Drug Interactions between amoxicillin / clarithromycin / omeprazole and clozapine

MONITOR CLOSELY: Clozapine has the potential to prolong QT interval of the electrocardiogram. Theoretically, coadministration with other agents that can cause QT prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Clozapine treatment alone has been associated with ventricular arrhythmia, torsade de pointes, cardiac arrest, and sudden death. 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, hypocalcemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Certain QT-prolonging agents (e.g., neuroleptics; phenothiazines; tricyclic antidepressants; some antihistamines, antispasmodics, and skeletal muscle relaxants) may also have additive parasympatholytic and central nervous system-depressant effects with clozapine. Excessive parasympatholytic effects can result in paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MANAGEMENT: Caution is recommended if clozapine is used in combination with other drugs that can prolong the QT interval. Serum electrolytes, including potassium, magnesium and calcium, should be measured at baseline and periodically during treatment, and any abnormalities corrected prior to initiating clozapine. Routine ECG assessment may detect QTc prolongation, but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. 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. Additional precaution is required when using QT-prolonging agents with anticholinergic properties, particularly in the elderly and those with underlying organic brain disease. Patients should be advised to notify their physician if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Dosage adjustments may be necessary if excessive adverse effects develop. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

MONITOR: Coadministration with omeprazole may decrease the plasma concentrations of clozapine. The proposed mechanism is omeprazole induction of clozapine metabolism via CYP450 1A2. Two case reports describe patients stabilized on clozapine who experienced a 42% and 45% decrease in their plasma clozapine levels following the addition of omeprazole. No changes in their clinical presentation were noted, however. In a retrospective study of the medical files of 13 psychiatric patients receiving both clozapine and omeprazole, a switch to pantoprazole was associated with a significant rise of the serum clozapine levels in all nonsmokers relative to smokers, although the daily dosage of clozapine was unchanged. Presumably, the increase was due to the discontinuation of CYP450 1A2 induction by omeprazole in nonsmokers, whereas the isoenzyme remained induced in patients who smoked, as cigarette smoke is a known inducer of CYP450 1A2. Theoretically, this interaction could also occur with esomeprazole, the S-enantiomer of omeprazole.

MANAGEMENT: Pharmacologic response and serum clozapine levels should be monitored more closely whenever omeprazole or esomeprazole is added to or withdrawn from therapy, and the clozapine dosage adjusted as necessary. Alternatively, use of another proton pump inhibitor such as pantoprazole may be considered.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.