These include those related to the pharmacokinetics of the drug (comedication with inhibitors of the metabolism of the drug and patients with hepatic and/or renal dysfunctions) and those related to enhanced susceptibility to the undesirable pharmacodynamic effect, of the drug on cardiac repolarization (predisposition to hypokalemia, bradycardia, cardiac disease, and/or arrhythmias, preexisting prolongation Inhibitors,research,lifescience,medical of QT interval, and comedication with other QT-prolonging drugs). Specific contraindications may also be applied to suit, particular drugs. For example, since thioridazine is

metabolized by CYP2D6, it was determined that “thioridazine is also conlraitidicated inpatients known to have reduced levels of cytochrome P4502D6. ” Sertindole too is metabolized by CYP2D6, but in PMs of CYP2D6, an alternative pathway of elimination is that mediated by CYP3A4. Since PMs of CYP2D6 may not be routinely identified in clinical practice, Inhibitors,research,lifescience,medical it was considered essential that sertindolc was contraindicated with inhibitors of CYP3A4 generally in order to specifically protect the PMs. Special warnings and precautions may be required with regard to the use of a QT-prolonging NCE

in special populations, such as patients with cardiac disease, the elderly, or patients receiving diuretics and other relevant, drug classes. JQ1 Statements may also be required on special monitoring requirements. These may include Inhibitors,research,lifescience,medical ECG recordings pretreatment and periodically while the patient, is on treatment. Pimozide, once again, illustrates the case well. Inhibitors,research,lifescience,medical ECG monitoring is recommended at baseline, annually, and (even more frequently) in those patients receiving pimozide in excess of 16 mg/day. A review of the need to continue treatment with pimozide is recommended in those Inhibitors,research,lifescience,medical showing certain specified ECG changes. The US labeling of thioridazine also requires serum potassium levels to be measured and normalized before starting treatment. It is also recommended that patients with

a QTc interval greater than 450 ms should not receive thioridazine. It is further advised that periodic monitoring of E’CGs and serum potassium levels during ADP ribosylation factor thioridazine treatment may be useful and thioridazine should be discontinued in patients who are found to have a QTc interval over 500 ms. The interaction section of pimozide, for example, describes pharmacodynamic interactions associated with comedications, such as neuroleptics, risk of diuretic therapy, drugs that prolong the QT interval, drugs with arrhythmogenic potential (antidepressants, antiarrhythmics), its CYP3A4- and CYP2D6-mediated metabolic profile (including in vitro data) and the consequences of the concurrent use of the inhibitors of its metabolism. The labeling of sertindole includes an elaborate drug interactions section describing its metabolism by CYP2D6 and CYP3A4 and the probable interactions at these loci.