Genesafe

Genesafe is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults.

Genesafe should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration.

The recommended dose of Genesafe is 250 mg to 350 mg three times a day and at bedtime. The recommended maximum duration of Genesafe use is up to two or three weeks.

Genesafe is contraindicated in patients with a history of acute intermittent porphyria or a hypersensitivity reaction to a carbamate such as meprobamate.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Sedation

Genesafe has sedative properties (in the low back pain trials, 13% to 17% of patients who received Genesafe experienced sedation compared to 6% of patients who received placebo) and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. There have been post-marketing reports of motor vehicle accidents associated with the use of Genesafe.

Since the sedative effects of Genesafe and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously.

Abuse, Dependence and Withdrawal

Carisoprodol, the active ingredient in Genesafe, has been subject to abuse, dependence, withdrawal, misuse, and criminal diversion.. Abuse of Genesafe poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures, and other disorders.

Post-marketing experience cases of carisoprodol abuse and dependence have been reported in patients with prolonged use and a history of drug abuse. Although most of these patients took other drugs of abuse, some patients solely abused carisoprodol. Withdrawal symptoms have been reported following abrupt cessation of Genesafe after prolonged use. Reported withdrawal symptoms included insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, ataxia, hallucinations, and psychosis. One of carisoprodol's metabolites, meprobamate (a controlled substance), may also cause dependence.

To reduce the risk of Genesafe abuse, assess the risk of abuse prior to prescribing. After prescribing, limit the length of treatment to three weeks for the relief of acute musculoskeletal discomfort, keep careful prescription records, monitor for signs of abuse and overdose, and educate patients and their families about abuse and on proper storage and disposal.

Seizures

There have been post-marketing reports of seizures in patients who received Genesafe. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol.

Genesafe was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromoGenesafel aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vivo mouse micronucleus assay of circulating blood cells.

Genesafe was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spent in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known.

Use In Specific Population

Pregnancy

Pregnancy Category C

There are no data on the use of Genesafe during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations.

Teratogenic effects

Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post-marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent.

Nonteratogenic effects

In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1-1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in-utero, one study found no adverse effects on mental or motor development or IQ scores. Genesafe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Labor and Delivery

There is no information about the effects of Genesafe on the mother and the fetus during labor and delivery.

Nursing Mothers

Very limited data in humans show that Genesafe is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4-6% of the maternal daily dose through breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning were decreased. This information suggests that maternal use of Genesafe may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when Genesafe is administered to a nursing woman.

Pediatric Use

The efficacy, safety, and pharmacokinetics of Genesafe in pediatric patients less than 16 years of age have not been established.

Geriatric Use

The efficacy, safety, and pharmacokinetics of Genesafe in patients over 65 years old have not been established.

Renal Impairment

The safety and pharmacokinetics of Genesafe in patients with renal impairment have not been evaluated. Since Genesafe is excreted by the kidney, caution should be exercised if Genesafe is administered to patients with impaired renal function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis.

Hepatic Impairment

The safety and pharmacokinetics of Genesafe in patients with hepatic impairment have not been evaluated. Since Genesafe is metabolized in the liver, caution should be exercised if Genesafe is administered to patients with impaired hepatic function.

Patients with Reduced CYP2C19 Activity

Patients with reduced CYP2C19 activity have higher exposure to carisoprodol. Therefore, caution should be exercised in administration of Genesafe to these patients.

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in practice.

The data described below are based on 1387 patients pooled from two double blind, randomized, multicenter, placebo controlled, one-week trials in adult patients with acute, mechanical, lower back pain. In these studies, patients were treated with 250 mg of Genesafe, 350 mg of Genesafe, or placebo three times a day and at bedtime for seven days. The mean age was about 41 years old with 54% females and 46% males and 74 % Caucasian, 16 % Black, 9% Asian, and 2% other.

There were no deaths and there were no serious adverse reactions in these two trials. In these two studies, 2.7%, 2%, and 5.4%, of patients treated with placebo, 250 mg of Genesafe, and 350 mg of Genesafe, respectively, discontinued due to adverse events; and 0.5%, 0.5%, and 1.8% of patients treated with placebo, 250 mg of Genesafe, and 350 mg of Genesafe, respectively, discontinued due to central nervous system adverse reactions.

Table 1 displays adverse reactions reported with frequencies greater than 2% and more frequently than placebo in patients treated with Genesafe in the two trials described above.

Table 1: Patients with Adverse Reactions in Controlled Studies

Post-marketing Experience

The following events have been reported during postapproval use of Genesafe. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Tachycardia, postural hypotension, and facial flushing.

Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures.

Gastrointestinal: Nausea, vomiting, and epigastric discomfort.

Hematologic: Leukopenia, pancytopenia

Overdosage of Genesafe commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with Genesafe overdosage. Serotonin syndrome has been reported with carisoprodol intoxication. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of Genesafe have been reported alone or in combination with CNS depressants.

Treatment of Overdosage

Basic life support measures should be instituted as dictated by the clinical presentation of the Genesafe overdose. Vomiting should not be induced because of the risk of CNS and respiratory depression, and subsequent aspiration. Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support.

For decontamination in cases of severe toxicity, activated charcoal should be considered in a hospital setting in patients with large overdoses who present early and are not demonstrating CNS depression and can protect their airway.

For more information on the management of an overdose of Genesafe, contact a Poison Control Center.

Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax skeletal muscles.

A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Genesafe is unknown.

The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a crossover study of 24 healthy subjects (12 male and 12 female) who received single doses of 250 mg and 350 mg Genesafe (see Table 2). The exposure of carisoprodol and meprobamate was dose proportional between the 250 mg and 350 mg doses. The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of Genesafe, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate.

Table 2: Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24)

Absorption

Absolute bioavailability of carisoprodol has not been determined. The mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with Genesafe (350 mg tablet) had no effect on the pharmacokinetics of carisoprodol. Therefore, Genesafe may be administered with or without food.

Metabolism

The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below).

Elimination

Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours. The half-life of meprobamate is approximately 10 hours.

Gender

Exposure of carisoprodol is higher in female than in male subjects (approximately 30-50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects.

Patients with Reduced CYP2C19 Activity

Genesafe should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and concomitant 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3-5% and in Asians is approximately 15-20%.