Clozapine adverse drug reactions

Sassim N, Grohmann R. Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry 1988 21 306-307. 

The relation between neuroleptic drug therapy and myocarditis and cardiomyopathy has been examined using the international database on adverse drug reactions run by the World Health Organization (152). Myocarditis and cardiomyopathy were reported rarely as suspected adverse drug reactions, and accounted for under 0.1% (n = 2121) of almost 2.5 million reports. The association of clozapine with those adverse reactions was statistically significant (231 reports out of 24 730), as was the association with other antipsychotics (89 of 60 775). 

A thorough study of the risk of myocarditis or cardiomyopathy in Australia detected 23 cases (mean age 36 years 20 men) out of 8000 patients treated with clozapine from January 1993 to March 1999 (absolute risk 0.29% relative risk about 1000-2000) (17). AH the accumulated data on previous reports of sudden death, myocarditis, or cardiac disease noted in connection with clozapine treatment were requested from the Adverse Drug Reactions... 

Pirmohamed M, Williams D, Madden S et al (1995) Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther 272 984—990 Pirmohamed M, Breckenridge AM, Kitteringham NR et al (1998) Adverse drug reactions. BMJ 316 1295-1298... 

Yang L, Wang K, Chen J et al (2011) Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome-clozapine-induced agranulocytosis as a case study. PLoS ComputBiol 7 el002016. doi 10.1371/journal.pcbi.1002016... 

Management of adverse drug reactions Side effects such as sedation, hypotension and seizures are correlated with clozapine serum levels, and monitoring is recommended with doses >600 mg per day or when there has been a change in concomitant pharmacotherapy or cigarette use [141 ]. 

Agranulocytosis Because of a significant risk of agranulocytosis, a potentially life-threatening adverse reaction, reserve clozapine for use in the treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with clozapine, it... 

According to the FDA reports, painkillers are the most commonly reported cause of adverse reactions. The five drugs causing the most adverse reactions include oxycodone, fentanyl, morphine, acetaminophen, and methadone—all painkillers. The sixth most common cause of adverse reactions, clozapine is an antipsychosis drug. Other drugs reported to the FDA for adverse reactions include estrogens, insulin, paroxetine (the active ingre-... 

Risperdal was first marketed in 1994 as an atypical neuroleptic. The clinical trials, most of which lasted a few weeks, were too short to determine the rate of tardive dyskinesia and many other adverse effects. Indeed, the brief controlled clinical trials used for the approval of both clozapine and risperidone do not provide sufficient information to determine either efficacy or safety since the drugs would be used for months and years in individual patients, rather than for a few weeks (see chapter 13). Patients taking the medications over the coming years will provide the experimental data. However, since Risperdal is a potent dopamine blocker, it should have been anticipated that it would cause similar adverse reactions as the older neuroleptics. In my own experience, I have evaluated many cases of tardive dyskinesia caused by Risperdal, Zyprexa, and Geodon. Meanwhile, the Food and Drug Administration (FDA) has required the same tardive dyskinesia and neuroleptic malignant syndrome warnings on the labels of clozapine and risperidone as on the labels of the older neuroleptics. 

A woman was taking thiamazole for Graves disease, at times with various different antipsychotics including haloperidol, flupentixol, zuclopen-thixol and perphenazine for schizophrenia. Because of the severe extrapyramidal reactions and failure to control the schizophrenia, clozapine, increased over 5 days to 250 mg daily, was started instead. Within 5 days her white cell count had fallen to 2200/mm, which rose to 4000/mm, one month after both drugs were stopped. Later, after the thiamazole was stopped she was given the same dose of clozapine without these adverse effects. ... 

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