Two good examples of drugs requiring gradual upward titration are CP-868596 supplier pimozide and sertindole. Pimozide is an effective neuroleptic agent, that has been on the market since 1971. It has a long mean half-life of approximately 55 h in most individuals. This is highly variable and may be as long as 150 h in some patients. When first approved, its starting dosage was 2 to 4 mg/day with a slow upward titration to a maximum dosage of 10 mg/day. Subsequently, the slow Inhibitors,research,lifescience,medical titration schedule was removed, the starting dosage increased to 20 mg/day and the maximum dosage was increased to 60 mg/day. Following reports of QTc

interval prolongation and torsade de pointes (TdP), the recommended dosing schedule for patients with chronic schizophrenia was amended to a starting dosage of

2 mg/day. Subsequent titration was to be slow and shallow, with increases of 2 to 4 mg in the daily dose being made at weekly intervals or Inhibitors,research,lifescience,medical longer. The maximum dosage was reduced from 60 to 20 mg/day. In 1981, trials investigating the use of pimozide in schizophrenia in the USA had to be suspended following Inhibitors,research,lifescience,medical the sudden deaths of two patients during acute titration of pimozide to 70 to 80 mg/day.5 In the USA, pimozide is not approved for use in schizophrenia; it was approved in 1984 only for use in Tourette’s syndrome. Sertindole is one of the relatively new, atypical antipsychotic agents. It was introduced onto the market in 1995. It has powerful α-adrenoceptor-blocking activity Inhibitors,research,lifescience,medical and an acute administration of a single dose of 8 mg or more can result in marked orthostatic hypotension. Initiation of therapy with sertindolc, therefore, requires a starting dosage of 4 mg/day. Sertindole is metabolized by the cytochrome P450 enzyme CYP2D6 and exhibits a high interindividual variability of metabolism. Its half-life ranges from 60 to 100

h, and a given dose requires well over 10 days for steady-state plasma concentration to be reached. Therefore, the dosing scheme approved requires that the dose should be Inhibitors,research,lifescience,medical increased in 4 mg increments Mephenoxalone after 4 to 5 days on each dose to the optimal maintenance dosage range of 1 2 to 20 mg/day. Depending upon individual patient response, the dosage may be increased to a maximum of 24 mg/day. Patients’ blood pressure should be monitored during the period of dose titration and during the early part of maintenance treatment. The dosing section warns, “A starting dose of 8 mg or a rapid increase in dose carries a significant risk of severe hypotension. ” Despite its otherwise favorable profile in terms of extrapyramidal side effects, this shallow dose titration renders the drug worthless for use in acute situations. In one study, all 499 labels of drugs approved by the US Food and Drug Administration (FDA) between 1 January 1980 and 31 December 1999 were examined for significant dose changes.