WARNINGS SECTION.


WARNINGSCyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS). Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants.

PREGNANCY SECTION.


Pregnancy Pregnancy Category B: Reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS Ingestion of L-Tryptophan, L-Arginine, or Choline at high doses of 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. Theramine contains less than 1 gram per dose of amino acids however, some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each Theramine capsule does not exceed 300 mg.

OTC - KEEP OUT OF REACH OF CHILDREN SECTION.


KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.


INDICATIONS FOR USE Theramine is intended for the clinical dietary management of the metabolic processes of pain disorders and inflammatory conditions.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenesis, Mutagenesis, Impairment of Fertility In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups this microscopic change was seen after 26 weeks and even earlier in rats which died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks. Cyclobenzaprine did not affect the onset, incidence or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat. At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose.

DRUG ABUSE AND DEPENDENCE SECTION.


DRUG ABUSE AND DEPENDENCEPharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when cyclobenzaprine hydrochloride is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION Recommended Administration For the dietary management of the metabolic processes associated with pain disorders and inflammatory conditions. Take two (2) capsules every four hours or as directed by physician. As with most amino acid formulations Theramine should be taken without food to increase the absorption of key ingredients.

HOW SUPPLIED SECTION.


How Supplied Theramine is supplied in purple and white, size 0 capsules in bottles of 60 and 90 capsules. Physician Supervision Theramine is a Medical Food product available by prescription only and may be used per FDA law, and product labeling only while the patient is under ongoing physician supervision. U.S. patent pending Manufactured by Arizona Nutritional Supplements, Inc. Chandler AZ 85225 Distributed exclusively by Physician Therapeutics LLC, a wholly owned subsidiary of Targeted Medical Pharma Inc. Los Angeles, CA www.ptlcentral.com NDC: 68405-008-02 NDC: 68405-008-03

SPL UNCLASSIFIED SECTION.


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, unique or distinctive 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, and that are used only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the Medical Food. Theramine has been developed, manufactured, and labeled in accordance with both the statutory definition of a Medical Food and FDAs regulatory labeling guidelines. 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 that the product must address the distinct nutritional requirements of a particular disease or condition. FDA scientists have proposed a physiologic definition of distinctive nutritional requirements 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 a pain disorder responds to a tryptophan formulation by decreasing perceived pain, then a deficiency of tryptophan is assumed to exist. Patients with pain disorders and inflammatory conditions are known to have increased nutritional requirements for tryptophan, choline, arginine, GABA, flavonoids, and certain antioxidants. These nutritional requirements are such that they cannot be achieved by the modification of the normal diet alone, or by supplementing the diet. 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-hydroxytryptophan 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 rate 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. 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, producing cortisol to reduce inflammation.

DESCRIPTION SECTION.


PRODUCT DESCRIPTION Primary Ingredients Theramine consists of a proprietary formulation of Gamma Aminobutyric Acid, Choline Bitartrate, Whey Protein Hydrolysate, L-Arginine, L-Histidine, L-Glutamine, Theobromine, Griffonia See, Grape Seed, L-Serine, and Cinnamon in specific proportions. These ingredients fall into the classification of Generally Recognized 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 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 and are GRAS listed as they have been safely ingested by humans for thousands of years. The formulations 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. 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: Gelatin, Silicon Dioxide, Tricalcium Phosphate, Vegetable Magnesium stearate, Cellulose, FDandC Blue#1, FDandC Red #3, Titanium Dioxide. Physical Description Theramine is a yellow to light brown powder. Theramine contains Gamma Aminobutyric Acid, Choline Bitartrate, Whey Protein Hydrolysate, L-Arginine, L-Histidine HCL, L-Glutamine, Theobromine, Griffonia Seed, Grape Seed, L-Serine, and Cinnamon. Each capsule consists of a proprietary blend of these ingredients in an amount of 366mg or 732mg per two (2) capsule dose.

OVERDOSAGE SECTION.


OVERDOSE There is a negligible risk of overdose with Theramine as the total amount of amino acids in a one month supply (90 capsules) is less than 30 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 Grape Seed. These reactions were temporary, transient in nature and subsided within 24-hours.

PRECAUTIONS SECTION.


PRECAUTIONS General Because of its atropine-like action, cyclobenzaprine hydrochloride should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. Impaired Hepatic Function The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Hepatic Impairment). These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine. Cyclobenzaprine hydrochloride tablets should be used with caution in subjects with mild hepatic impairment starting with a 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride tablets in subjects with moderate to severe impairment is not recommended.

PEDIATRIC USE SECTION.


Pediatric Use Safety and effectiveness of cyclobenzaprine hydrochloride in pediatric patients below 15 years of age have not been established. Use in the Elderly The plasma concentration of cyclobenzaprine is increased in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Elderly ). The elderly may also be more at risk for CNS adverse events such as hallucinations and confusion, cardiac events resulting in falls or other sequelae, drug-drug and drug-disease interactions. For these reasons, in the elderly, cyclobenzaprine should be used only if clearly needed. In such patients cyclobenzaprine should be initiated with a 5 mg dose and titrated slowly upward.

NURSING MOTHERS SECTION.


Nursing Mothers It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when cyclobenzaprine hydrochloride is administered to a nursing woman.

STORAGE AND HANDLING SECTION.


Storage Store in a cool dry place 45-90 F (8-32 C) relative humidity below 50%. Theramine is supplied in a recyclable plastic bottle with a child-resistant cap.

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.

PHARMACOKINETICS SECTION.


Pharmacokinetics Estimates of mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady state within 3-4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n=18), peak plasma concentration was 25.9 ng/mL (range, 12.8-46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 nghr/mL (range, 80-319 nghr/mL). Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min. The plasma concentration of cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment (see PRECAUTIONS, Use in the Elderly and PRECAUTIONS, Impaired Hepatic Function). ElderlyIn a pharmacokinetic study in elderly individuals (65 yrs old), mean (n=10) steady state cyclobenzaprine AUC values were approximately 1.7-fold (171.0 nghr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 nghr/mL, range 36.1-182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4-fold (198.3 nghr/mL, range 155.6-255.3 versus 83.2 nghr/mL, range 41.1-142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2-fold (143.8 nghr/mL, range 96.1-196.3 versus 115.9 nghr/mL, range 36.1-182.9 for younger females). In light of these findings, therapy with cyclobenzaprine hydrochloride tablets in the elderly should be initiated with a 5 mg dose and titrated slowly upward. Hepatic ImpairmentIn a pharmacokinetic study of sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and Cmax were approximately double the values seen in the healthy control group. Based on the findings, cyclobenzaprine hydrochloride tablets should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride tablets in subjects with moderate to severe impairment is not recommended. No significant effect on plasma levels or bioavailability of cyclobenzaprine hydrochloride tablets or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of cyclobenzaprine hydrochloride tablets and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of cyclobenzaprine hydrochloride tablets with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that cyclobenzaprine hydrochloride tablets enhance the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of cyclobenzaprine hydrochloride tablets in acute musculoskeletal conditions. Clinical StudiesEight double-blind controlled clinical studies were performed in 642 patients comparing cyclobenzaprine hydrochloride 10 mg, diazepam, and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with cyclobenzaprine than with diazepam, while in the other studies the improvement following both treatments was comparable. Although the frequency and severity of adverse reactions observed in patients treated with cyclobenzaprine were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with cyclobenzaprine and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs. The efficacy of cyclobenzaprine hydrochloride tablets 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared cyclobenzaprine hydrochloride tablets 5 and 10 mg t.i.d. to placebo; and a second study compared cyclobenzaprine hydrochloride tablets 5 and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician's evaluation of the presence and extent of palpable muscle spasm. Comparisons of cyclobenzaprine hydrochloride tablets 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with cyclobenzaprine hydrochloride tablets 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that cyclobenzaprine hydrochloride tablets 5 mg was associated with a greater reduction in palpable muscle spasm than placebo. Analysis of the data from controlled studies shows that cyclobenzaprine produces clinical improvement whether or not sedation occurs. Surveillance Program A post-marketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with cyclobenzaprine hydrochloride tablets 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS).

INFORMATION FOR PATIENTS SECTION.


Information for Patients Cyclobenzaprine hydrochloride tablets, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. In the elderly, the frequency and severity of adverse events associated with the use of cyclobenzaprine, with or without concomitant medications, is increased. In elderly patients, cyclobenzaprine hydrochloride tablets should be initiated with a 5 mg dose and titrated slowly upward.

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.


CCLINICAL 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.

CONTRAINDICATIONS SECTION.


PRECAUTIONS AND CONTRAINDICATIONS Theramine is contraindicated in an extremely small number of patients with hypersensitivity to any of the nutritional components of Theramine.