DOSAGE FORMS & STRENGTHS SECTION.
3 DOSAGE FORMS AND STRENGTHS 3 DOSAGE FORMS AND STRENGTHS Carisoprodol Tablets, USP 350 mg are white, round, unscored tablets; imprinted WW 176.
ADVERSE REACTIONS SECTION.
ADVERSE REACTIONS Oral supplementation with L-tryptophan, L-arginine or choline at high doses up to 15 grams daily is generally well tolerated. The most common adverse reactions of higher doses from 15 to 30 grams daily are nausea, abdominal cramps, and diarrhea. Some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each Theramine capsule does not exceed 400 mg
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category C. 8.1 Pregnancy: Category Pregnancy C. There are no data on the use of Carisoprodol Tablets 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 1-1.5 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 Tablets should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
INDICATIONS & USAGE SECTION.
INDICATIONS FOR USE Theramine is intended for the clinical dietary management of the metabolic processes of pain disorders and inflammatory conditions.
DRUG ABUSE AND DEPENDENCE SECTION.
9 DRUG ABUSE AND DEPENDENCE 9 DRUG ABUSE AND DEPENDENCE [see Warnings and Precautions (5.2)] 5.2 Drug Dependence, Withdrawal, and Abuse In the postmarketing experience with Carisoprodol Tablets, 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 Tablets in combination with other drugs with abuse potential. Withdrawal symptoms have been reported following abrupt cessation after prolonged use. To reduce the chance of Carisoprodol Tablets dependence, withdrawal, or abuse, Carisoprodol Tablets should be used with caution in addictionprone patients and in patients taking other CNS depressants including alcohol, and Carisoprodol Tablets should not be used more than two to three weeks for the relief of acute musculoskeletal discomfort. One of the metabolites of Carisoprodol Tablets, meprobamate (a controlled substance), may cause dependence. [see Clinical Pharmacology (12.3)].
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 Tablets were 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 Tablets were 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.
DOSAGE & ADMINISTRATION SECTION.
DOSAGE AND ADMINISTRATION Recommended Administration For the dietary management of the metabolic processes associated with pain disorders and inflammatory conditions. Take (2) capsules one to three times daily or as directed by physician. As with most amino acid formulations Theramine should be taken without food to increase the absorption of key ingredients.
GERIATRIC USE SECTION.
8.5 Geriatric Use 8.5 Geriatric Use The efficacy, safety, and pharmacokinetics of Carisoprodol Tablets in patients over 65 years old have not been established.
HOW SUPPLIED SECTION.
How Supplied Theramine is supplied in purple and white, size 0 capsules in bottles of 60 or 90 capsules. Physician Supervision Theramine is a Medical Food product available by prescription only and must be used while the patient is under ongoing physician supervision. U.S. patent pending. Manufactured by Arizona Nutritional Supplements, Inc. Chandler AZ 85225 Distributed by Physician Therapeutics LLC, Los Angeles, CA 90077. www.ptlcentral.com Copyright 2003-2006, Physician Therapeutics LLC, all rights reserved NDC: 68405-1008-02 NDC: 68405-1008-03
SPL UNCLASSIFIED SECTION.
Theramine PRODUCT INFORMATION Theramine (U.S. patent pending) capsules by oral administration. A specially formulated Medical Food product, consisting of a proprietary blend of amino acids and polyphenol ingredients in specific proportions, for the dietary management of the metabolic processes associated with pain disorders and inflammatory conditions. (PD) (IC). Must be administered under physician supervision. Medical Foods Medical Food products are often used in hospitals (e.g., for burn victims or kidney dialysis patients) and outside of a hospital setting under a physicians care for the dietary management of diseases in patients with particular medical or metabolic needs due to their disease or condition. Congress defined "Medical Food" in the Orphan Drug Act and Amendments of 1988 as "a food which is formulated to be consumed or administered enterally [or orally] under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation." Medical Foods are complex formulated products, requiring sophisticated and exacting technology. Theramine has been developed, manufactured, and labeled in accordance with both the statutory and the FDA regulatory definition of a Medical Food. Theramine must be used while the patient is under the ongoing care of a physician. PAIN DISORDERS (PD) INFLAMMATORY CONDITIONS (IC) PD and IC as a Metabolic Deficiency Disease A critical component of the definition of a Medical Food is the requirement for a distinctive nutritional deficiency. FDA scientists have proposed a physiologic definition of a distinctive nutritional deficiency as follows: the dietary management of patients with specific diseases requires, in some instances, the ability to meet nutritional requirements that differ substantially from the needs of healthy persons. For example, in establishing the recommended dietary allowances for general, healthy population, the Food and Nutrition Board of the Institute of Medicine National Academy of Sciences, recognized that different or distinctive physiologic requirements may exist for certain persons with "special nutritional needs arising from metabolic disorders, chronic diseases, injuries, premature birth, other medical conditions and drug therapies. Thus, the distinctive nutritional needs associated with a disease reflects the total amount needed by a healthy person to support life or maintain homeostasis, adjusted for the distinctive changes in the nutritional needs of the patient as a result of the effects of the disease process on absorption, metabolism and excretion. It was also proposed that in patients with certain disease states who respond to nutritional therapies, a physiologic deficiency of the nutrient is assumed to exist. For example, if a patient with pain disorders responds to a tryptophan formulation by decreasing perceived pain, a deficiency of tryptophan is assumed to exist. Patients with pain disorders and inflammatory conditions are known to have nutritional deficiencies of tryptophan, choline, arginine, GABA, flavonoids, and certain antioxidants. Patients with pain disorders and inflammatory conditions frequently exhibit reduced plasma levels of tryptophan and GABA and have been shown to respond to oral administration of GABA, arginine, tryptophan, or a 5-hydoxytryptophan formulation. Research has shown that tryptophan, arginine or GABA reduced diets result in a fall of circulating tryptophan, arginine, and/or GABA. Patients with pain disorders frequently exhibit activation of the degradation pathways that increases the turnover of GABA, arginine and/or tryptophan leading to a reduced level of production of serotonin, GABA or nitric oxide for a given precursor blood level. Research has also shown that a genetic predisposition to accelerated degradation can lead to increased precursor requirements in certain patients with pain disorders and inflammatory conditions. Choline is required to fully potentiate acetylcholine synthesis by brain neurons. A deficiency of choline leads to reduced acetylcholine production by the neurons. Flavonoids potentiate the production of acetylcholine by the neurons thereby reducing delta pain. Diets deficient in flavonoid rich foods and choline result in inadequate flavonoid concentrations, impeding acetylcholine production in certain patients with pain disorders and/or inflammatory conditions. Acetylcholine in pre-synaptic ganglia is necessary for the production of serotonin and nitric oxide in post-synaptic ganglia. Provision of tryptophan, arginine, GABA, choline and flavonoids with antioxidants, in specific proportions can restore the production of beneficial serotonin, nitric oxide, and acetylcholine, thereby reducing the perception of pain and reducing inflammation. L-Histidine is known to produce brain histamine that stimulates production of ACTH.
PRODUCT DESCRIPTION Primary Ingredients Theramine consists of a proprietary blend of amino acids, cocoa, caffeine, cinnamon, and flavonoids in specific proportions. These ingredients fall into the category of Generally Regarded as Safe (GRAS) as defined by the Food and Drug Administration (FDA) (Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act). A GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. The standard for an ingredient to achieve GRAS status requires not only technical demonstration of non-toxicity and safety, but also general recognition of safety through widespread usage and agreement of that safety by experts in the field. Many ingredients have been determined by the U.S. Food and Drug Administration (FDA) to be GRAS, and are listed as such by regulation, in Volume 21 Code of Federal Regulations (CFR) Sections 182, 184, and 186. Amino Acids Amino Acids are the building blocks of protein. All amino acids are GRAS listed as they have been ingested by humans for thousands of years. The doses of the amino acids in Theramine are equivalent to those found in the usual human diet. Patients with pain disorders may require an increased amount of certain amino acids that cannot be obtained from normal diet alone. Tryptophan, for example, is an obligatory amino acid. The body cannot make tryptophan and must obtain tryptophan from the diet. Tryptophan is needed to produce serotonin. Serotonin is required to reduce pain. Patients with pain disorders and inflammatory conditions have altered serotonin metabolism. Some patients with pain disorders and inflammatory conditions have a resistance to the use of tryptophan that is similar to the mechanism found in insulin resistance. Patients with pain disorders and inflammatory conditions cannot acquire sufficient tryptophan from the diet to alter the perception of pain and the inflammatory process without ingesting a prohibitively large amount of calories, particularly calories from protein. Flavonoids Flavonoids are a group of phytochemical compounds found in all vascular plants including fruits and vegetables. They are a part of a larger class of compounds known as polyphenols. Many of the therapeutic or health benefits of colored fruits and vegetables, cocoa, red wine, and green tea are directly related to their flavonoid content. The specially formulated flavonoids found in Theramine cannot be obtained from conventional foods in the necessary proportions to elicit a therapeutic response. Other Ingredients Theramine contains the following inactive or other ingredients, as fillers, excipients, and colorings: magnesium stearate, microcrystalline cellulose, Maltodextrin NF, gelatin (as the capsule material). Physical Description Theramine is a yellow to light brown powder. Theramine contains L-Glutamine, L-Arginine, L-Histidine, and L-Serine, 5-Hydroxytryptophan as Griffonia Seed Extract, GABA, Choline Bitartrate, Cinnamon, Cocoa, Hydrolyzed Whey Protein, and Grape Seed Extract.
OVERDOSE There is a negligible risk of overdose with Theramine as the total dosage of amino acids in a one month supply (90 capsules) is less than 36 grams. Overdose symptoms may include diarrhea, weakness, and nausea. POST-MARKETING SURVEILLANCE Post-marketing surveillance has shown no serious adverse reactions. Reported cases of mild rash and itching may have been associated with allergies to Theramine flavonoid ingredients, including cinnamon, cocoa, and chocolate. These reactions were transient in nature and subsided within 24 hours.
PEDIATRIC USE SECTION.
8.4 Pediatric Use 8.4 Pediatric Use The efficacy, safety, and pharmacokinetics of Carisoprodol Tablets in pediatric patients less than 16 years of age have not been established.
NURSING MOTHERS SECTION.
8.3 Nursing Mothers 8.3 Nursing Mothers Very limited data in humans show that Carisoprodol Tablets 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 Carisoprodol Tablets may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when Carisoprodol Tablets are administered to a nursing woman
STORAGE AND HANDLING SECTION.
Storage Store at room temperature, 59-86OF (15-30OC) Protect from light and moisture. Theramine is supplied to physicians in a recyclable plastic bottle with a child-resistant cap.
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS 5.1 Sedation 5.2 Drug Dependence, Withdrawal, and Abuse 5.3 Seizures 5 WARNINGS AND PRECAUTIONS 5.1 Sedation Carisoprodol Tablets may 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. 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 Drug Dependence, Withdrawal, and Abuse In the postmarketing experience with Carisoprodol Tablets, 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 Tablets in combination with other drugs with abuse potential. Withdrawal symptoms have been reported following abrupt cessation after prolonged use. To reduce the chance of Carisoprodol Tablets dependence, withdrawal, or abuse, Carisoprodol Tablets should be used with caution in addiction prone patients and in patients taking other CNS depressants including alcohol, and Carisoprodol Tablets should not be used more than two to three weeks for the relief of acute musculoskeletal discomfort. One of the metabolites of Carisoprodol Tablets, 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 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)].
LABOR & DELIVERY SECTION.
8.2 Labor and Delivery 8.2 Labor and Delivery There is no information about the effects of Carisoprodol Tablets on the mother and the fetus during labor and delivery.
DRUG INTERACTIONS SECTION.
DRUG INTERACTIONS Theramine does not directly influence the pharmacokinetics of prescription drugs. Clinical experience has shown that administration of Theramine may allow for lowering the dose of co-administered drugs under physician supervision.
12.3 Pharmacokinetics 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 350 mg carisoprodol (see Table 2). The Cmax of meprobamate was 2.5 0.5 g/mL (mean SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 g/mL) after administration of a single 400 mg dose of meprobamate. Table 2. Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean SD, n=24) Carisoprodol 350 mg Carisoprodol Carisoprodol Cmax (g/mL) 1.8 1.0 AUCinf (g*hr/mL) 7.0 5.0 Tmax (hr) 1.7 0.8 T1/2 (hr) 2.0 0.5 Meprobamate Meprobamate Cmax (g/mL) 2.5 0.5 AUCinf (g*hr/mL) 46 9.0 Tmax (hr) 4.5 1.9 T1/2 (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 Tablets 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 Tablets 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%.
12.2 Pharmacodynamics 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 Tablets is unkown.
USE IN SPECIFIC POPULATIONS SECTION.
8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Patients with Reduced CYP2C19 Activity 8.6 Renal Impairment The safety and pharmacokinetics of Carisoprodol Tablets in patients with renal impairment have not been evaluated. Since Carisoprodol Tablets are excreted by the kidney, caution should be exercised if Carisoprodol Tablets are administered to patients with impaired renal function. Carisoprodol Tablets are dialyzable by hemodialysis and peritoneal dialysis. 8.7 Hepatic Impairment The safety and pharmacokinetics of Carisoprodol Tablets in patients with hepatic impairment have not been evaluated. Since Carisoprodol Tablets are metabolized in the liver, caution should be exercised if Carisoprodol Tablets are administered to patients with impaired hepatic function. 8.8 Patients with Reduced CYP2C19 Activity Patients with reduced CYP2C19 activity have higher exposure to Carisoprodol Tablets. Therefore, caution should be exercised in administration of Carisoprodol Tablets to these patients. [see Clinical Pharmacology (12.3)].
RECENT MAJOR CHANGES SECTION.
Indications and Usage (1) 9/2007 Dosage and Administration (2) 9/2007
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION 17.1 Sedation 17.2 Avoidance of Alcohol and Other CNS Depressants 17.3 Carisoprodol Should Only Be Used for Short-Term Treatment 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: West-ward Pharmaceutical Corp Eatontown, NJ 07724 Manufactured by: Shasun Chemical and Drugs Ltd. Pondicherry, India
CLINICAL STUDIES SECTION.
CLINICAL EXPERIENCE Administration of Theramine has demonstrated significant reduction in symptoms of pain and inflammation in patients with acute and chronic pain when used for the dietary management of the metabolic processes associated with pain disorders and inflammatory conditions. Administration of Theramine results in the induction and maintenance of pain relief in patients with pain disorders and inflammatory conditions.
CLINICAL PHARMACOLOGY SECTION.
CLINICAL PHARMACOLOGY Mechanism of Action Theramine acts by restoring and maintaining the balance of the neurotransmitters; GABA, nitric oxide, serotonin, and acetylcholine that are associated with pain disorders and inflammatory conditions. Theramine stimulates the production ACTH to reduce inflammation. Metabolism The amino acids in Theramine are primarily absorbed by the stomach and small intestines. All cells metabolize the amino acids in Theramine. Circulating tryptophan, arginine and choline blood levels determine the production of serotonin, nitric oxide, and acetylcholine. Excretion Theramine is not an inhibitor of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4. These isoenzymes are principally responsible for 95% of all detoxification of drugs, with CYP3A4 being responsible for detoxification of roughly 50% of drugs. Amino acids do not appear to have an effect on drug metabolizing enzymes.
PRECAUTIONS AND CONTRAINDICATIONS Theramine is contraindicated in an extremely small number of patients with hypersensitivity to any of the nutritional components of Theramine.