CARISOPRODOL: 2,660 Adverse Event Reports & Safety Profile

Carisoprodol tablets, USP are available as 350 mg round, white tablets. Carisoprodol, USP is a white, crystalline powder, having a mild, characteristic odor. It is very 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 the Carisoprodol tablets USP, 350 mg include microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize), croscarmellose sodium, povidone, silicon dioxide and magnesium stearate. This in an image of the structural formula of CARISOPRODOL.

AND USAGE Carisoprodol Tablets, USP are indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults.

Carisoprodol

Tablets, USP are 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 ) Limitation of Use Carisoprodol tablets 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) ] .

AND ADMINISTRATION The recommended dose of Carisoprodol tablets, USP is 250 mg to 350 mg three times a day and at bedtime. The recommended maximum duration of carisoprodol tablets, USP use is up to two or three weeks.

• Recommended dose is 250 mg to 350 mg three times a day and at bedtime. (2)

Carisoprodol tablets, USP is 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)

REACTIONS Most common adverse reactions (incidence > 2%) are drowsiness, dizziness, and headache (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Nostrum Laboratories, Inc. at [email protected] or call 1-877-770-1288 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 tablets, 350 mg of carisoprodol tablets, 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 tablets, and 350 mg of carisoprodol tablets, respectively, discontinued due to adverse events; and 0.5%, 0.5%, and 1.8% of patients treated with placebo, 250 mg of carisoprodol tablets, and 350 mg of carisoprodol tablets, 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 tablets in the two trials described above.

Table

1. Patients with Adverse Reactions in Controlled Studies Adverse Reaction Placebo (n=560) n (%)

Carisoprodol Tablets

250 mg (n=548) n (%)

Carisoprodol Tablets

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 tablets. 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

AND PRECAUTIONS Due to sedative properties, may impair ability to perform hazardous tasks such as driving or operating machinery ( 5.1 ) Additive sedative effects when used with other CNS depressants including alcohol ( 5.1 ) Cases of abuse, dependence and withdrawal ( 5.2 , 9.2 , 9.3 ) Seizures ( 5.3 )

5.1 Sedation Carisoprodol Tablets have sedative properties (in the low back pain trials, 13% to 17% of patients who received Carisoprodol Tablets 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 Tablets. Since the sedative effects of Carisoprodol Tablets 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 Tablets, has been subject to abuse, dependence, and withdrawal, misuse and criminal diversion. [ see Drug Abuse and Dependence (9.1 , 9.2 , 9.3) ]. Abuse of Carisoprodol Tablets poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures, and other disorders [ see Overdosage (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 Tablets 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 [ see Clinical Pharmacology (12.3) ]. To reduce the risk of Carisoprodol Tablets 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 Tablets. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) [ see Overdosage (10) ].

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 Carisoprodol Tablets 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 Tablets and meprobamate, a metabolite of Carisoprodol Tablets, 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 Tablets 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 Tablets 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 Tablets is unknown.