Drug Interactions between clarithromycin and quetiapine

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of quetiapine, which is primarily metabolized by the isoenzyme. In 12 healthy volunteers, administration of a single 25 mg dose of quetiapine with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 4 days) increased mean quetiapine peak plasma concentration (Cmax) and systemic exposure (AUC) by 3.4- and 6.2-fold, respectively, and decreased mean oral clearance by 84% compared to quetiapine administered alone. High plasma levels of quetiapine may increase the risk and/or severity of serious adverse effects such as extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases (in children and adolescents), QT prolongation, cognitive and motor impairment, dysphagia, and heat-related illnesses due to disruption of body temperature regulation. A case report describes a patient treated with quetiapine 700 mg/day who developed severely impaired consciousness and respiratory depression requiring intensive care surveillance following two 500 mg doses of clarithromycin, another potent CYP450 3A4 inhibitor. Quetiapine plasma level was found to be nearly 5 times the high end of the recommended therapeutic range. The patient recovered a week after quetiapine was withdrawn. The interaction was also suspected in a case report of two patients receiving quetiapine with ritonavir-boosted atazanavir. One patient experienced significant increases in appetite and serum glucose and a weight gain of more than 22 kg over six months. The patient's weight returned to baseline five months after stopping both treatments. The second patient had increased sedation and mental confusion, which resolved several days following self-discontinuation of quetiapine.

GENERALLY AVOID: There is some concern that quetiapine may have additive cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram, including saquinavir, azole antifungal agents, and macrolide or ketolide antibiotics. In clinical trials, quetiapine was not associated with a persistent increase in QT intervals, and there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation and torsade de pointes have been reported during postmarketing use in cases of quetiapine overdose and in patients with risk factors such as underlying illness or concomitant use of drugs known to cause electrolyte imbalance or increase QT interval. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of quetiapine with potent CYP450 3A4 inhibitors that can also prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if coadministration is required. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. In addition, the dosage of quetiapine should be reduced due to CYP450 3A4 inhibition. The product labeling recommends a reduction to one-sixth of the original dosage. Following discontinuation of the CYP450 3A4 inhibitor, the dosage of quetiapine should be increased by 6-fold.