Disalcid

JUNE 1998

3M Pharmaceuticals
Northridge, CA 91324

DISALCID (salsalate) is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorders.

Adults

The usual dosage is 3000 mg daily, given in divided doses as follows: 1) two doses of two 750 mg tablets: 2) two doses of three 500 mg tablets/capsules; or 3) three doses of two 500 mg tablets/capsules. Some patients, e.g., the elderly, may require a lower dosage to achieve therapeutic blood concentrations and to avoid the more common side effects such as auditory.

Alleviation of symptoms is gradual, and full benefit may not be evident for 3 to 4 days, when plasma salicylate levels have achieved steady state. There is no evidence for development of tissue tolerance (tachyphylaxis) but salicylate therapy may induce increased activity of metabolizing liver enzymes, causing a greater rate of salicyluric acid production and excretion, with a resultant increase in dosage requirement for maintenance of therapeutic serum salicylate levels.

Children

Dosage recommendations and indications for DISALCID (salsalate) use in children have not been established.

DISALCID is contraindicated in patients hypersensitive to salsalate.

WARNINGS

Reye's Syndrome may develop in individuals who have chicken pox, influenza, or flu symptoms. Some studies suggest a possible association between the development of Reye's Syndrome and the use of medicines containing salicylate or aspirin. DISALCID (salsalate) contains a salicylate and therefore is not recommended for use in patients with chicken pox, influenza, or flu symptoms.

PRECAUTIONS

General

Patients on treatment with DISALCID (salsalate) should be warned not to take other salicylates so as to avoid potentially toxic concentrations. Great care should be exercised when DISALCID (salsalate) is prescribed in the presence of chronic renal insufficiency or peptic ulcer disease. Protein binding of salicylic acid can be influenced by nutritional status, competitive binding of other drugs, and fluctuations in serum proteins caused by disease (rheumatoid arthritis, etc.).

Although cross reactivity, induding bronchospasm, has been reported occasionally with non- acetylated salicylates, including salsalate, in aspirin-sensitive patients,^8,9 salsalate is less likely than aspirin to induce asthma in such patients.¹⁰

Laboratory Tests

Plasma salicylic acid concentrations should be periodically monitored during longterm treatment with DISALCID (salsalate) to aid maintenance of therapeutically effective levels: 10 to 30 mg/100 ml. Toxic manifestations are not usually seen until plasma concentrations exceed 30 mg/l00 ml (see OVERDOSAGE). Urinary pH should also be regularly monitored: sudden acidification, as from pH 6.5 to 5.5, can double the plasma level, resulting in toxicity.

Carcinogenesis

No long-term animal studies have been performed with DISALCID (salsalate) to evaluate its carcinogenic potential.

Use in Pregnancy

Pregnancy Category C: Salsalate and salicylic acid have been shown to be teratogenic and embryocidal in rats when given in doses 4 to 5 times the usual human dose. The effects were not observed at doses twice as great as the usual human dose. There are no adequate and well-controlled studies in pregnant women. DISALCID (salsalate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

There exist no adequate and well-controlled studies in pregnant women. Although adverse effects on mother or infant have not been reported with DISALCID (salsalate) use during labor, caution is advised when anti-inflammatory dosage is involved. However, other salicylates have been associated with prolonged gestation and labor, maternal and neonatal bleeding sequelae, potentiation of narcotic and barbiturate effects (respiratory or cardiac arrest in the mother), delivery problems and stillbirth.

Nursing Mothers

It is not known whether salsalate per se is excreted in human milk; salicylic acid, the primary metabolite of DISALCID (salsalate) , has been shown to appear in human milk in concentrations approximating the maternal blood level. Thus, the infant of a mother on DISALCID (salsalate) therapy might ingest in mother†s milk 30 to 80% as much salicylate per kg body weight as the mother is taking. Accordingly, caution should be exercised when DISALCID (salsalate) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. (See WARNINGS)

SIDE EFFECTS

In two well-controlled clinical trials (n= 280 patients), the following reversible adverse experiences characteristic of salicylates were most commonly reported with DISALCID (salsalate) , listed in descending order of frequency: tinnitus, nausea, hearing impairment, rash, and vertigo. These common symptoms of salicylates, i.e., tinnitus or reversible hearing impairment, are often used as a guide to therapy.

Although cause-and-effect relationships have not been established, spontaneous reports over a ten-year period have included the following additional medically significant adverse experiences: abdominal pain, abnormal hepatic function, anaphylactic shock, angioedema, bronchospasm, decreased creatinine dearance, diarrhea, G.I. bleeding, hepatitis, hypotension, nephritis and urticaria.

DRUG ABUSE AND DEPENDENCE

Drug abuse and dependence have not been reported with DISALCID (salsalate).

DRUG INTERACTIONS

Salicylates antagonize the uricosuric action of. drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID (salsalate) AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids.

Drug/ Laboratory Test Interactions

Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T₄ value in some patients; thyroid function and basal metabolism are unaffected.

In two well-controlled clinical trials (n= 280 patients), the following reversible adverse experiences characteristic of salicylates were most commonly reported with DISALCID (salsalate) , listed in descending order of frequency: tinnitus, nausea, hearing impairment, rash, and vertigo. These common symptoms of salicylates, i.e., tinnitus or reversible hearing impairment, are often used as a guide to therapy.

Although cause-and-effect relationships have not been established, spontaneous reports over a ten-year period have included the following additional medically significant adverse experiences: abdominal pain, abnormal hepatic function, anaphylactic shock, angioedema, bronchospasm, decreased creatinine dearance, diarrhea, G.I. bleeding, hepatitis, hypotension, nephritis and urticaria.

DRUG ABUSE AND DEPENDENCE

Drug abuse and dependence have not been reported with DISALCID (salsalate).

Death has followed ingestion of 10 to 30 g of salicylates in adults, but much larger amounts have been ingested without fatal outcome.

Symptoms

The usual symptoms of salicylism - tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting and diarrhea - will occur. More severe intoxication will lead to disruption of electrolyte balance and blood pH, and hyperthermia and dehydration.

Treatment

Further absorption of DISALCID (salsalate) from the G.I. tract should be prevented by emesis (syrup of ipecac) and if necessary, by gastric lavage.

Fluid and electrolyte imbalance should be corrected by the administration of appropriate I.V. therapy. Adequate renal function should be maintained. Hemodialysis or peritoneal dialysis may be required in extreme cases.