CARISOPRODOL 350 mg

CARISOPRODOL  - carisoprodol tablet 
Lake Erie Medical DBA Quality Care Products LLC

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CARISOPRODOL 350 mg

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 N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and the molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula is:

Other ingredients in Carisoprodol Tablets, USP include croscarmellose sodium, hydrogenated vegetable oil, hypromellose, magnesium stearate and microcrystalline cellulose.

12 CLINICAL PHARMACOLOGY

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

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 350 mg carisoprodol (see Table 2). 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 2. Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24)
  350 mg Carisoprodol
  Carisoprodol
 Cmax (μg/mL) 1.8 ± 1.0
 AUCinf (μg*hr/mL) 7.0 ± 5.0
 Tmax (hr) 1.7 ± 0.8
 T½ (hr) 2.0 ± 0.5
  Meprobamate
 Cmax (μg/mL) 2.5 ± 0.5
 AUCinf (μg*hr/mL) 46 ± 9.0
 Tmax (hr) 4.5 ± 1.9
 T½ (hr) 9.6 ± 1.5
Absorption:  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. 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.

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. The half-life of meprobamate is approximately 10 hours.

Gender:  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 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.




1 INDICATIONS AND USAGE

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

  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)].

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.

6 ADVERSE REACTIONS

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 839 patients pooled from a double blind, randomized, multicenter, placebo controlled, one-week trial in adult patients with acute, mechanical, lower back pain [see Clinical Studies (14)]. In the study, patients were treated with 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 the trial. In the study, 2.7% and 5.4% of patients treated with placebo and 350 mg of carisoprodol, respectively, discontinued due to adverse events; 0.5% and 1.8% of patients treated with placebo 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 trial described above.

Table 1. Patients with Adverse Reactions in the Controlled Study
 Adverse
Reaction
 Placebo
(n=560)
n (%)
 Carisoprodol 350 mg
(n=279)
n (%)
 Drowsiness 31 (6) 47 (17)
 Dizziness 11 (2) 19 (7)
 Headache 11 (2) 9 (3)

6.2 Postmarketing 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.


10 OVERDOSAGE

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. 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. Induced emesis is not recommended due to the risk of CNS and respiratory depression, which may increase the risk of aspiration pneumonia. Gastric lavage should be considered soon after ingestion (within one hour). 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.

The following types of treatment have been used successfully with an overdose of meprobamate, a metabolite of carisoprodol: activated charcoal (oral or via nasogastric tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is also dialyzable). Careful monitoring of urinary output is necessary and overhydration should be avoided. Observe for possible relapse due to incomplete gastric emptying and delayed absorption. For more information on the management of an overdose of carisoprodol, contact a Poison Control Center.

2 DOSAGE AND ADMINISTRATION

The recommended dose of Carisoprodol Tablets, USP is 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

350 mg Tablets: white, round, unscored tablets debossed "2410 V" on one side and plain on the reverse side; available in bottles of 100, 500 and 1000.

Storage:
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Patients should be advised to contact their physician if they experience any adverse reactions to carisoprodol tablets.

17.1 Sedation

Since carisoprodol tablets may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to carisoprodol tablets before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery [see Warnings and Precautions (5.1)].

17.2 Avoidance of Alcohol and Other CNS Depressants

Patients should be advised to avoid alcoholic beverages while taking carisoprodol tablets and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives [see Warnings and Precautions (5.1)].

17.3 Carisoprodol Tablets Should Only Be Used for Short-Term Treatment

Patients should be advised that treatment with carisoprodol tablets should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. If symptoms still persist, patients should contact their healthcare provider for further evaluation.

Manufactured for:
QUALITEST PHARMACEUTICALS
Huntsville, AL 35811

8181281
Revised 2/2009
R4


14 CLINICAL STUDIES14.1 Neuropathic pain associated with diabetic peripheral neuropathy

The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1)]. For a range of degrees of improvement in pain from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

14.2 Postherpetic Neuralgia

The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions. For various degrees of improvement in pain from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study

14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

14.4 Management of Fibromyalgia

The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A total of 64% of patients randomized to LYRICA completed the study. There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1)]. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized in Figure 8 and Table 8.

For various degrees of improvement in pain from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that degree of improvement. The figure is cumulative. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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CARISOPRODOL 
carisoprodol   tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)49999-064 (0603-2582)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CARISOPRODOL (CARISOPRODOL) CARISOPRODOL350 mg
Inactive Ingredients
Ingredient NameStrength
CROSCARMELLOSE SODIUM 
HYPROMELLOSE 
MAGNESIUM STEARATE 
CELLULOSE, MICROCRYSTALLINE 
Product Characteristics
ColorwhiteScore no score
ShapeROUNDSize12mm
FlavorImprint Code 2410;V
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
149999-064-01120 BOTTLE In 1 BOTTLE, PLASTICNone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA04024508/13/2010

Labeler - Lake Erie Medical DBA Quality Care Products LLC (831276758)
Establishment
NameAddressID/FEIOperations
Vintage Pharmaceuticals Huntsville958430845repack
Revised: 08/2010Lake Erie Medical DBA Quality Care Products LLC