Drug interactions, smoking and QTc risk (MEQ)

(i) Interaction types. Pharmacokinetic: smoking cessation removes CYP1A2 induction → rising clozapine exposure; fluvoxamine potently inhibits CYP1A2 → further level rise. Pharmacodynamic / multi-hit QTc: clarithromycin (macrolide QT effect) + rising clozapine exposure context + female sex + hypokalaemia reduce repolarisation reserve. Also PD sedation stack if other CNS depressants present.[1][2][3][5][6]

(ii) CYP mechanisms. Clozapine is primarily metabolised by CYP1A2. Cigarette smoke PAHs induce CYP1A2; cessation raises levels over days. Fluvoxamine is a potent CYP1A2 inhibitor classically elevating clozapine serum concentrations — often treated as a high-risk combination without intensive TDM. Nicotine replacement does not fully replace smoke induction.[1][2][3]

(iii) Immediate management. Medical review; continuous monitoring if QTc near 500 ms with symptoms/risk; replete K+ (and Mg2+) aggressively; stop or switch clarithromycin if alternatives exist; hold/reduce clozapine and check trough level; stop fluvoxamine or do not continue without specialist level-guided plan; 12-lead ECG serial review; treat as evolving drug-induced long QT prevention pathway (Drew).[4][5][6][7]

(iv) Medium-term plan. Restart clozapine only with registry/bloods rules and a lower dose anticipating non-smoking state; avoid fluvoxamine — choose OCD strategy with weaker 1A2 effect; smoking-cessation plan with planned level checks; ECG when clinically indicated; deprescribe unnecessary QT drugs; document pharmacy alert.[1][7][6]

(v) TdP emergency. Unstable: defibrillation/ACLS. IV magnesium even if Mg "normal"; correct K+; stop all QT-prolonging drugs; specialist consideration of overdrive pacing/isoprenaline in refractory pause-dependent TdP; avoid stacking further QT-active antiarrhythmics.[4][5]