Drug Interactions between celecoxib / tramadol and pimozide

CONTRAINDICATED: Pimozide can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes 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). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with pimozide. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MANAGEMENT: Coadministration of pimozide with other drugs that can prolong the QT interval is considered contraindicated.

GENERALLY AVOID: Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations of pimozide, which is partially metabolized by the isoenzyme. In a controlled study of healthy volunteers, administration of pimozide (2 mg single dose) with the potent inhibitor paroxetine (60 mg daily) resulted in mean increases of 62% and 151% in pimozide peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to pimozide given alone. Quinidine, another potent inhibitor of CYP450 2D6, has been shown in vitro to also inhibit the metabolism of pimozide. Pretreatment with a moderate CYP450 2D6 inhibitor, sertraline (200 mg daily to steady state), increased the Cmax and AUC of a single 2 mg dose of pimozide by about 40%. While no EKG changes were reported in the study, the effect on pharmacokinetic parameters of pimozide when given at doses greater than 2 mg is not currently known. The use of pimozide has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death.

MANAGEMENT: Due to the narrow therapeutic index of pimozide, concomitant use of pimozide in combination with moderate inhibitors of CYP450 2D6 should preferably be avoided if possible. Otherwise, close monitoring for the development of electrocardiographic abnormalities, extrapyramidal reactions (i.e., acute dystonic reactions, tardive dyskinesia, akathisia, Parkinson-like symptoms), and hypotension is recommended if concurrent use is required. Depending on the elimination half-life of these drugs, a considerable waiting period may also be appropriate following their discontinuation before pimozide is initiated. For example, the moderate CYP450 2D6 inhibitor rolapitant may increase plasma concentrations and the risk of adverse effects of CYP450 2D6 substrates for at least 28 days after concomitant therapy. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. The manufacturers consider the use of pimozide with potent CYP450 2D6 inhibitors such as fluoxetine, paroxetine, and quinidine to be contraindicated.

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.