warnings
WARNINGS General Diazepam rectal gel should only be administered by caregivers who in the opinion of the prescribing physician 1) are able to distinguish the distinct cluster of seizures (and/or the events presumed to herald their onset) from the patient’s ordinary seizure activity, 2) have been instructed and judged to be competent to administer the treatment rectally, 3) understand explicitly which seizure manifestations may or may not be treated with diazepam rectal gel, and 4) are able to monitor the clinical response and recognize when that response is such that immediate professional medical evaluation is required. CNS Depression Because diazepam rectal gel produces CNS depression, patients receiving this drug who are otherwise capable and qualified to do so should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle until they have completely returned to their level of baseline functioning. Although diazepam rectal gel is indicated for use solely on an intermittent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS depressants must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver. Prolonged CNS depression has been observed in neonates treated with diazepam. Therefore, diazepam rectal gel is not recommended for use in children under six months of age. Pregnancy Risks No clinical studies have been conducted with diazepam rectal gel in pregnant women. Data from several sources raise concerns about the use of diazepam during pregnancy. Animal Findings: Diazepam has been shown to be teratogenic in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m 2 basis). Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis. Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce longterm changes in cellular immune responses, brain neurochemistry, and behavior. General Concerns and Considerations About Anticonvulsants: Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but a smaller number of systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. The reports suggesting an elevated incidence of birth defects in children of drug treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus. 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 on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Advice Regarding the Use of Diazepam rectal gel in Women of Childbearing Potential: In general, the use of Diazepam rectal gel in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The specific considerations addressed above regarding the use of anticonvulsants in epileptic women of childbearing potential should be weighed in treating or counseling these women. Because of experience with other members of the benzodiazepine class, Diazepam rectal gel is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. 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. Withdrawal Symptoms Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of regular use of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section). Chronic Use Diazepam rectal gel is not recommended for chronic, daily use as an anticonvulsant because of the potential for development of tolerance to diazepam. Chronic daily use of diazepam may increase the frequency and/or severity of tonic clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures. Use in Patients with Petit Mal Status Tonic status epilepticus has been precipitated in patients treated with IV diazepam for petit mal status or petit mal variant status.