NIOSH justification of clonazepam (Klonopin) as a hazardous drug.

NIOSH monitors all new FDA drug approvals and new warnings on existing drugs.  Each of these drugs is evaluated according to the NIOSH criteria for a hazardous drug.  In April 2009, the FDA issued a new warning on clonazepam based on suicidal behavior and use in pregnancy. 

Usage in Pregnancy

To provide information regarding the effects of in utero exposure to Klonopin, physicians are advised to recommend that pregnant patients taking Klonopin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/."  (FDA, April, 2009).

These warnings alerted us to evaluate clonazepam as a hazardous drug.

The following information was available in the drug package insert (319 KB PDF):

"Animal Findings: In three studies in which Klonopin was administered orally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).

"General Concerns about Benzodiazepines: An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.

There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.

"Because of experience with other members of the benzodiazepine class, Klonopin is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug." © 2010 Genentech, Inc. All rights reserved.

Following review of clonazepam by the NIOSH committee, the 10-member expert panel and public comment, it was classified as a hazardous drugs, based primarily on its teratogenic potential at relatively low doses.  Some of the public comments were opposed to adding clonazepam to the list of hazardous drugs, but no valid, scientific support was provided.  It was also noted that the tablets are often cut and/or crushed for patients unable to swallow them, thus increasing the potential for occupational exposure by healthcare workers.

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