Dorilax

Acetaminophen:

• Pharmacological action
• Why is Dorilax (Acetaminophen) prescribed?
• Dorilax dosage and administration
• Dorilax side effects, adverse reactions
• Contraindications
• Using during pregnancy and breastfeeding
• Special Instructions
• Dorilax (Acetaminophen) Drug Interactions
• Dorilax in case of emergency / overdose
• Dorilax (Acetaminophen) reviews

Pharmacological action

Dorilax is an analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, the predominant influence on the thermoregulation center in the hypothalamus, enhances heat transfer.

Why is Dorilax (Acetaminophen) prescribed?

Pain weak and moderate intensity of different genesis (including headache, migraine, toothache, neuralgia, myalgia, algomenorrhea; pain in trauma, burns). Fever in infectious and inflammatory diseases.

Dorilax dosage and administration

Oral or rectally adults and adolescents with a body weight over 60 kg is used in a single dose of 500 mg, the multiplicity of admission - up to 4 times / Maximum duration of treatment - 5-7 days.

Maximum dose: single - 1 g, daily - 4 g.

Single dose for oral administration for children aged 6-12 years - 250-500 mg, 1-5 years - 120-250 mg, from 3 months to 1 year - 60-120 mg, up to 3 months - 10 mg / kg. Single dose rectal in children aged 6-12 years - 250-500 mg, 1-5 years - 125-250 mg.

Multiplicity - 4 at intervals of not less than 4 h. The maximum duration of treatment - 3 days.

Maximum dose: 4 single dose per day.

Dorilax side effects, adverse reactions

Digestive system: rarely - dyspepsia; long-term use at high doses - hepatotoxic effects, methemoglobinemia, renal dysfunction and liver, hypochromic anemia. Hemopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis. Allergic reactions: rarely - skin rash, itching, hives.

Contraindications

Chronic active alcoholism, increased sensitivity to Dorilax, marked disturbances of liver function and / or kidney disease, anemia, pregnancy (I term).

Using during pregnancy and breastfeeding

Dorilax (Acetaminophen) crosses the placental barrier. So far, no observed adverse effects of Dorilax (Acetaminophen) on the fetus in humans.

Dorilax (Acetaminophen) is excreted in breast milk: the content in milk was 0.04-0.23% of the dose adopted mother.

If necessary, use of Dorilax (Acetaminophen) during pregnancy and lactation (breastfeeding) should carefully weigh the potential benefits of therapy for the mother and the potential risk to the fetus or child.

In experimental studies found no embryotoxic, teratogenic and mutagenic action of Dorilax (Acetaminophen).

Special Instructions

Dorilax is used with caution in patients with disorders of the liver and kidneys, with benign hyperbilirubinemia, as well as in elderly patients.

With prolonged use of Dorilax (Acetaminophen) is necessary to monitor patterns of peripheral blood and functional state of the liver.

Used for treatment of premenstrual tension syndrome in combination with pamabrom (diuretic, a derivative of xanthine) and mepyramine (Histamine H1-receptors blocker).

Dorilax (Acetaminophen) Drug Interactions

With the simultaneous use with inducers of microsomal liver enzymes, means having hepatotoxic effect, increasing the risk of hepatotoxic action of Dorilax (Acetaminophen).

With the simultaneous use of anticoagulants may be slight to moderate increase in prothrombin time.

With the simultaneous use of anticholinergics may decrease absorption of Dorilax (Acetaminophen).

With the simultaneous use of oral contraceptives accelerated excretion of Dorilax (Acetaminophen) from the body and may reduce its analgesic action.

With the simultaneous use with urological means reduced their effectiveness.

With the simultaneous use of activated charcoal reduced bioavailability of Dorilax (Acetaminophen).

When Dorilax (Acetaminophen) applied simultaneously with diazepam may decrease excretion of diazepam.

There have been reports about the possibility of enhancing mielodepression effect of zidovudine while applying with Dorilax (Acetaminophen). A case of severe toxic liver injury.

Described cases of toxic effects of Dorilax (Acetaminophen), while the use of isoniazid.

When applied simultaneously with carbamazepine, phenytoin, phenobarbital, primidonom decreases the effectiveness of Dorilax (Acetaminophen), which is caused by an increase in its metabolism and excretion from the body. Cases of hepatotoxicity, while the use of Dorilax (Acetaminophen) and phenobarbital.

In applying cholestyramine a period of less than 1 h after administration of Dorilax (Acetaminophen) may decrease of its absorption.

At simultaneous application with lamotrigine moderately increased excretion of lamotrigine from the body.

With the simultaneous use of metoclopramide may increase absorption of Dorilax (Acetaminophen) and its increased concentration in blood plasma.

When applied simultaneously with probenecid may decrease clearance of Dorilax (Acetaminophen), with rifampicin, sulfinpyrazone - may increase clearance of Dorilax (Acetaminophen) due to increasing its metabolism in the liver.

At simultaneous application of Dorilax (Acetaminophen) with ethinylestradiol increases absorption of Dorilax (Acetaminophen) from the gut.

Enhances the effect of indirect anticoagulants (coumarin derivatives and indandione). Antipyretic and analgesic activity of caffeine increases, reduce - rifampicin, phenobarbital and alcohol (accelerated biotransformation, inducing microsomal liver enzymes).

Dorilax in case of emergency / overdose

At a reception in toxic doses (10-15 g in adults) may develop liver necrosis.

Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, extreme tiredness, unusual bleeding or bruising, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms

Caffeine:

• Dorilax (Caffeine) reviews

Active ingredient (in each tablet)

Dorilax (Caffeine) 200mg

Purpose

Alertness aid

Use

• helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness

Warnings

For occasional use only

Do not use

• in children under 12 years of age
• as a substitute for sleep

When using this product limit the use of Dorilax (Caffeine) containing medications, foods, or beverages because too much Dorilax (Caffeine) may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat. The recommended dose of this product contains about as much Dorilax (Caffeine) as a cup of coffee.

Stop use and ask a doctor if fatigue or drowsiness persists or continues to recur

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

• adults and children 12 years of age and over: take 1 tablet not more often than every 3 to 4 hours.

Other information

• store at room temperature
• avoid excessive heat (greater than 100°F) or humidity

Inactive ingredients

carnauba wax, colloidal silicon dioxide, D&C yellow #10 aluminum lake, dextrose, FD&C yellow #6 aluminum lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, starch, titanium dioxide

Questions or comments?

Call toll-free 1-855-874-0970 weekdays

Display Panel Dorilax (Caffeine): 16 ct. Package

Dorilax (Caffeine)^®

CAFFEINE ALERTNESS AID

16 TABLETS

200mg each

FUNCTIONAL Dorilax (Caffeine)^® for Mental Alertness

SAFE & EFFECTIVE

One tablet is equal to about a cup of coffee

Dorilax (Caffeine)^®

Making the Most of Every Day.^®

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use if foil or plastic bubble is torn or punctured.

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CAFFEINE® are registered trademarks of Meda AB.

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16 ct. Package

Display Panel Dorilax (Caffeine): 40 ct. Package

SAFE & EFFECTIVE

FUNCTIONAL Dorilax (Caffeine)^® for Mental Alertness

Dorilax (Caffeine)^®

Dorilax (Caffeine) ALERTNESS AID

40 Tablets

200mg each

FUNCTIONAL Dorilax (Caffeine)^® for Mental Alertness

Tamper Evident Feature: Individually sealed in foil for your protection. Do not use if foil or plastic bubble is torn or punctured.

VIVARIN® helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness (FDA approved uses), so you can accomplish all the things you want to do and all the things you need to do.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Made in the U.S.A.

Dorilax (Caffeine)^®

Making the Most of Every Day.^®

Distributed by:

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40 ct. Package

Carisoprodol:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Dorilax (Carisoprodol) reviews

1 INDICATIONS AND USAGE

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

Dorilax (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) ].

Dorilax (Carisoprodol) Tablets are indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions. (1)

Important Limitations:

• Should only be used for acute treatment periods up to two or three weeks (1)
• Not recommended in pediatric patients less than 16 years of age (8.4)

2 DOSAGE AND ADMINISTRATION

The recommended dose of Dorilax (Carisoprodol) is 250 mg to 350 mg three times a day and at bedtime. The recommended maximum duration of Dorilax (Carisoprodol) 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 "2410 V" on one side and plain on the reverse side.

Tablets: 350 mg (3)

4 CONTRAINDICATIONS

Dorilax (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)

5 WARNINGS AND PRECAUTIONS

• Due to sedative properties, may impair ability to perform hazardous tasks such as driving or operating machinery
• Additive sedative effects when used with other CNS depressants including alcohol (5.1)
• Cases of Drug Dependence, Withdrawal, and Abuse (5.2)
• Seizures (5.3)

5.1 Sedation

Carisoprodol has sedative properties (in the low back pain trials, 13% to 17% of patients who received Dorilax (Carisoprodol) 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 Dorilax (Carisoprodol).

Since the sedative effects of Dorilax (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.

5.2 Drug Dependence, Withdrawal, and Abuse

In the postmarketing experience with Dorilax, 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 Dorilax (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 Dorilax (Carisoprodol) dependence, withdrawal, or abuse, Dorilax (Carisoprodol) should be used with caution in addiction-prone patients and in patients taking other CNS depressants including alcohol, and Dorilax (Carisoprodol) should not be used more than two to three weeks for the relief of acute musculoskeletal discomfort.

Dorilax (Carisoprodol), and one of its metabolites, meprobamate (a controlled substance), may cause dependence [see Clinical Pharmacology (12.3) ].

5.3 Seizures

There have been postmarketing reports of seizures in patients who received Dorilax (Carisoprodol). Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) [see Overdosage (10) ].

6 ADVERSE REACTIONS

Most common adverse reactions are drowsiness, dizziness, and headache (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1‑800‑444-4011 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 Dorilax (Carisoprodol), 350 mg of Dorilax (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 Dorilax (Carisoprodol), and 350 mg of Dorilax (Carisoprodol), respectively, discontinued due to adverse events; 0.5%, 0.5%, and 1.8% of patients treated with placebo, 250 mg of Dorilax (Carisoprodol), and 350 mg of Dorilax (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 Dorilax (Carisoprodol) in the two trials described above.

6.2 Postmarketing Experience

The following events have been reported during postapproval use of Dorilax (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 - additive sedative effects (5.1 and 7.1)

7.1 CNS Depressants

The sedative effects of Dorilax (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 Dorilax (Carisoprodol) and meprobamate, a metabolite of Dorilax (Carisoprodol), is not recommended [see Warnings and Precautions (5.1) ].

7.2 CYP2C19 Inhibitors and Inducers

Dorilax (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 Dorilax (Carisoprodol) could result in increased exposure of Dorilax (Carisoprodol) and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John's Wort, with Dorilax (Carisoprodol) could result in decreased exposure of Dorilax (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 Dorilax (Carisoprodol) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. There are no data on the use of Dorilax during human pregnancy. Animal studies indicate that Dorilax (Carisoprodol) crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of Dorilax (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 Dorilax (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, Dorilax (Carisoprodol) reduced fetal weights, postnatal 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 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. Dorilax (Carisoprodol) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

8.2 Labor and Delivery

There is no information about the effects of Dorilax (Carisoprodol) on the mother and the fetus during labor and delivery.

8.3 Nursing Mothers

Very limited data in humans show that Dorilax 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 4–6% 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 Dorilax (Carisoprodol) may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when Dorilax (Carisoprodol) is administered to a nursing woman.

8.4 Pediatric Use

The efficacy, safety, and pharmacokinetics of Dorilax (Carisoprodol) in pediatric patients less than 16 years of age have not been established.

8.5 Geriatric Use

The efficacy, safety, and pharmacokinetics of Dorilax in patients over 65 years old have not been established.

8.6 Renal Impairment

The safety and pharmacokinetics of Dorilax (Carisoprodol) in patients with renal impairment have not been evaluated. Since Dorilax (Carisoprodol) is excreted by the kidney, caution should be exercised if Dorilax (Carisoprodol) is administered to patients with impaired renal function. Dorilax (Carisoprodol) is dialyzable by hemodialysis and peritoneal dialysis.

8.7 Hepatic Impairment

The safety and pharmacokinetics of Dorilax in patients with hepatic impairment have not been evaluated. Since Dorilax (Carisoprodol) is metabolized in the liver, caution should be exercised if Dorilax (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 Dorilax (Carisoprodol). Therefore, caution should be exercised in administration of Dorilax (Carisoprodol) to these patients [see Clinical Pharmacology (12.3) ].

9 DRUG ABUSE AND DEPENDENCE

Dorilax (Carisoprodol) is not a controlled substance [see Warnings and Precautions (5.2) ]. Discontinuation of Dorilax (Carisoprodol) in animals or in humans after chronic administration can produce withdrawal signs, and there are published case reports of human Dorilax (Carisoprodol) dependence.

In vitro studies demonstrate that Dorilax (Carisoprodol) elicits barbiturate-like effects. Animal behavioral studies indicate that Dorilax (Carisoprodol) produces rewarding effects. Monkeys self administer Dorilax (Carisoprodol). Drug discrimination studies using rats indicate that Dorilax (Carisoprodol) has positive reinforcing and discriminative effects similar to barbital, meprobamate, and chlordiazepoxide.

10 OVERDOSAGE

Overdosage of Dorilax (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 Dorilax (Carisoprodol) overdosage. Many of the Dorilax (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 Dorilax (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 Dorilax (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 Dorilax (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 Dorilax (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 Dorilax (Carisoprodol), contact a Poison Control Center.

11 DESCRIPTION

Dorilax (Carisoprodol) Tablets, USP are available as 350 mg round, white tablets for oral administration. Dorilax (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. Dorilax (Carisoprodol) is present as a racemic mixture. Chemically, Dorilax (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 Dorilax (Carisoprodol) Tablets, USP include croscarmellose sodium, hydrogenated vegetable oil, hypromellose, magnesium stearate and microcrystalline cellulose.

This in an image of the structural formula of Dorilax (Carisoprodol).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Dorilax in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified.

In animal studies, muscle relaxation induced by Dorilax (Carisoprodol) is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain.

12.2 Pharmacodynamics

Dorilax (Carisoprodol) is a centrally acting skeletal muscle relaxant that does not directly relax skeletal muscles.

A metabolite of Dorilax (Carisoprodol), meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Dorilax (Carisoprodol) is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of Dorilax (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 250 mg and 350 mg Dorilax (Carisoprodol). The exposure of Dorilax (Carisoprodol) and meprobamate was dose proportional between the 250 mg and 350 mg doses. The C_max of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of Dorilax (Carisoprodol), which is approximately 30% of the C_max of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate.

Absorption: Absolute bioavailability of Dorilax (Carisoprodol) has not been determined. The mean time to peak plasma concentrations (T_max) of Dorilax (Carisoprodol) was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with Dorilax (Carisoprodol) (350 mg tablet) had no effect on the pharmacokinetics of Dorilax (Carisoprodol). Therefore, Dorilax (Carisoprodol) may be administered with or without food.

Metabolism: The major pathway of Dorilax (Carisoprodol) metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism.

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 Dorilax (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 Dorilax (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 Dorilax (Carisoprodol).

Dorilax (Carisoprodol) was not formally evaluated for genotoxicity. In published studies, Dorilax (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. Dorilax (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. Dorilax (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.

Dorilax (Carisoprodol) was not formally evaluated for effects on fertility. Published reproductive studies of Dorilax (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 Dorilax (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.

14 CLINICAL STUDIES

The safety and efficacy of Dorilax (Carisoprodol) for the relief of acute, idiopathic mechanical low back pain was evaluated in two 7-day, double blind, randomized, multicenter, placebo 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 with chronic 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 were excluded from participation. 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 drugs was prohibited.

In Study 1, patients were randomized to one of three treatment groups (i.e., Dorilax (Carisoprodol) 250 mg, Dorilax (Carisoprodol) 350 mg, or placebo) and in Study 2 patients were randomized to two treatment groups (i.e., Dorilax (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-point rating scale from 0 (worst outcome) to 4 (best outcome) in both studies. The primary statistical comparison was between the Dorilax (Carisoprodol) 250 mg and placebo groups in both studies.

The proportion of patients who used concomitant acetaminophen, NSAIDs, tramadol, opioid agonists, other muscle relaxants, and benzodiazepines was similar in the treatment groups.

The results for the primary efficacy evaluations in the acute, low back pain studies are presented in Table 3.

^aThe primary efficacy endpoints (Relief from Starting Backache and Global Impression of Change) were assessed by the patients on Study Day 3. These endpoints were scored on a 5-point rating scale from 0 (worst outcome) to 4 (best outcome).

^b Mean is the least squared mean and SE is the standard error of the mean. The ANOVA model was used for the primary statistical comparison between the Dorilax (Carisoprodol) 250 mg and placebo groups.

Patients treated with Dorilax (Carisoprodol) experienced improvement in function as measured by the Roland-Morris Disability Questionnaire (RMDQ) score on Days 3 and 7.

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

49999-064-01

Storage:

Store at 20°-25°C (68°-77°F).

17 PATIENT COUNSELING INFORMATION

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

17.1 Sedation

Patients should be advised that Dorilax (Carisoprodol) tablets may cause drowsiness and/or dizziness, and has been associated with motor vehicle accidents. Patients should be advised to avoid taking Dorilax (Carisoprodol) 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 Dorilax 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 Dorilax (Carisoprodol) Tablets Should Only Be Used for Short-Term Treatment

Patients should be advised that treatment with Dorilax (Carisoprodol) tablets should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketing experience with Dorilax (Carisoprodol) tablets, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If the musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation.

To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1-800-444-4011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8181281

Revised: 10/2010

R5

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