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HIGHLIGHTS OF PRESCRIBING INFORMATION
WARNINGS AND PRECAUTIONS
These highlights do not include all the information needed to use Carisoprodol safely
• Due to sedative properties, may impair ability to perform hazardous tasks such as driv- and effectively. See full prescribing information for Carisoprodol.
ing or operating machinery (5.1)• Additive sedative effects when used with other CNS depressants including Carisoprodol Tablets for Oral Use
Initial U.S. Approval: 1959
• Cases of Drug Dependence, Withdrawal, and Abuse (5.2) RECENT MAJOR CHANGES
Warnings and Precautions, Drug Dependence, Withdrawal, and Abuse (5.2) 1/2012 ADVERSE REACTIONS
INDICATIONS AND USAGE
Most common adverse reactions (incidence > 2%) are drowsiness, dizziness, and Carisoprodol is indicated for the relief of discomfort associated with acute, painful mus- To report SUSPECTED ADVERSE REACTIONS, contact Wallace Pharmaceuticals Inc. at 1-
800-619-6344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Should only be used for acute treatment periods up to two or three weeks (1) DRUG INTERACTIONS
• Not recommended in pediatric patients less than 16 years of age (8.4) • CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic anti depressants) - DOSAGE AND ADMINISTRATION
• Recommended dose is 250 mg to 350 mg three times a day and at bedtime. (2) See 17 for PATIENT COUNSELING INFORMATION
Revised 1/12
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
• Acute intermittent porphyria (4)• Hypersensitivity reactions to a carbamate such as meprobamate (4) FULL PRESCRIBING INFORMATION: CONTENTS*
DRUG ABUSE AND DEPENDENCE
INDICATIONS AND USAGE
OVERDOSAGE
DOSAGE AND ADMINSTRATION
DESCRIPTION
DOSAGE FORMS AND STRENGTHS
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
NONCLINICAL TOXICOLOGY
ADVERSE REACTIONS
6.1
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND HANDLING
DRUG INTERACTIONS
PATIENT COUNSELING INFORMATION
17.2 Avoidance of Alcohol and Other CNS Depressants USE IN SPECIFIC POPULATIONS
17.3 Carisoprodol Should Only Be Used for Short-Term Treatment * Sections or subsections omitted from the full prescribing FULL PRESCRIBING INFORMATION
Since the sedative effects of Carisoprodol and other CNS depressants (e.g., alcohol, INDICATIONS AND USAGE
benzodiazepines, opioids, tricyclic antidepressants) may be additive, appropriate caution Carisoprodol is indicated for the relief of discomfort associated with acute, painful should be exercised with patients who take more than one of these CNS depressants musculoskeletal conditions in adults.
Carisoprodol should only be used for short periods (up to two or three weeks) 5.2 Drug Dependence, Withdrawal, and Abuse
because adequate evidence of effectiveness for more prolonged use has not been In the post-marketing experience with Carisoprodol, cases of dependence, withdraw- established and because acute, painful musculoskeletal conditions are generally of short al, and abuse have been reported with prolonged use. Most cases of dependence, with- duration. [see Dosage and Administration (2)].
drawal, and abuse occurred in patients who have had a history of addiction or who usedCarisoprodol in combination with other drugs with abuse potential. However, there have DOSAGE AND ADMINISTRATION
been post-marketing adverse event reports of Carisoprodol-associated abuse when used The recommended dose of Carisoprodol is 250 mg to 350 mg three times a day and without other drugs with abuse potential. Withdrawal symptoms have been reported follow- at bedtime. The recommended maximum duration of Carisoprodol use is up to two or ing abrupt cessation after prolonged use. To reduce the chance of Carisoprodol depend- ence, withdrawal, or abuse, Carisoprodol should be used with caution in addiction-prone DOSAGE FORMS AND STRENGTHS
patients and in patients taking other CNS depressants including alcohol, and Carisoprodol 250 mg Tablets: round, convex, white tablets, inscribed with WP 5901 should not be used more than two to three weeks for the relief of acute musculoskeletal CONTRAINDICATIONS
Carisoprodol is contraindicated in patients with a history of acute intermittent porphyr- Carisoprodol, and one of its metabolites, meprobamate (both controlled substances), ia or a hypersensitivity reaction to a carbamate such as meprobamate.
may cause dependence [see Clinical Pharmacology (12.3)].
WARNINGS AND PRECAUTIONS
5.3 Seizures
5.1 Sedation
There have been post-marketing reports of seizures in patients who received Carisoprodol has sedative properties (in the low back pain trials, 13% to 17% of Carisoprodol. Most of these cases have occurred in the setting of multiple drug over doses patients who received Carisoprodol experienced sedation compared to 6% of patients who (including drugs of abuse, illegal drugs, and alcohol) [see Overdosage (10)].
received placebo) [see ADVERSE REACTIONS (6.1)] and may impair the mental and/or 6 ADVERSE
REACTIONS
physical abilities required for the performance of potentially hazardous tasks such as 6.1 Clinical Studies Experience
driving a motor vehicle or operating machinery. There have been post-marketing reports Because clinical studies are conducted under widely varying conditions, adverse of motor vehicle accidents associated with the use of Carisoprodol.
reaction rates observed in clinical studies of a drug cannot be directly compared to ratesin 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, 8.4 Pediatric Use
randomized, multicenter, placebo controlled, one-week trials in adult patients with acute, The efficacy, safety, and pharmacokinetics of Carisoprodol in pediatric patients less mechanical, lower back pain [see Clinical Studies (14)]. In these studies, patients were than 16 years of age have not been established.
treated with 250 mg of Carisoprodol, 350 mg of Carisoprodol, or placebo three times a 8.5 Geriatric Use
day and at bedtime for seven days. The mean age was about 41 years old with 54% The efficacy, safety, and pharmacokinetics of Carisoprodol in patients over 65 years 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 8.6 Renal Impairment
these two studies, 2.7%, 2%, and 5.4%, of patients treated with placebo, 250 mg of The safety and pharmacokinetics of Carisoprodol in patients with renal impairment have Carisoprodol, and 350 mg of Carisoprodol, respectively, discontinued due to adverse events; and not been evaluated. Since Carisoprodol is excreted by the kidney, caution should be exer- 0.5%, 0.5%, and 1.8% of patients treated with placebo, 250 mg of Carisoprodol, and 350 mg of cised if Carisoprodol is administered to patients with impaired renal function. Carisoprodol Carisoprodol, respectively, discontinued due to central nervous system adverse reactions. is dialyzable by hemodialysis and peritoneal dialysis.
Table 1 displays adverse reactions reported with frequencies greater than 2% and more 8.7 Hepatic Impairment
frequently than placebo in patients treated with Carisoprodol in the two trials described above.
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 Table 1. Patients with Adverse Reactions in Controlled Studies
exercised if Carisoprodol is administered to patients with impaired hepatic function.
Carisoprodol 250 mg Carisoprodol 350 mg
8.8 Patients with Reduced CYP2C19 Activity
Reaction (n=560)
Patients with reduced CYP2C19 activity have higher exposure to carisoprodol.
Therefore, caution should be exercised in administration of Carisoprodol to these patients.
DRUG ABUSE AND DEPENDENCE
Carisoprodol is a controlled substance [see Warnings and Precautions (5.2)].
Discontinuation of carisoprodol in animals or in humans after chronic administration can produce withdrawal signs, and there are published case reports of human cariso-prodol dependence.
6.2 Post-marketing Experience
In vitro studies demonstrate that carisoprodol elicits barbiturate-like effects. Animal The following events have been reported during postapproval use of Carisoprodol.
behavioral studies indicate that carisoprodol produces rewarding effects. Monkeys self Because these reactions are reported voluntarily from a population of uncertain size, it is administer carisoprodol. Drug discrimination studies using rats indicate that carisoprodol not always possible to reliably estimate their frequency or establish a causal relationship has positive reinforcing and discriminative effects similar to barbital, meprobamate, and Cardiovascular: Tachycardia, postural hypotension, and facial flushing [see 10 OVERDOSAGE
Overdosage of Carisoprodol commonly produces CNS depression. Death, coma, res- Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritabil- piratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, ity, headache, depressive reactions, syncope, insomnia, and seizures [see Overdosage (10)].
nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/orheadache have been reported with Carisoprodol overdosage. Many of the Carisoprodol Gastrointestinal: Nausea, vomiting, and epigastric discomfort.
overdoses have occurred in the setting of multiple drug overdoses (including drugs of Hematologic: Leukopenia, pancytopenia.
abuse, illegal drugs, and alcohol). The effects of an overdose of Carisoprodol and other DRUG INTERACTIONS
CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can 7.1 CNS Depressants
be additive even when one of the drugs has been taken in the recommended dosage. Fatal The sedative effects of Carisoprodol and other CNS depressants (e.g., alcohol, ben- accidental and non-accidental overdoses of Carisoprodol have been reported alone or in zodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants Treatment of Overdosage: Basic life support measures should be instituted as dic-
simultaneously. Concomitant use of Carisoprodol and meprobamate, a metabolite of tated by the clinical presentation of the Carisoprodol overdose. Induced emesis is not rec- Carisoprodol, is not recommended [see Warnings and Precautions (5.1)].
ommended due to the risk of CNS and respiratory depression, which may increase the risk 7.2 CYP2C19 Inhibitors and Inducers
of aspiration pneumonia. Gastric lavage should be considered soon after ingestion (with- Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate [see in one hour). Circulatory support should be administered with volume infusion and vaso- Clinical Pharmacology (12.3)]. Co-administration of CYP2C19 inhibitors, such as omepra- pressor agents if needed. Seizures should be treated with intravenous benzodiazepines zole or fluvoxamine, with Carisoprodol could result in increased exposure of carisoprodol and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such CNS depression, airway protective reflexes may be compromised and tracheal intubation as rifampin or St. John’s Wort, with Carisoprodol could result in decreased exposure of should be considered for airway protection and respiratory support. carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed The following types of treatment have been used successfully with an overdose of induction effect on CYP2C19. The full pharma cological impact of these potential alter- meprobamate, a metabolite of Carisoprodol: activated charcoal (oral or via nasogastric ations of exposures in terms of either efficacy or safety of Carisoprodol is unknown.
tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is also dialyz- USE IN SPECIFIC POPULATION
able). Careful monitoring of urinary output is necessary and over hydration should beavoided. Observe for possible relapse due to incomplete gastric emptying and delayed 8.1 Pregnancy: Pregnancy Category C.
absorption. For more information on the management of an overdose of Carisoprodol, There are no data on the use of Carisoprodol during human pregnancy. Animal stud- contact a Poison Control Center.
ies indicate that carisoprodol crosses the placenta and results in adverse effects on fetalgrowth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, 11 DESCRIPTION
is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent Carisoprodol Tablets are available as 250 mg round, white tablets. Carisoprodol is a association between maternal use of meprobamate and an increased risk for particular white, crystalline powder, having a mild, characteristic odor and a bitter taste. It is slightly soluble in water; freely soluble in alcohol, in chloroform, and in acetone; and its solubilityis practically independent of pH. Carisoprodol is present as a racemic mixture. Chemically, Teratogenic effects: Animal studies have not adequately evaluated the teratogenic carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and the effects of carisoprodol. There was no increase in the incidence of congenital malforma- tions noted in reproductive studies in rats, rabbits, and mice treated with meprobamate.
12H24N2O4, with a molecular weight of 260.33. The structural Retrospective, post-marketing studies of meprobamate during human pregnancy wereequivocal for demonstrating an increased risk of congenital malformations following first trimester exposure. Across studies that indicated an increased risk, the types of malfor-mations were inconsistent.
Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postna- tal 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 meprobamatein-utero showed behavioral alterations that persisted into adulthood. For children Other ingredients in the Carisoprodol drug product include alginic acid, magnesium exposed to meprobamate in-utero, one study found no adverse effects on mental or motor stearate, potassium sorbate, starch, and tribasic calcium phosphate.
development or IQ scores. Carisoprodol should be used during pregnancy only if the poten-tial benefit justifies the risk to the fetus.
12 CLINCIAL
PHARMACOLOGY
8.2 Labor and Delivery
12.1 Mechanism of Action
There is no information about the effects of Carisoprodol on the mother and the fetus The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. 8.3 Nursing Mothers
In animal studies, muscle relaxation induced by carisoprodol is associated with Very limited data in humans show that Carisoprodol is present in breast milk and may altered interneuronal activity in the spinal cord and in the descending reticular formation of 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 12.2 Pharmacodynamics
experienced no adverse effects. However, milk production was inadequate and the baby was Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax 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 Carisoprodol may A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties.
lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk produc- The degree to which these properties of meprobamate contribute to the safety and effica- tion. Caution should be exercised when Carisoprodol is administered to a nursing woman.
12.3 Pharmacokinetics
The proportion of patients who used concomitant acetaminophen, NSAIDs, tra- The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied madol, opioid agonists, other muscle relaxants, and benzodiazepines was similar in the 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 The results for the primary efficacy evaluations in the acute, low back pain studies and meprobamate was dose proportional between the 250 mg and 350 mg doses. The Cmax of meprobamate was 2.5 ± 0.5 ␮g/mL (mean ± SD) after administration of a single 350 mg dose of Carisoprodol, which is approximately 30% of the Cmax of meprobamate Table 3. Results of the Primary Efficacy Endpointsa in Studies 1 and 2
(approximately 8 ␮g/mL) after administration of a single 400 mg dose of meprobamate. Parameter
Placebo Carisoprodol Carisoprodol
Table 2. Pharmacokinetic Parameters of Carisoprodol and Meprobamate
(Mean ± SD, n=24)
Number of Patients
250 mg Carisoprodol
350 mg Carisoprodol
Relief from Starting Backache, Mean (SE)b 1.4 (0.1)
Carisoprodol
Difference between Carisoprodol and Placebo, Cmax (␮g/mL)
Global Impression of Change, Mean (SE)b
AUCinf (␮g*hr/mL)
Difference between Carisoprodol and Placebo, Tmax (hr)
T1/2 (hr)
Number of Patients
Meprobamate
Relief from Starting Backache, Mean (SE)b 1.1 (0.1)
Cmax (␮g/mL)
Difference between Carisoprodol and Placebo, inf (␮g*hr/mL)
Tmax (hr)
Global Impression of Change, Mean (SE)b
T1/2 (hr)
Difference between Carisoprodol and Placebo, Absorption: Absolute bioavailability of carisoprodol has not been determined. The mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 a The primary efficacy endpoints (Relief from Starting Backache and Global to 2 hours. Co-administration of a high-fat meal with Carisoprodol (350 mg tablet) had no Impression of Change) were assessed by the patients on Study Day 3. These end- effect on the pharmacokinetics of carisoprodol. Therefore, Carisoprodol may be adminis- points were scored on a 5-point rating scale from 0 (worst outcome) to 4 (best Metabolism: The major pathway of carisoprodol metabolism is via the liver by b Mean is the least squared mean and SE is the standard error of the mean. The cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic poly- ANOVA model was used for the primary statistical comparison between the morphism (see Patients with Reduced CYP2C19 Activity below). Carisoprodol 250 mg and placebo groups.
Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a ter- Patients treated with Carisoprodol experienced improvement in function as measured minal elimination half-life of approximately 2 hours. The half-life of meprobamate is by the Roland-Morris Disability Questionnaire (RMDQ) score on Days 3 and 7.
16 HOW SUPPLIED/STORAGE AND HANDLING
Gender: Exposure of carisoprodol is higher in female than in male subjects (approx- 250 mg Tablets: round, convex, white tablets, inscribed with WP 5901; available in imately 30-50% on a weight adjusted basis). Overall exposure of meprobamate is compa- bottles of 100 (NDC 51525-5901-1), and bottles of 30 (NDC 51525-5901-3).
rable between female and male subjects.
Storage:
Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in Store at controlled room temperature 20° - 25°C (68° - 77°F). patients with reduced CYP2C19 activity. Published studies indicate that patients who arepoor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 17 PATIENT COUNSELING INFORMATION
concomitant 50% reduced exposure to meprobamate compared to normal CYP2C19 metab- Patients should be advised to contact their physician if they experience any adverse olizers. The prevalence of poor metabolizers in Caucasians and African Americans is approx- imately 3-5% and in Asians is approximately 15-20%.
17.1 Sedation
NONCLINICAL TOXICOLOGY
Patients should be advised that Carisoprodol may cause drowsiness and/or dizzi- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
ness, and has been associated with motor vehicle accidents. Patients should be advised Long term studies in animals have not been performed to evaluate the carcino- to avoid taking Carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery [see Warnings and Precautions (5.1)].
Carisoprodol was not formally evaluated for genotoxicity. In published studies, cariso- 17.2 Avoidance of Alcohol and Other CNS Depressants
prodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metab- Patients should be advised to avoid alcoholic beverages while taking Carisoprodol olizing enzymes, but was not mutagenic in the presence of metabolizing enzymes.
and to check with their doctor before taking other CNS depressants such as benzodi- Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese azepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives hamster ovary cells with or without the presence of metabolizing enzymes. Other types of [see Warnings and Precautions (5.1)].
genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames 17.3 Carisoprodol Should Only Be Used for Short-Term Treatment
reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, Patients should be advised that treatment with Carisoprodol should be limited to and was not clastogenic in an in vivo mouse micronucleus assay of circulating blood cells.
acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort.
Carisoprodol was not formally evaluated for effects on fertility. Published reproductive In the post-marketing experience with Carisoprodol, cases of dependence, withdrawal, and studies of carisoprodol in mice found no alteration in fertility although an alteration in repro- abuse have been reported with prolonged use. If the musculoskeletal symptoms still per- ductive cycles characterized by a greater time spent in estrus was observed at a sist, patients should contact their healthcare provider for further evaluation.
carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not To report SUSPECTED ADVERSE REACTIONS, contact Wallace Pharmaceuticals Inc. at 1-
determine fertility, mouse testes weight and sperm motility were reduced at a dose of 800-619-6344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding toapproximately 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.
CLINICAL STUDIES
The safety and efficacy of Carisoprodol for the relief of acute, idiopathic mechanical low back pain was evaluated in two, 7-day, double blind, randomized, multicenter, place- bo controlled, U.S. trials (Studies 1 and 2). Patients had to be 18 to 65 years old and had to have acute back pain (≤ 3 days of duration) to be included in the trials. Patients withchronic back pain; at increased risk for vertebral fracture (e.g., history of osteoporosis);with a history of spinal pathology (e.g., herniated nucleus pulposis, spondylolisthesis or spinal stenosis); with inflammatory back pain, or with evidence of a neurologic deficit wereexcluded from par ticipation. Concomitant use of analgesics (e.g., acetaminophen, NSAIDs, tramadol, opioid agonists), other muscle relaxants, botulinum toxin, sedatives(e.g., barbiturates, benzodiazepines, promethazine hydrochloride), and anti-epileptic In Study 1, patients were randomized to one of three treatment groups (i.e., Carisoprodol 250 mg, Carisoprodol 350 mg, or placebo) and in Study 2 patients were ran-domized to two treatment groups (i.e., Carisoprodol 250 mg or placebo). In both studies,patients received study medication three times a day and at bedtime for seven days. The primary endpoints were the relief from starting backache and the global impression of change, as reported by patients, on Study Day 3. Both endpoints were scored on a 5-pointrating scale from 0 (worst outcome) to 4 (best outcome) in both studies. The primary statis-tical com parison was between the Carisoprodol 250 mg and placebo groups in both studies.

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