Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder.
BACKGROUND
Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking.


OBJECTIVE
This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max).


METHODS
This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting.


RESULTS
A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%).


CONCLUSIONS
In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.
Miceli
Jeffrey J
JJ
Pfizer Global Research and Development, New London, Connecticut 06320, USA. jeffrey.j.miceli@pfizer.com
Tensfeldt
Thomas G
TG
Shiovitz
Thomas
T
Anziano
Richard J
RJ
O'Gorman
Cedric
C
Harrigan
Rachel H
RH
D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D011618:Psychotic Disorders / Q000188:drug therapy; D012559:Schizophrenia / Q000188:drug therapy; D016037:Single-Blind Method; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D006220:Haloperidol