Prescription Drugs

CLINICAL PHARMACOLOGY TRILISATE (choline magnesium trisalicylate) Tablets/ Liquid contain salicylate with anti- inflammatory, analgesic and antipyretic action. On ingestion of TRILISATE (choline magnesium trisalicylate) Tablets/ Liquid, the salicylate moiety is absorbed rapidly and reaches peak blood levels within an average of one to two hours after single doses of the tablets or liquid. The primary route of excretion is renal; the excretion products are chiefly the glycine and glucuronide conjugates. At higher serum salicylate concentrations, the glycine conjugation pathway becomes rapidly saturated. Thus, the slower glucuronide conjugation pathway becomes the rate limiting step for salicylate excretion. In addition, salicylate excreted in the bile as glucuronide conjugate may be reabsorbed. These factors account for the prolongation of salicylate half-life and the nonlinear increase in plasma salicylate level as the salicylate dose is increased. The serum concentration of salicylate is increased by conditions that decrease glomerular filtration rate or proximal tubular secretion. The bioequivalence of TRILISATE (choline magnesium trisalicylate) Liquid and Tablets 500 mg/ 750 mg/ 1000 mg has been established. With the tablets, a steady- state condition is usually reached after 4 to 5 doses, and the half- life of elimination, on repeated administration of tablets, is 9 to 17 hours. This permits a maintenance dosage schedule of once or twice daily. Unlike aspirin and certain other non-steroidal anti-inflammatory agents, such as arylpropionic acid derivatives and arylacetic acid derivatives, choline magnesium trisalicylate, at therapeutic dosage levels, does not affect platelet aggregation, as shown by in vitro and in vivo studies.

DESCRIPTION Trilisate (choline magnesium trisalicylate) ® (choline magnesium trisalicylate) TABLETS/LIQUID 500 mg, 750 mg or 1000 mg salicylate content TRILISATE (choline magnesium trisalicylate) Tablets/ Liquid are nonsteroidal, anti-inflammatory preparations containing choline magnesium trisalicylate which is freely soluble in water. The absolute structure of choline magnesium trisalicylate is not known at this time. Choline magnesium trisalicylate has a molecular formula of C26H29O10NMg, and a molecular weight of 539.8. This substance when dissolved in water would appear to form 5 ions (1 choline ion, 1 magnesium ion and 3 salicylate ions). TRILISATE (choline magnesium trisalicylate) Tablets/ Liquid are available in scored, pale pink 500 mg tablets; in scored, white, film-coated 750 mg tablets, and in scored, red, film-coated 1000 mg tablets. TRILISATE (choline magnesium trisalicylate) Liquid is a cherry cordial-flavored liquid providing 500 mg salicylate content per teaspoonful (5 ml) for oral administration. Each 500 mg tablet contains 293 mg of choline salicylate combined with 362 mg of magnesium salicylate to provide 500 mg salicylate content. Each 750 mg tablet contains 440 mg of choline salicylate combined with 544 mg of magnesium salicylate to provide 750 mg salicylate content. Each 1000 mg tablet contains 587 mg of choline salicylate combined with 725 mg magnesium salicylate to provide 1000 mg salicylate content. TRILISATE (choline magnesium trisalicylate) Liquid contains 293 mg of choline salicylate combined with 362 mg of magnesium salicylate to provide 500 mg salicylate per teaspoonful (5 ml) in a clear amber, cherry cordial-flavored vehicle. Inactive Ingredients Each 500 mg tablet contains: Carboxymethylcellulose sodium, Corn starch, Edetate disodium, FD& C Yellow No. 6, Stearic acid, and other ingredients. Each 750 mg tablet contains: Carboxymethylcellulose sodium, Edetate disodium, Hydroxypropyl methylcellulose, Polyethylene glycol, Polysorbate 20, Stearic acid, Talc, Titanium dioxide, and other ingredients. Each 1000 mg tablet contains: Carboxymethylcellulose sodium, Edetate disodium, FD& C Red No. 40, FD& C Yellow No. 6, FD& C Blue No. 2, Hydroxypropyl methylcellulose, Polyethylene glycol, Polysorbate 20, Polysorbate 80, Stearic acid, Talc, Titanium dioxide, and other ingredients. Each teaspoonful (5 ml) of Liquid contains: Caramel, Carboxymethylcellulose sodium, Edetate disodium, FD& C Yellow No. 6, Glycerin, High fructose corn syrup, Potassium sorbate, Water, and Artificial flavors.

INDICATIONS Osteoarthritis, Rheumatoid Arthritis and Acute Painful Shoulder Salicylates are considered the base therapy of choice in the arthritides; and TRILISATE (choline magnesium trisalicylate) preparations are indicated for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and other arthritides. TRILISATE (choline magnesium trisalicylate) Tablets or Liquid are indicated in the long-term management of these diseases and especially in the acute flare of rheumatoid arthritis. TRILISATE (choline magnesium trisalicylate) Tablets or Liquid are also indicated for the treatment of acute painful shoulder. TRILISATE (choline magnesium trisalicylate) preparations are effective and generally well tolerated, and are logical choices whenever salicylate treatment is indicated. They are particularly suitable when a once-a-day or b.i.d. dosage regimen is important to patient compliance; when gastrointestinal intolerance to aspirin is encountered; when gastrointestinal microbleeding or hematologic effects of aspirin are considered a patient hazard; and when interference (or the risk of interference) with normal platelet function by aspirin or by propionic acid derivatives is considered to be clinically undesirable. Use of TRILISATE (choline magnesium trisalicylate) Liquid is appropriate when a liquid dosage form is preferred, as in the elderly patient. The efficacy of TRILISATE (choline magnesium trisalicylate) preparations has not been studied in those patients who are designated by the American Rheumatism Association as belonging in Functional Class IV (incapacitated, largely or wholly bedridden or confined to a wheelchair, with little or no self-care). Analgesic and Antipyretic Action TRILISATE (choline magnesium trisalicylate) Tablets/ Liquid are also indicated for the relief of mild to moderate pain and for antipyresis. In children, TRILISATE (choline magnesium trisalicylate) preparations are indicated for conditions requiring anti- inflammatory or analgesic action such as juvenile rheumatoid arthritis and other appropriate conditions. DOSAGE AND ADMINISTRATION ADULTS In rheumatoid arthritis, osteoarthritis, the more severe arthritides, and acute painful shoulder, the recommended starting dosage is 1500 mg given b.i.d. Some patients may be treated with 3000 mg given once per day (h.s.) In the elderly patient, a daily dosage of 2250 mg given as 750 mg t.i.d. may be efficacious and well tolerated. Dosage should be adjusted in accordance with the patients response. In patients with renal dysfunction, monitor salicylate levels and adjust dose accordingly. For mild to moderate pain or for antipyresis, the usual dosage is 2000 mg to 3000 mg daily in divided doses (b.i.d.). Based on patient response or salicylate blood levels, dosage may be adjusted to achieve optimum therapeutic effect. Salicylate blood levels should be in the range of 15 to 30 mg/ 100 mL for anti-inflammatory effect and 5 to 15 mg/ 100 mL for analgesia and antipyresis. Each 500 mg tablet or teaspoonful is equivalent in salicylate content to 10 g of aspirin; each 750 mg tablet, to 15 g of aspirin; and each 1000 mg tablet, to 20 g of aspirin. If the physician prefers, the recommended daily dosage may be administered on a t.i.d. schedule. As with other therapeutic agents, individual dosage adjustment is advisable, and a number of patients may require higher or lower dosages than those recommended. Certain patients require 2 to 3 weeks of therapy for optimal effect. CHILDREN Usual daily dose for children for anti- inflammatory or analgesic action: TRILISATE (choline magnesium trisalicylate) 500 mg Tablets/ Liquid and TRILISATE (choline magnesium trisalicylate) 750 mg and 1000 mg Tablets, 50 mg/ kg/ day. Weight (kg) Total daily dose 12- 13 500 mg 14- 17 750 mg 18- 22 1000 mg 23- 27 1250 mg 28- 32 1500 mg 33- 37 1750 mg Total daily doses should be administered in divided doses (b.i.d.). Doses of TRILISATE (choline magnesium trisalicylate) preparations are calculated as the total daily dose of 50 mg/ kg/ day for children of 37 kg body weight or less and 2250 mg/ day for heavier children. TRILISATE (choline magnesium trisalicylate) Liquid is available for greater convenience in treating younger patients and those adult patients unable to wswallow a solid dosage form. HOW SUPPLIED NDC 0034-0500-80: TRILISATE (choline magnesium trisalicylate) 500 mg Tablets (pale pink, scored) supplied in bottles of 100 tablets. NDC 0034-0500-50: TRILISATE (choline magnesium trisalicylate) 500 mg Tablets (pale pink, scored) supplied in bottles of 500 tablets. NDC 0034-0500-10: TRILISATE (choline magnesium trisalicylate) 500 mg Tablets (pale pink, scored) supplied in unit dose packaging with 10 tablets per card. Ten cards are packed in each carton; 10 cartons are packed in each shipper. NDC 0034-0505-80: TRILISATE (choline magnesium trisalicylate) 750 mg Tablets (scored, white, film-coated) in bottles of 100 tablets. NDC 0034-0505-50: TRILISATE (choline magnesium trisalicylate) 750 mg Tablets (scored, white, film-coated) in bottles of 500 tablets. NDC 0034-0505-10: TRILISATE (choline magnesium trisalicylate) 750 mg Tablets (scored, white, film-coated) supplied in unit dose packaging with 10 tablets per card. Ten cards are packed in each carton; 10 cartons are packed in each shipper. NDC 0034-0510-60: TRILISATE (choline magnesium trisalicylate) 1000 mg Tablets (scored, red, film-coated) in bottles of 60 tablets. NDC 0034-0510-80: TRILISATE (choline magnesium trisalicylate) 1000 mg Tablets (scored, red, film-coated) in bottles of 100 tablets. NDC 0034-0520-80: TRILISATE (choline magnesium trisalicylate) Liquid in bottles of 8 fl. oz. (237 mL). Store at controlled room temperature 59° to 86° F( 15° to 30° C). CAUTION: Federal law prohibits dispensing without a prescription. REFERENCES 1. Szczeklik, A et al; Choline magnesium trisalicylate in patients with aspirin- induced asthma; Eur Respir J; 3: 535- 539, 1990. 2. Zucker, MB and Rothwell KB; Differential influences of salicylate compounds on platelet aggregation and serotonin release; Current Therapeutic Research; 23(2), Feb 1987. 3. Stuart, JJ and Pisko, EJ; Choline magnesium trisalicylate does not impair platelet aggregation; Pharmatherapeutica; 2(8): 547, 1981. 4. Danesh, BJZ, Saniabadi, AR, Russell, RI et al; Therapeutic potential of choline magnesium trisalicylate as an alternative to aspirin for patients with bleeding tendencies; Scottish Medical Journal; 32: 167- 168, 1987. 5. Danesh, BJZ, McLaren, M, Russell, RI et al; Does non- acetylated salicylate inhibit thromboxane biosynthesis in human platelets? Scottish Medical Journal; 33: 315- 316, 1988. 6. Danesh, BJZ, McLaren, M, Russell, RI etal; Comparison of the effect of aspirin and choline magnesium trisalicylate on thromboxane biosynthesis in human platelets: role of the acetyl moiety; Haemostasis; 19: 169- 173, 1989. 7. Data on file. Medical Department. The Purdue Frederick Company, 1989. 8. Blechman, WJ, and Lechner, BL; Clinical comparative evalua- tion of choline magnesium trisalicylate and acetylsalicylic acid in rheumatoid arthritis; Rheumatology and Rehabilitation; 18: 119- 124, 1979. 9. McLaughlin, G; Choline magnesium trisalicylate vs. naproxen in rheumatoid arthritis; Current Therapeutic Research; 32(4): 579- 585, 1982. 10. Ehrlich, GE; Miller, SB; and Zeiders, RS; Choline magnesium trisalicylate vs. ibuprofen in rheumatoid arthritis; Rheumatol- ogy and Rehabilitation; 19: 30- 41, 1980. 11. Goldenberg, A; Rudnicki, AD, and Koonce, ML; Clinical com- parison of efficacy and safety of choline magnesium trisalicylate and indomethacin in treating osteoarthritis; Current Therapeutic Research; 24(3): 245- 260, 1978. 12. Guerin, BK and Burnstein, SL; Conservative therapy of acute painful shoulder; Orthopedic Review; XI (7) :29- 37, 1982.

PATIENT INFORMATION See WARNINGS, PRECAUTIONS and CONTRAINDICATIONS.

OVERDOSE Death in adults has been reported following ingestion of doses from 10 to 30 grams of salicylate; however, larger doses have been taken without resulting fatality. Symptoms Salicylate intoxication, known as salicylism, may occur with large doses or extended therapy. Common symptoms of salicylism include headache, dizziness, tinnitus, hearing impairment, confusion, drowsiness, sweating, vomiting, diarrhea, and hyperventilation. A more severe degree of salicylate intoxication can lead to CNS disturbances, alteration in electrolyte balance, respiratory and metabolic acidosis, hyperthermia, and dehydration. Treatment Reduction of further absorption of salicylate from the gastrointestinal tract can be achieved via emesis, gastric lavage, use of activated charcoal, or a combination of the above. Appropriate I.V. fluids should be administered to correct dehydration, electrolyte imbalance, and acidosis and to maintain adequate renal function. To accelerate salicylate excretion, forced diuresis with alkalinizing solution is recommended. In extreme cases, peritoneal dialysis or hemodialysis should be considered for effective salicylate removal. CONTRAINDICATIONS Patients who are hypersensitive to non-acetylated salicylates should not take TRILISATE (choline magnesium trisalicylate) Tablets or Liquid.

SIDE EFFECTS The most frequent adverse reactions observed with TRILISATE (choline magnesium trisalicylate) preparations in clinical trials (7- 12) are tinnitus and gastrointestinal complaints (including nausea, vomiting, gastric upset, indigestion, heartburn, diarrhea, constipation and epigastric pain). These occur in less than twenty percent (20%) of patients. Should tinnitus develop, reduction of daily dosage is recommended until the tinnitus is resolved. Less frequent adverse reactions, occurring in less than two percent (2%) of patients, are: hearing impairment, headache, lightheadedness, dizziness, drowsiness, and lethargy. Adverse reactions occurring in less than one percent (1%) of patients are: gastric ulceration, positive fecal occult blood, elevation in serum BUN and creatinine, rash, pruritus, anorexia, weight gain, edema, epistaxis and dysgeusia. Spontaneous reporting has yielded isolated or rare reports of the following adverse experiences: duodenal ulceration, elevated hepatic transaminases, hepatitis, esophagitis, asthma, erythema multiforme, urticaria, ecchymoses, irreversible hearing loss and/ or tinnitus, mental confusion, hallucinations. DRUG ABUSE AND DEPENDENCE Drug abuse and dependence have not been reported with TRILISATE (choline magnesium trisalicylate) preparations. DRUG INTERACTIONS Foods and drugs that alter urine pH may affect renal clearance of salicylate and plasma salicylate concentrations. Raising urine pH, as with chronic antacid use, can enhance renal salicylate clearance and diminish plasma salicylate concentration; urine acidification can decrease urinary salicylate excretion and increase plasma levels. When salicylate drug products are concurrently dosed with other plasma protein bound drug products, adverse effects may result. Although TRILISATE (choline magnesium trisalicylate) preparations are a rational choice for anti- inflammatory and analgesic therapy in patients on oral anticoagulants due to their demonstrated lack of effect in vivo and in vitro on platelet aggregation, bleeding time, platelet count, prothrombin time, and serum thromboxane B2 generation (7), the potential exists for increased levels of unbound warfarin with their concurrent use. Prothrombin time should be closely monitored and warfarin dose appropriately adjusted when therapy with TRILISATE (choline magnesium trisalicylate) preparations is initiated. The effect of TRILISATE (choline magnesium trisalicylate) on blood prothrombin levels has not been established. Salicylates may increase the therapeutic as well as toxic effects of methotrexate, particularly when administered in chemotherapeutic doses, by inhibition of renal methotrexate excretion and by displacement of plasma protein bound methotrexate. Caution should be exercised in administering TRILISATE (choline magnesium trisalicylate) to rheumatoid arthritis patients on methotrexate. When sulfonylurea oral hypoglycemic agents are co- administered with salicylates, the hypoglycemic effect may be enhanced via increased insulin secretion or by displacement of sulfonylurea agents from binding sites. Insulin- treated diabetics on high doses of salicylates should also be closely monitored for a similar hypoglycemic response. Other drugs with which salicylate competes for protein binding sites, and whose plasma concentration or free fraction may be altered by concurrent salicylate administration, include the following: phenytoin, valproic acid, and carbonic anhydrase inhibitors. The efficacy of uricosuric agents may be decreased when administered with salicylate products. Although low doses of salicylate (1 to 2 grams per day) have been reported to decrease urate excretion and elevate plasma urate concentrations, intermediate doses (2 to 3 grams per day) usually do not alter urate excretion. Larger salicylate doses (over 5 grams per day) can induce uricosuria and lower plasma urate levels. Corticosteroids can reduce plasma salicylate levels by increasing renal elimination and perhaps by also stimulating hepatic metabolism of salicylates. By monitoring plasma salicylate levels, salicylate dosage may be titrated to accommodate changes in corticosteroid dose or to avoid salicylate toxicity during corticosteroid taper.

WARNINGS Reye Syndrome is a rare but serious disease which may develop in children and teenagers who have chicken pox, influenza, or flu symptoms. While the cause of Reye Syndrome is unknown, some studies suggest a possible association between the development of Reye Syndrome and the use of medicines containing acetylated salicylates or aspirin. TRILISATE (choline magnesium trisalicylate) Tablets and Liquid are a combination of choline salicylate and magnesium salicylate which are nonacetylated salicylates, and there have been no reported cases associating TRILISATE (choline magnesium trisalicylate) with Reye Syndrome. Nevertheless, TRILISATE (choline magnesium trisalicylate) , as a salicylate-containing product, is not recommended for use in children and teenagers with chicken pox, influenza or flu symptoms. PRECAUTIONS General As with other salicylates and non- steroidal anti-inflammatory drugs, TRILISATE (choline magnesium trisalicylate) preparations should be used with caution in patients with acute or chronic renal insufficiency, with acute or chronic hepatic dysfunction, or with gastritis or peptic ulcer disease. Although reports exist of cross reactivity, including bronchospasm, with the use of non-acetylated salicylate products in aspirin- sensitive patients, TRILISATE (choline magnesium trisalicylate) preparations were found to be well tolerated with regard to pulmonary function and respiratory symptoms when these parameters were monitored in a group of documented aspirin-sensitive asthmatics dosed with TRILISATE (choline magnesium trisalicylate) in both controlled and open label studies.1 Concurrent use of other salicylate-containing products and TRILISATE (choline magnesium trisalicylate) preparations can lead to an increase in plasma salicylate concentration and may result in potentially toxic salicylate levels. Laboratory Tests Plasma salicylate levels can be periodically assessed during treatment with TRILISATE (choline magnesium trisalicylate) preparations to determine whether a therapeutically effective anti-inflammatory concentration of 15 to 30 mg/ 100 ml (150-300 µg/ mL) is being maintained. Manifestations of systemic salicylate intoxication are usually not seen until the concentration exceeds 30 mg/100 mL. However, such tests rarely differentiate between the active free and inactive protein bound salicylate components. Since protein binding of salicylate is affected by age, nutritional status, competitive binding of other drugs, and underlying disease (e.g. rheumatoid arthritis), plasma salicylate level determinations may not always accurately reflect efficacious or toxic levels of active free salicylate. Acidification of the urine can significantly diminish the renal clearance of salicylate and increase plasma salicylate concentrations. Drug/ Laboratory Test Interactions Free T4 values may be increased in patients on salicylate drug products due to competitive plasma protein binding; a concurrent decrease in total plasma T4 may be observed. Thyroid function is not affected. Carcinogenesis No long-term animal studies have been performed with TRILISATE (choline magnesium trisalicylate) to evaluate its carcinogenic potential. Use in Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with TRILISATE (choline magnesium trisalicylate) preparations. It is also not known whether TRILISATE (choline magnesium trisalicylate) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TRILISATE (choline magnesium trisalicylate) should be given to a pregnant woman only if clearly needed. Because of the known effects of other salicylate drug products on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided. Labor and Delivery The effects of TRILISATE (choline magnesium trisalicylate) on labor and delivery in pregnant women are unknown. Since prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported with the use of other salicylate products, the use of TRILISATE (choline magnesium trisalicylate) preparations near term is not recommended. Other salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms and with perinatal mortality. Nursing Mothers Salicylate is excreted in human milk. Peak milk salicylate levels are delayed, occurring as long as 9 to 12 hours post dose, and the milk: plasma ratio has been reported to be as high as 0.34. Because of the potential for significant salicylate absorption by the nursing infant, caution should be exercised when TRILISATE (choline magnesium trisalicylate) is administered to a nursing woman. Pediatric Use In a four-week, open-label pilot study of patients with juvenile rheumatoid arthritis, children from 6 to 16 years of age previously on aspirin received weight-adjusted doses (50-60 mg/ kg) of TRILISATE (choline magnesium trisalicylate) 500 mg tablets on a divided b.i.d. schedule with subsequent dose titration to achieve therapeutic serum salicylate levels. Eighty-three percent (83%) of the patients rated the therapeutic effect of TRILISATE (choline magnesium trisalicylate) as good or excellent. Tinnitus was reported by one patient and elevated SGOT levels at Week 1, which decreased during the trial, were detected in two patients. (See WARNINGS section.)