Carisoprodol Tablets, USP, 350 mg

1 INDICATIONS AND USAGE Carisoprodol Tablets, USP are indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Limitation of Use Carisoprodol Tablets, USP 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 [ see Dosage and Administration (2) ]. Carisoprodol Tablet is a muscle relaxant indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. (1) Limitation of Use : Should only be used for acute treatment periods up to two or three weeks (1)

2 DOSAGE AND ADMINISTRATION The recommended dose of Carisoprodol Tablets is 250 mg to 350 mg three times a day and at bedtime. The recommended maximum duration of Carisoprodol Tablets use is up to two or three weeks. Recommended dose is 250 mg to 350 mg three times a day and at bedtime. (2)

3 DOSAGE FORMS AND STRENGTHS 350 mg Tablets: White, round, unscored tablets debossed "E 17" on one side and plain on the other side. Tablets: 350 mg (3)

4 CONTRAINDICATIONS Carisoprodol Tablets are contraindicated in patients with a history of acute intermittent porphyria or a hypersensitivity reaction to a carbamate such as meprobamate. Acute intermittent porphyria (4) Hypersensitivity reactions to a carbamate such as meprobamate (4)

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 2%) are drowsiness, dizziness, and headache (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Granulation Technology, Inc. at 1-973-276-0740 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 1. Patients with Adverse Reactions in Controlled Studies Adverse Reaction Placebo (n=560) n (%) Carisoprodol 250 mg (n=548) n (%) Carisoprodol 350 mg (n=279) n (%) Drowsiness 31 (6) 73 (13) 47 (17) Dizziness 11 (2) 43 (8) 19 (7) Headache 11 (2) 26 (5) 9 (3) 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 [ see Overdosage (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 DRUG INTERACTIONS CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) - additive sedative effects ( 5.1, 7.1 ) 7.1 CNS Depressants The sedative effects of Carisoprodoland 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 USE IN SPECIFIC POPULATIONS 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 (see Clinical 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) ].

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.

11 DESCRIPTION Carisoprodol Tablets, USP are available as 350 mg, round, white tablets for oral administration. Carisoprodol is a 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 solubility is practically independent of pH. Carisoprodol is present as a racemic mixture. Chemically, carisoprodol is (±)-2-Methyl-2-propyl-1,3-propanediol carbamate isopropylcarbamate and the molecular formula is C 12 H 24 N 2 O 4 , with a molecular weight of 260.33. The structural formula is: Other ingredients in Carisoprodol Tablets, USP include lactose monohydrate NF, sodium starch glycolate NF, povidone NF, sodium lauryl sulfate NF, microcrystalline cellulose (PH 101) NF, and magnesium stearate NF. Carisoprodol Structural Formula

10 OVERDOSAGE Clinical Presentation Overdosage of Carisoprodol 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 Carisoprodol 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 Carisoprodol 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 Carisoprodol 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 Carisoprodol, contact a Poison Control Center.

16 HOW SUPPLIED/STORAGE AND HANDLING Carisoprodol Tablets, USP, 350 mg: White, round, unscored tablets debossed "E 17" on one side and plain on the other side; available as follows: NDC: 72162-2525-0: 1000 Tablets in a BOTTLE NDC: 72162-2525-1: 100 Tablets in a BOTTLE NDC: 72162-2525-2: 100 Tablets in a BOTTLE Storage: Store at controlled room temperature 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504