Pharmacokinetics, Toxicology

CAUTION: Concomitant Administration of Clozapine and Lorazepam (Clozaril and Ativan)

Compiled By Hakeem Alexander

(Exercising Your Mind)

“There may be a risk in combining clozapine with a benzodiazepine, especially if the dose is rapidly increased. There have been at least seven reported incidents of people stopping breathing after they were given a benzodiazepine while on clozapine.”
– Ronald J. Diamond, M.D.; Instant Psychopharmacology, 2002.

“Marked sedation, excessive salivation, ataxia, and, rarely, death have been reported with the concomitant use of clozapine and lorazepam.

The risk of using lorazepam in combination with scopolamine, loxapine, clozapine, haloperidol, or other CNS-depressant drugs has not been systematically evaluated. Therefore, caution is advised if the concomitant administration of lorazepam and these drugs is required.”

“Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.”
-; RxList, Ativan: Side Effects and Drug Interactions

“Delirium has been reported in four clozaril-treated patients in whom lorazepam was initiated.(4,7) Respiratory arrest and death were reported in one patient in whom clozapine was initiated who had been maintained on oral lorazepam. The patient received three supplemental doses of intravenous lorazepam for increased psychosis and was found dead 12 hours later.(8)”

4.Jackson CW, Markowitz JS, Brewerton TD. Delirium associated with clozapine and benzodiazepine combinations. Ann Clin Psychiatry 1995 Sep;7(3):139-41.

7.Cobb CD, Anderson CB, Seidel DR. Possible interaction between clozapine and lorazepam. Am J Psychiatry 1991 Nov;148(11):1606-7.

8.Klimke A, Klieser E. Sudden death after intravenous application of lorazepam in a patient treated with clozapine. Am J Psychiatry 1994 May; 151(5):780.

Ann Clin Psychiatry. 1995 Sep;7(3):139-41.

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Delirium associated with clozapine and benzodiazepine combinations.

Institute of Psychiatry, Medical University of South Carolina, Charleston, USA.

Delirium has many organic causes, one of which is the combination of medications. This is sometimes difficult to differentiate in the psychotic individual. To our knowledge there are no published cases of delirium definitively established by “rechallenge” with a combination of clozapine and benzodiazepines. Lorazepam was given for agitation in two individuals on clozapine. Because of either the short half-life, or the lack of knowledge about this interaction, multiple doses were given. Clonazepam was given to a third individual. Two of the reported individuals developed a delirium associated with the administration and onset of lorazepam. These patients had received both lorazepam and clozapine singularly in the past without the adverse effects seen with the combination. Both patients were rechallenged with second doses of lorazepam, when they again developed a delirium. In one case the patient was admitted on clonazepam and then started on clozapine. A delirium developed at a clozapine dose of 150 mg/day; she was not rechallenged. In all three cases the patients’ sensorium cleared when benzodiazepines were discontinued. The combination of benzodiazepines and clozapine should be avoided if possible, and if they are used in combination, it should be with great caution.

PMID: 8646274 [PubMed – indexed for MEDLINE]


Clozapine Drug-Drug Interactions: A Review of the Literature
Psychopharmacy, Institute of Psychiatry, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29465, USA
2Department of Pharmacy Practice, Institute of Psychiatry, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29465, USA
3Department of Psychiatry and Behavioral Sciences, Institute of Psychiatry, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29465, USA
*Correspondence to JOHN S. MARKOWITZ, Department of Pharmacy Practice, Institute of Psychiatry, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29465, USA
clozapine • drug interaction • polypharmacy
Clozapine is often used in combination with other medications. To date, there has been no comprehensive review of drug-drug interactions involving clozapine. This review summarizes published reports of suspected drug-drug interactions, and assesses their clinical significance. A computerized search was conducted using MEDLINE (1975-1996) to retrieve all reports of adverse events associated with the concurrent use of clozapine and other agents. Forty-three reports involving 19 different drugs were evaluated. Clozapine appeared to be involved in pharmacokinetic and pharmacodynamic interactions when prescribed concurrently with most major classes of therapeutic agents. In general, the addition of other medications with similar pharmacological effects or side-effects to clozapine may enhance these effects in an additive or possibly synergistic manner. The selective serotonin reuptake inhibitor fluvoxamine was involved in the most thoroughly documented pharmacokinetic interactions, while a number of reports were found implicating various benzodiazepines in apparent pharmacodynamic interactions. No clozapine-drug combination is absolutely contraindicated, but some members of a given therapeutic class may pose less risk than others when used concurrently with clozapine. © 1997 John Wiley & Sons, Ltd (emphasis added)

H. H. Keller1   Contact Information, R. Schaffner1 and W. Haefely1
(1) Pharmaceutical Research Division, F. Hoffman-LaRoche & Co., Ltd. Grenzacherstrasse 124, CH-4002, Basel, Switzerland
Received: 3 December 1975  Accepted: 9 March 1976
Summary  Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain, and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics.

It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.
Key words  Neuroleptics – Benzodiazepines – Dopamine – HVA – GABA – Catalepsy

1: Am J Psychiatry. 1994 May;151(5):780.

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Sudden death after intravenous application of lorazepam in a patient treated with clozapine.

PMID: 8166326 [PubMed – indexed for MEDLINE]

Am J Psychiatry. 1991 Nov;148(11):1606-7.

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Possible interaction between clozapine and lorazepam.

PMID: 1928489 [PubMed – indexed for MEDLINE]

1: J Clin Psychiatry. 1999 Jun;60(6):408-9.

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Seizures after discontinuation of low-dose lorazepam from originally seizure-free clozapine regimen: combined effects?

PMID: 10401922 [PubMed – indexed for MEDLINE]

Clozapine: Serious Adverse Side Effects, Drug Interactions, and Other Complications of Therapy

Deanna M. Guith

Clozapine (Clozaril®, Sandoz, East Hanover, NJ), an atypical antipsychotic agent with pharmacological properties considerably different from standard neuroleptics, has been found to be of great benefit especially to patients with treatment-resistant psychotic disorders. However, it is these unique pharmacological properties that have also been associated with mul tiple side effects ranging from the relatively benign (ie, sialorrhea during sleep, dizziness) to the potentially fatal (ie, agranulocytosis, seizures, and respiratory depression) which have limited its use. These untoward side effects are particularly problematic in the elderly population who often have concomitant medi cal illnesses requiring multiple medication regimens, including psychotropics that may interact with cloza pine (ie, benzodiazepines, cimetidine, fluoxetine). Because even the most benign of side effects has the potential of becoming fatal in certain circumstances if left unaddressed, it is imperative for patients, clinicians, pharmacists, and all health care professionals to be aware of adverse reactions and possible complica tions of clozapine therapy to prevent significant morbidity and mortality. Copyright © 1996 by W.B. Saunders Company (emphasis added)

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