Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: 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. Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body's production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting 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. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti-inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Pharmacokinetics Carisoprodol The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). 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. Table 1: Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) carisoprodol meprobamate Cmax (μg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (μg•hour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T½ (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, 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 350 mg of carisoprodol had no effect on the pharmacokinetics of carisoprodol. 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 after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender Exposure of carisoprodol is higher in female than in male subjects (approximately 30 to 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 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin Absorption The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence or absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. Distribution Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid < 100 μg/mL and > 400 μg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. Elimination The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage). Clearance of salicylic acid is also reduced in patients with renal impairment.

SOMA® COMPOUND c DESCRIPTION Soma Compound (carisoprodol and aspirin tablets, USP) is a fixed-dose combination product containing the following two products: 200 mg of carisoprodol, a centrally-acting muscle relaxant 325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties. It is available as a two-layered, white and orange, round tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula of carisoprodol is: Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: Other ingredients in the Soma Compound (carisoprodol and aspirin) drug product are croscarmellose sodium, FD&C Red #40, FD&C Yellow #6, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, starch, and stearic acid.

INDICATIONS Soma Compound (carisoprodol and aspirin) is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound (carisoprodol and aspirin) 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). DOSAGE AND ADMINISTRATION The recommended dose of Soma Compound (carisoprodol and aspirin) is 1 or 2 tablets, four times daily in adults. One Soma Compound (carisoprodol and aspirin) tablet contains 200 mg of carisoprodol and 325 mg of aspirin. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol and 2600 mg of aspirin per day. The recommended maximum duration of Soma Compound (carisoprodol and aspirin) use is up to two or three weeks. HOW SUPPLIED Soma Compound (carisoprodol and aspirin) Tablets are round, convex, two-layered and inscribed on the white layer with SOMA C and on the light orange layer with WALLACE 2103. The tablets are available in bottles of 100 (NDC 0037-2103-01) and 500 (NDC 0037-2103-03) and unit-dose packages of 100 (NDC 0037-2103-85). Storage: Store at controlled room temperature 20- 25° C (68 to 77° F). Protect from moisture. Dispense in a tight container. To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Revised 10/09. Meda Pharmaceuticals Inc., Somerset, New Jersey 08873-4120

SIDE EFFECTS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound (carisoprodol and aspirin) . The following events have been reported during post-approval individual use of carisoprodol and aspirin. 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. Carisoprodol: The following events have been reported during post-approval 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). Central Nervous System Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a symptom of high serum salicylate levels (see OVERDOSAGE). Drug Abuse And Dependence Carisoprodol is not a controlled substance (see WARNINGS). Discontinuation of carisoprodol in animals or in humans after chronic administration can produce withdrawal signs, and there are published case reports of human carisoprodol dependence. In vitro studies demonstrate that carisoprodol elicits barbiturate-like effects. Animal behavioral studies indicate that carisoprodol produces rewarding effects. Monkeys self administer carisoprodol. Drug discrimination studies using rats indicate that carisoprodol has positive reinforcing and discriminating effects similar to barbital, meprobamate, and chlordiazepoxide. DRUG INTERACTIONS Carisoprodol 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, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Coadministration 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. Aspirin Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants Concomitant use of aspirin with anticoagulants (e.g., heparin, warfarin, clopidogrel) increases the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin's inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids Concomitant administration of aspirin and corticosteriods may decrease salicylate plasma levels. Methotrexate Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. Nonsteroidal anti-inflammatory drugs (NSAIDs) The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Oral Hypoglycemics Agents Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Products that effect urinary pH Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone.

WARNINGS Carisoprodol Sedation Carisoprodol has sedative properties 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. Drug Dependence, Withdrawal, and Abuse In the postmarketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. Most cases of dependence, withdrawal, and abuse occurred in patients who have had a history of addiction or who used carisoprodol in combination with other drugs with abuse potential. However, there have been post-marketing adverse event reports of carisoprodol-associated abuse when used without other drugs with abuse potential. Withdrawal symptoms have been reported following abrupt cessation after prolonged use. To reduce the chance of carisoprodol dependence, withdrawal, or abuse, carisoprodol should be used with caution in addiction prone patients and in patients taking other CNS depressants including alcohol, and carisoprodol should be not be used more than two to three weeks for the relief of acute musculoskeletal discomfort. One of the metabolites of cCarisoprodol, and one of its metabolites, meprobamate (a controlled substance), may cause dependence (see CLINICAL PHARMACOLOGY). Aspirin Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin-associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin-associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for an aspirin-associated GI serious adverse reaction, the lowest effective aspirin dose should be used for the shortest possible duration. Anaphylaxis and Anaphylactoid Reactions Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphalaxis or anaphylactoid reaction should receive emergency care. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound (carisoprodol and aspirin) in patients with renal or hepatic impairment have not been evaluated. Carisoprodol Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been postmarketing 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). Aspirin Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies of carcinogenesis have been done with Soma Compound (carisoprodol and aspirin) . Carisoprodol: Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. 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. Carisoprodol 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. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy.) Pregnancy Pregnancy Category D. It is not known whether Soma Compound (carisoprodol and aspirin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal reproduction studies have not been conducted with Soma Compound. Soma Compound (carisoprodol and aspirin) should be given to a pregnant woman only if clearly needed. Carisoprodol: There are no data on the use of carisoprodol 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 to 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. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in rodents have shown salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Nursing Mothers Carisoprodol: Very limited data in humans show that carisoprodol 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 to 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 carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Pediatric Use The efficacy, safety, and pharmacokinetics of Soma Compound (carisoprodol and aspirin) in pediatric patients less than 16 years of age have not been established. Geriatric Use The efficacy, safety, and pharmacokinetics of Soma Compound (carisoprodol and aspirin) in patients over 65 years old have not been established.