5.1 Sedation

CARISOPRODOL has sedative properties (in the low back pain trials, 13% to 17% of patients who received CARISOPRODOL experienced sedation compared to 6% of patients who received placebo) [see ADVERSE REACTIONS (6.1)] 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 CARISOPRODOL.

Since the sedative effects of CARISOPRODOL 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.

5.2 Abuse, Dependence, and Withdrawal

Carisoprodol, the active ingredient in CARISOPRODOL, has been subject to abuse, dependence, and withdrawal, misuse and criminal diversion. [seeDrug Abuse and Dependence (9.1, 9.2, 9.3)]. Abuse of CARISOPRODOL poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders [seeOverdosage (10)].

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 CARISOPRODOL 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 [seeClinical Pharmacology (12.3)].

To reduce the risk of CARISOPRODOL 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.

5.3 Seizures

There have been post-marketing reports of seizures in patients who received CARISOPRODOL. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) [see Overdosage (10)].

6.1 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 [see Clinical Studies (14)]. In these studies, patients were treated with 250 mg of CARISOPRODOL, 350 mg of CARISOPRODOL, 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 CARISOPRODOL, and 350 mg of CARISOPRODOL, respectively, discontinued due to adverse events; and 0.5%, 0.5%, and 1.8% of patients treated with placebo, 250 mg of CARISOPRODOL, and 350 mg of CARISOPRODOL, 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 CARISOPRODOL in the two trials described above.

6.2 Post-marketing Experience

The following events have been reported during postapproval use of CARISOPRODOL. 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 [seeOverdosage (10)].

Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures [see Overdosage (10)].

Gastrointestinal: Nausea, vomiting, and epigastric discomfort.

Hematologic: Leukopenia, pancytopenia.

7.1 CNS Depressants

The sedative effects of CARISOPRODOL and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of CARISOPRODOL and meprobamate, a metabolite of CARISOPRODOL, is not recommended [see Warnings and Precautions (5.1)].

7.2 CYP2C19 Inhibitors and Inducers

Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate [see Clinical Pharmacology (12.3)]. Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with CARISOPRODOL could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with CARISOPRODOL could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect on CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of CARISOPRODOL is unknown.

8.1 Pregnancy

Risk Summary

Data over many decades of carisoprodol use in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Data on meprobamate, the primary metabolite of carisoprodol, also do not show a consistent association between maternal use of meprobamate and an increased risk of major birth defects (see Data).

In a published animal reproduction study, pregnant mice administered carisoprodol orally at 2.6- and 4.1-times the maximum recommended human dose ([MRHD] of 1400 mg per day [350 mg QID] based on body surface area [BSA] comparison) from gestation through weaning resulted in reduced fetal weights, postnatal weight gain, and postnatal survival (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Retrospective case-control and cohort studies of meprobamate use during the first trimester of pregnancy have not consistently identified an increased risk or pattern of major birth defects. For children exposed to meprobamate in-utero, one study found no adverse effect on mental or motor development or IQ scores.

Animal Data

Embryofetal development studies in animals have not been completed.

In a published pre-and post-natal development animal study, pregnant mice administered carisoprodol orally at 300, 750, or 1200 mg/kg/day (approximately 1-, 2.6-, and 4.1-times the MRHD based on BSA comparison) from 7-days prior to gestation through birth and from lactation through weaning resulted in reduced fetal weights, postnatal weight gain, and postnatal survival at 2.6-and 4.1-times the MRHD.

8.2 Lactation

Risk Summary

Data from published literature report that carisoprodol and its metabolite, meprobamate, are present in breastmilk. There are no data on the effect of carisoprodol on milk production. There is one report of sedation in an infant who was breastfed by a mother taking carisoprodol (seeClinical Considerations). Because there have been no consistent reports of adverse events in breastfed infants over decades of use, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARISOPRODOL and any potential adverse effects on the breastfed infant from CARISOPRODOL or from the underlying maternal condition.

Clinical Considerations

Infants exposed to CARISOPRODOL through breast milk should be monitored for sedation.

8.4 Pediatric Use

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

8.5 Geriatric Use

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

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

8.8 Patients with Reduced CYP2C19 Activity

Patients with reduced CYP2C19 activity have higher exposure to carisoprodol. Therefore, caution should be exercised in administration of CARISOPRODOL to these patients. [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

CARISOPRODOL contains carisoprodol, a Schedule IV controlled substance. Carisoprodol has been subject to abuse, misuse, and criminal diversion for nontherapeutic use [seeWarnings and Precautions (5.2)].

9.2 Abuse

Abuse of carisoprodol poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders [seeWarnings and Precautions (5.2) and Overdosage (10)]. Patients at high risk of CARISOPRODOL abuse may include those with prolonged use of carisoprodol, with a history of drug abuse, or those who use CARISOPRODOL in combination with other abused drugs.

Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction may not be accompanied by tolerance or physical dependence) [seeDrug Abuse and Dependence (9.3)].

9.3 Dependence

Tolerance is when a patient’s reaction to a specific dosage and concentration is progressively reduced in the absence of disease progression, requiring an increase in the dosage to maintain the same. Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Both tolerance and physical dependence have been reported with the prolonged use

of CARISOPRODOL. Reported withdrawal symptoms with CARISOPRODOL include insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, anxiety, ataxia, hallucinations, and psychosis. Instruct patients taking large doses of CARISOPRODOL or those taking the drug for a prolonged time to not abruptly stop CARISOPRODOL [seeWarnings and Precautions (5.2)].

12.1 Mechanism of Action

The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified.

In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain.

12.2 Pharmacodynamics

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 CARISOPRODOL is unknown.

12.3 Pharmacokinetics

Absorption

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 CARISOPRODOL (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 CARISOPRODOL, which is approximately 30% of the Cmax of meprobamate (approximately 8 µg/mL) after administration of a single 400 mg dose of meprobamate.

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.

Food Effect

Co-administration of a high-fat meal with CARISOPRODOL (350 mg tablet) had no effect on the pharmacokinetics of carisoprodol. Therefore, CARISOPRODOL may be administered with or without food.

Elimination

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).

Excretion:

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.

Specific Populations

Sex

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

CARISOPRODOL 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%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

CARISOPRODOL 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 chromosomal 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.

Impairment of Fertility

CARISOPRODOL was not formally evaluated for effects on fertility. A published reproductive study in which female mice received carisoprodol orally at doses of 300, 750, or 1200 mg/kg/day (approximately 1, 2.6, and 4.1 times the MRHD of 1400 mg per day [350 mg QID] based on body surface area [BSA] comparison) from 1-week prior to mating, to 27-weeks post-mating 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 (maternal doses equivalent to 4.2-times the MRHD based on BSA comparison). In both studies, the no effect level was 750 mg/kg/day, corresponding

to approximately 2.6-times the MRHD based on a BSA comparison. The significance of these findings for human fertility is not known.

Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]