine therapy, increase alprazolam by 50% or switch to lorazepam/oxazepam (glucuronidated, no CYP3A4 dependence). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Dual mechanism. Carbamazepine induces CYP3A4 and lowers amiodarone levels. Amiodarone blocks CYP3A4 and partially suppresses carbamazepine metabolism, so carbamazepine plasma levels may rise.

Symptoms

From amiodarone fall: atrial fibrillation symptoms return. From carbamazepine rise: ataxia, diplopia, nausea, hyponatraemia, drowsiness.

Management

Avoid the combination. Alternative anticonvulsants without induction: levetiracetam, lamotrigine. Alternative antiarrhythmic: beta-blocker for rate control or catheter ablation. If unavoidable, check carbamazepine plasma levels at 1–2 weeks.

Mechanism

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II liver enzymes (carbamazepine SmPC). It speeds up the metabolism of tricyclic antidepressants, their plasma levels fall and the antidepressant response weakens (amitriptyline SmPC).

Symptoms

Return of depressive symptoms or neuropathic pain. In depression: relapse risk.

Management

Per the carbamazepine SmPC, adjust the amitriptyline dose to clinical response. After carbamazepine is started or its dose changed, watch for return of depressive symptoms or pain; if they return, increase the amitriptyline dose. The FDA label also allows monitoring amitriptyline plasma levels. When carbamazepine is stopped, induction wears off, so review the amitriptyline dose again.

Mechanism

Carbamazepine induces CYP3A4 – the main amlodipine metabolic route. Amlodipine plasma levels fall and the antihypertensive effect weakens.

Symptoms

Blood pressure returns to baseline or higher, headache. In angina, episodes reappear. Symptoms emerge 1–2 weeks after starting carbamazepine.

Management

During carbamazepine therapy, increase amlodipine 1.5- to 2-fold with blood pressure monitoring, or switch to an ACE-I (enalapril) or diuretic (hydrochlorothiazide). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine is a strong inducer of CYP3A4 and P-glycoprotein. Apixaban exposure falls by about half (by 54% with rifampicin), weakening protection against stroke in atrial fibrillation and against recurrent venous thromboembolism. The FDA recommends avoiding the combination.

Symptoms

No overdose symptoms – the danger is undertreatment: ischemic stroke, recurrent DVT or PE despite ongoing anticoagulant.

Management

Avoid the combination. The AEMPS label splits by indication: apixaban is not used with carbamazepine to treat deep vein thrombosis or pulmonary embolism, and is used with caution in atrial fibrillation and to prevent recurrent thrombosis. Alternative anticoagulant when carbamazepine is needed: warfarin, whose effect is tracked by INR, so the induction can be offset by dose. Alternative anticonvulsant: levetiracetam or lacosamide, neither induces CYP3A4.

Mechanism

Carbamazepine induces CYP3A4 – the main atorvastatin metabolic route. Atorvastatin plasma levels fall by 30–60%; lipid-lowering effect drops proportionally.

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 carbamazepine therapy, increase atorvastatin 1.5- to 2-fold with lipid profile and creatine kinase monitoring, or switch to pravastatin (CYP3A4-independent). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine induces CYP3A4 – the main cyclosporine metabolic route. Cyclosporine plasma levels drop sharply; immunosuppression weakens, raising transplant rejection risk.

Symptoms

Rejection symptoms depend on the organ: fever, graft tenderness, rising creatinine (kidney); jaundice and rising liver enzymes (liver); dyspnoea (heart, lungs). Symptoms appear 1–3 weeks after starting carbamazepine.

Management

Avoid the combination. Alternative anticonvulsants in transplant patients: levetiracetam, lamotrigine, or gabapentin (minimal CYP3A4 effect). If carbamazepine is unavoidable, measure cyclosporine levels 2–3 times weekly and increase the dose.

Mechanism

Carbamazepine induces P-glycoprotein, the main dabigatran clearance route. Dabigatran plasma levels fall and anticoagulant effect weakens – stroke risk in atrial fibrillation rises.

Symptoms

The patient feels nothing. Stroke, deep vein thrombosis, and pulmonary embolism risks rise.

Management

Avoid the combination. Alternative anticoagulants: warfarin with INR monitoring or low molecular weight heparin for short courses. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine is a strong inducer of the CYP3A4 enzyme, and darunavir is cleared through CYP3A and is always given with a booster, ritonavir or cobicistat (darunavir SmPC). In a study of darunavir with ritonavir and carbamazepine 200 mg twice daily, carbamazepine exposure rose: area under the curve (AUC) by 45% and trough concentration by 54%, while the darunavir trough fell by 15% with an unchanged AUC (darunavir SmPC, 4.5). Darunavir boosted with cobicistat is more sensitive to CYP3A induction: strong inducers, carbamazepine among them, can lower cobicistat and darunavir concentrations to the point of lost antiviral effect, so the combination with cobicistat is contraindicated (darunavir SmPC, 4.3).

Symptoms

With ritonavir the main risk is carbamazepine toxicity from its higher concentration: drowsiness, dizziness, double vision, unsteadiness, nausea. With a cobicistat-based regimen the risk is loss of antiviral effect: rising viral load and darunavir resistance (darunavir SmPC, 4.3).

Management

Management depends on the booster. Darunavir boosted with cobicistat, including fixed-dose tablets, is contraindicated with carbamazepine (darunavir SmPC, 4.3). With ritonavir no darunavir dose adjustment is needed; if the combination is necessary, the patient is monitored for carbamazepine adverse reactions, carbamazepine blood levels are checked and the dose is adjusted: by the darunavir SmPC the carbamazepine dose sometimes has to be reduced by 25–50% in this combination (darunavir SmPC, 4.5). The documents do not name a replacement antiepileptic; the treating physician chooses it by indication.

Mechanism

The interaction works both ways. Diltiazem inhibits CYP3A4, the main enzyme of carbamazepine metabolism, and blood carbamazepine levels rise by 40–72%, in some patients to toxic levels (diltiazem and carbamazepine labels). Carbamazepine, in turn, is a potent CYP3A4 inducer and can lower levels of drugs metabolized by this enzyme (carbamazepine label). Diltiazem is metabolized by CYP3A4, and CYP3A4 inducers can lower its blood levels (diltiazem label).

Symptoms

Ataxia, diplopia, nausea, drowsiness, tremor. Severe cases: cardiac conduction abnormalities and AV block.

Management

The FDA diltiazem labels advise avoiding diltiazem with any CYP3A4 inducer and considering other treatment, and carbamazepine is a potent CYP3A4 inducer (carbamazepine label). If the combination is still needed, measure the blood carbamazepine level after diltiazem is added and adjust the carbamazepine dose if needed (diltiazem and carbamazepine labels). The usual adult therapeutic range of carbamazepine is 4–12 mcg/mL (FDA carbamazepine label). Warn the patient about signs of carbamazepine excess: dizziness, drowsiness, unsteady gait and double vision (carbamazepine label). The effect of diltiazem may weaken on carbamazepine, and its dose may also need adjustment (FDA carbamazepine label).

Mechanism

Carbamazepine induces CYP3A4 and accelerates hepatic doxycycline metabolism. Doxycycline half-life shortens from 16 to 7 hours; plasma levels fall.

Symptoms

The patient feels nothing. Risk of subtherapeutic antimicrobial concentrations and treatment failure rises – particularly with pathogens at the susceptibility breakpoint.

Management

Increase doxycycline to 200 mg twice daily during the course (instead of standard 100 mg twice daily). Alternative antibiotics without induction-driven loss: a cephalosporin, amoxicillin, azithromycin. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine is a strong CYP3A4 inducer, and dronedarone is cleared through this enzyme. The labels give no data for this pair; with another strong inducer, rifampicin, dronedarone levels fell by 80% and the antiarrhythmic effect weakens. The EU SmPC of dronedarone does not recommend strong CYP3A4 inducers and names carbamazepine; the FDA label says to avoid them. No label lists the pair as a contraindication.

Symptoms

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

Management

Avoid the combination. If long-term anticonvulsant therapy is needed, consider a drug without CYP3A4 induction, such as levetiracetam or lamotrigine, or another rhythm control strategy, including catheter ablation. While the pair continues, watch for recurrence of atrial fibrillation: pulse, ECG, palpitations and irregular heartbeat.

Mechanism

Carbamazepine induces CYP3A4 and accelerates ethinylestradiol metabolism. Combined oral contraceptive efficacy drops; pregnancies during regular use have been reported.

Symptoms

Breakthrough bleeding, missed periods, unplanned pregnancy. The patient feels no symptoms at the moment of dosing.

Management

Switch hormonal contraception to non-hormonal methods (copper IUD or barrier methods) for the duration of carbamazepine therapy. Alternatives: depot progesterone or a levonorgestrel IUD.

Mechanism

Carbamazepine induces CYP3A4 – a partial haloperidol clearance route. Haloperidol plasma levels fall by 50% and antipsychotic effect weakens.

Symptoms

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

Management

During carbamazepine therapy, increase haloperidol 1.5- to 2-fold under clinical monitoring. Alternative anticonvulsants without induction: sodium valproate, levetiracetam, lamotrigine (no CYP3A4 induction).

Mechanism

Carbamazepine induces the liver glucuronidation enzymes that clear lamotrigine, so lamotrigine leaves the blood faster (lamotrigine SmPC). According to the US Food and Drug Administration (FDA) label, carbamazepine lowers lamotrigine concentrations by about 40%. The effect also runs the other way: when lamotrigine is started in a patient on carbamazepine, central nervous system adverse effects can occur, and the FDA label notes that carbamazepine epoxide, the active metabolite, may rise.

Symptoms

If the lamotrigine dose is not adapted to carbamazepine, lamotrigine levels stay low and seizures may return. The lamotrigine SmPC notes a weaker response to lamotrigine when it is combined with enzyme inducers. After lamotrigine is started on top of carbamazepine, dizziness, ataxia, double vision, blurred vision and nausea can occur. When carbamazepine is stopped and the lamotrigine dose is not reduced, lamotrigine levels rise.

Management

The labels do not ban the pair, but lamotrigine with carbamazepine follows a separate schedule for inducers, and neither the starting dose nor the rate of increase may be exceeded (lamotrigine SmPC). In epilepsy, adults and adolescents from 13 years without valproate: 50 mg/day in weeks 1 and 2, 100 mg/day in two doses in weeks 3 and 4, then increases of no more than 100 mg every 1–2 weeks to the usual maintenance dose of 200–400 mg/day (lamotrigine SmPC). If the patient also takes valproate, the lower-dose valproate schedule applies (lamotrigine SmPC). In bipolar disorder, when carbamazepine is added to a stable lamotrigine dose of 200 mg, the dose stays at 200 mg in week 1, then 300 mg in week 2 and 400 mg from week 3. When carbamazepine is stopped, the steps go back down: from 400 mg to 300 mg in week 2 and 200 mg from week 3 (lamotrigine SmPC). The US Food and Drug Administration (FDA) label asks for these schedules to be followed closely; there is no target lamotrigine blood level, and the dose is set by clinical response (lamotrigine FDA label). If dizziness, ataxia or double vision appear after lamotrigine is started, the carbamazepine dose is reduced (lamotrigine SmPC).

Mechanism

Carbamazepine strongly induces CYP3A4, the liver enzyme that is the main route of quetiapine breakdown. In a study in patients, quetiapine exposure (area under the concentration-time curve) on carbamazepine fell on average to 13% of the baseline value, and even lower in some patients (quetiapine SmPC). The effect also runs the other way: quetiapine can raise the active carbamazepine metabolite, carbamazepine-10,11-epoxide (carbamazepine SmPC).

Symptoms

Quetiapine loses its effect: hallucinations, delusions and agitation return, and in bipolar disorder the risk of a new manic or depressive episode rises. Excess carbamazepine epoxide causes dizziness, somnolence, ataxia and double vision. If carbamazepine is stopped but the raised quetiapine dose is kept, quetiapine levels rise: somnolence, dizziness, orthostatic hypotension.

Management

Quetiapine may be started in a patient on carbamazepine only if its benefit outweighs the risk of withdrawing the inducer; the inducer is changed gradually and, if needed, replaced with a non-inducer such as sodium valproate (quetiapine SmPC). If the combination is needed for longer than 7–14 days, the quetiapine dose is increased up to 5-fold of the original dose, titrated to clinical response and tolerability (US Food and Drug Administration (FDA) quetiapine label). The Spanish SmPC caps the daily quetiapine dose at 750 mg in schizophrenia and 800 mg in bipolar disorder (quetiapine SmPC). After carbamazepine is stopped, the quetiapine dose is brought back to the original level within 7–14 days (quetiapine FDA label). Because of the epoxide rise, the carbamazepine dose is adjusted or its blood levels are monitored (carbamazepine SmPC).

Mechanism

As with apixaban, carbamazepine induces CYP3A4 and P-glycoprotein, and rivaroxaban levels fall. Rifampicin, an inducer of the same strength, lowers rivaroxaban AUC by about 50%. Anticoagulation loses effect, with a higher risk of stroke and recurrent thrombosis.

Symptoms

Ischemic stroke in atrial fibrillation patient or recurrent venous thrombosis on apparently active anticoagulant.

Management

Avoid the combination: this is what the rivaroxaban labels say (AEMPS, FDA), and the carbamazepine label calls for close watch for signs of thrombosis if the pair cannot be avoided. If carbamazepine cannot be replaced, switch to warfarin with a target INR of 2.0–3.0. Alternative anticonvulsant: levetiracetam.

Mechanism

Carbamazepine induces CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels fall 5- to 10-fold; lipid-lowering effect drops proportionally.

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 carbamazepine therapy, increase simvastatin 2- to 3-fold with lipid profile and creatine kinase monitoring, or switch to pravastatin/rosuvastatin (metabolism less CYP3A4-dependent). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine strongly induces CYP3A4 and P-glycoprotein. Tacrolimus plasma levels fall 2- to 3-fold; immunosuppression is lost, raising rejection risk.

Symptoms

Rejection symptoms depend on the organ: fever, graft tenderness, rising creatinine (kidney); jaundice and rising liver enzymes (liver). Symptoms appear 1–3 weeks after starting carbamazepine.

Management

Avoid the combination. Alternative anticonvulsants without induction: levetiracetam, lamotrigine, gabapentin. If carbamazepine is unavoidable, raise tacrolimus 2- to 3-fold with trough (C0) twice weekly.

Mechanism

Carbamazepine induces CYP1A2, which partly metabolises theophylline. Theophylline plasma levels fall by 25–50%; bronchodilator effect weakens.

Symptoms

Recurrence of asthma or COPD symptoms: dyspnoea, wheezing.

Management

During carbamazepine therapy, increase theophylline by 50% with level monitoring at 1–2 weeks. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine strongly induces CYP2C9 and CYP3A4. Warfarin plasma levels fall by 50–70% over 2–4 weeks; anticoagulant effect weakens.

Symptoms

INR drops below target. Thromboembolic risk rises: deep vein thrombosis, pulmonary embolism, ischaemic stroke in atrial fibrillation.

Management

After starting carbamazepine, check INR every 1–2 weeks for the first month and titrate warfarin (usually 1.5- to 2-fold dose increase). On carbamazepine withdrawal, induction persists for 2–4 weeks – return warfarin gradually. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carbamazepine is broken down in the liver mainly by CYP3A4, and clarithromycin inhibits this enzyme, so carbamazepine blood levels rise (carbamazepine SmPC). In clinical studies the increase was modest but statistically significant (clarithromycin SmPC). The interaction also works the other way: carbamazepine speeds up the breakdown of clarithromycin, and antibiotic levels may fall below the therapeutic range (clarithromycin SmPC).

Symptoms

Dizziness, drowsiness, unsteady gait, double vision, nausea. On the antibiotic side, a weaker response to treatment of the infection because of low clarithromycin levels.

Management

The combination can be used with monitoring. While the patient takes both drugs, monitor carbamazepine blood levels and adjust the dose if needed (carbamazepine SmPC). The US Food and Drug Administration (FDA) also advises close monitoring of carbamazepine levels and notes that the dose may need adjusting (carbamazepine FDA label). High carbamazepine levels cause dizziness, drowsiness, unsteady gait and double vision (carbamazepine SmPC). Use clarithromycin with caution in patients on carbamazepine because the antibiotic may be less effective (clarithromycin SmPC).

Mechanism

Carbamazepine is a strong CYP3A4 inducer. Plasma oestradiol falls by 40–60%. On menopausal hormone therapy, menopausal symptoms may return; on combined oral contraceptives, unplanned pregnancy risk arises.

Symptoms

Return of vasomotor symptoms: hot flushes, night sweats, sleep disturbance. On oral contraceptives: breakthrough bleeding, conception risk.

Management

On menopausal hormone therapy, double the oestradiol dose or switch to transdermal forms (patch, gel — minimal hepatic metabolism). For contraception on carbamazepine, combined oral contraceptives are unsuitable — choose a levonorgestrel IUS, copper IUD, or depot medroxyprogesterone acetate.

Mechanism

Isotretinoin alters the absorption and clearance of carbamazepine and its active metabolite, carbamazepine-10,11-epoxide; the carbamazepine SmPC lists isotretinoin among drugs that can lower carbamazepine levels. The labels do not describe any effect of carbamazepine on isotretinoin. The second risk concerns pregnancy: carbamazepine speeds up the breakdown of hormonal contraceptives and can make them fail (carbamazepine SmPC), while isotretinoin causes severe birth defects at a high rate and is contraindicated in pregnancy (isotretinoin SmPC).

Symptoms

If carbamazepine levels fall, seizures may return. Excess carbamazepine epoxide causes dizziness, somnolence, ataxia and double vision. If hormonal contraception fails and pregnancy occurs, isotretinoin exposes the fetus to severe birth defects.

Management

The pair is not banned. When isotretinoin is started or stopped, carbamazepine blood levels are checked, as the carbamazepine SmPC requires, and the carbamazepine dose is adjusted if needed (carbamazepine SmPC). Women who can become pregnant receive isotretinoin only within the pregnancy prevention programme: effective contraception without breaks from 1 month before starting, throughout treatment and for 1 month after, with at least one highly effective user-independent method or two complementary methods; pregnancy tests before, during (ideally monthly) and 1 month after treatment (isotretinoin SmPC). Hormonal contraceptives may fail with carbamazepine, so other effective methods are chosen, for example an intrauterine device (carbamazepine SmPC).

Mechanism

Verapamil inhibits CYP3A4, the main enzyme of carbamazepine metabolism (verapamil and carbamazepine labels). In patients with epilepsy, carbamazepine AUC rose by 46%, which can cause its side effects (verapamil label). The reverse effect is also possible: carbamazepine is a potent CYP3A4 inducer (carbamazepine label), and CYP3A4 inducers lower verapamil levels (verapamil labels).

Symptoms

Double vision, headache, ataxia, dizziness, drowsiness and nausea (verapamil and carbamazepine labels). Severe cases: cardiac conduction disorders and atrioventricular (AV) block (carbamazepine label).

Management

The combination is allowed but is managed by carbamazepine levels. After verapamil is added, measure the blood carbamazepine level and adjust its dose if needed (carbamazepine label). The usual adult therapeutic range of carbamazepine is 4–12 mcg/mL (FDA carbamazepine label). Warn the patient about signs of carbamazepine excess: double vision, headache, unsteady gait and dizziness (verapamil labels). Also monitor the effect of verapamil, because CYP3A4 inducers lower its levels (verapamil label).