Trilisate (Choline Magnesium Trisalicylate)

TRILISATE® Purdue Frederick Choline Magnesium Trisalicylate Anti-inflammatory–Analgesic

Action and Clinical

Choline magnesium trisalicylate is a combination of choline salicylate and magnesium salicylate.

Choline magnesium trisalicylate is a nonsteroidal anti-inflammatory drug (NSAID) which possesses the anti-inflammatory, analgesic and antipyretic activities characteristic of salicylates. It is, however, longer acting than acetylsalicylic acid and is less likely to cause gastrointestinal bleeding.

In clinical trials 6 Trilisate tablets (containing 3 g of salicylate) showed similar efficacy to a dose of ASA containing 3 g of salicylate and to indomethacin (100 mg/day), ibuprofen (2 400 mg/day) and naproxen (500 to 750 mg/day).

Choline magnesium trisalicylate is well absorbed. Maximum salicylate levels are reached within 2 hours. The half-life of the drug is 9 to 17 hours.

In a multi-dose bioavailability study, subjects who received 1 g (2 tablets) b.i.d. reached a mean steady-state serum salicylate level of 8.77 mg/100 mL, with a lower limit of 5.09 mg/100 mL and an upper limit of 12.45 mg/100 mL. Steady-state concentration was achieved at 55 hours after the first dose. Subjects who received 1.5 g (3 tablets) b.i.d. reached a mean steady-state serum salicylate level of 20.18 mg/100 mL, with a lower limit of 16.44 mg/100 mL and an upper limit of 23.93 mg/100 mL. Steady-state serum concentration was achieved at 85 hours after the first dose.

As with other salicylates the primary route of excretion is through the kidneys.

As for other salicylates, the pharmacologic profile of choline magnesium trisalicylate is a function of the salicylate blood level. Choline magnesium trisalicylate has been shown to be an effective anti-arthritic agent. Like other salicylates it has analgesic and antipyretic properties.

In contrast to ASA, nonacetylated salicylates, such as choline magnesium trisalicylate, do not irreversibly acetylate the enzyme cyclo-oxygenase and therefore would be expected to differ from ASA in their effects on a number of functions dependent on prostaglandin and thromboxane biosynthesis, such as platelet aggregation, renal blood flow and the integrity of the gastrointestinal mucosa.

Effects on Platelet Aggregation: Using in vitro methods, Trilisate did not inhibit platelet aggregation at salicylate concentrations forty-fold higher than those at which ASA did so. Also in contrast to results with ASA, in vivo studies have shown that single oral doses of Trilisate did not affect bleeding time, platelet aggregation, platelet 5HT release or plasma thromboxane levels. These results were confirmed in a parallel design multiple dose study in which 30 healthy volunteers were administered Trilisate (2´750 mg salicylate, q12h) or ASA (2´325 mg, q4h) for 5 days. Trilisate produced a statistically significant decrease in bleeding time on the second treatment day, whereas ASA significantly increased bleeding time over the 5-day treatment period and for 3 days thereafter. During the study, significantly more subjects in the ASA group showed changes in platelet aggregation from normal to abnormal than in the Trilisate group (8 subjects versus 1 subject). In 9 patients (7 of whom had rheumatoid or osteoarthritis) administered Trilisate for 7 to 15 months, 5 showed no abnormalities and 3 showed only minimal effects on platelet aggregation. The remaining patient showed a pattern of platelet aggregation abnormalities consistent with inadvertent use of ASA.

Indications And Clinical Uses:

For the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. The safety and efficacy of Trilisate have not been established in patients designated as functional class IV.

Contra-Indications:

Should not be administered to patients with peptic ulcer or active inflammatory disease of the gastrointestinal tract or to patients with known or suspected hypersensitivity to salicylates including those in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestation are precipitated by ASA or other nonsteroidal anti-inflammatory agents.:

Warnings in Clinical States:

Should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Since peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with other NSAIDs patients taking any NSAID including Trilisate should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).

Pregnancy and Lactation: The safety of this drug in pregnancy and lactation has not been established and its use is therefore not recommended. Due to the inhibition of prostaglandin synthesis by salicylates (including Trilisate) parturition may be prolonged.

Children: A possible association between Reye’s syndrome and the use of salicylates has been suggested but not established. Reye’s syndrome has also occurred in many patients not exposed to salicylates. However, caution is advised when prescribing salicylate-containing medications for children and teenagers with influenza or chickenpox. Trilisate is not recommended for use in patients under 12 years of age.

Precautions:

Precautions Specific to Trilisate: When salicylates are given with steroids, alcohol or the butazones, the risk of gastrointestinal ulceration is increased.

Trilisate is excreted primarily in the urine and adequate precautions including dose reduction and/or increasing the time interval between doses, together with careful monitoring, should be employed when it is administered to patients with renal insufficiency.

General Precautions for NSAIDs: Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, Trilisate should be discontinued, an appropriate treatment instituted and the patient closely monitored.

There is no definitive evidence that the concomitant administration of histamine H 2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of therapy with NSAIDs when and if these adverse reactions appear.

Renal: Long-term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

During long-term therapy, kidney function should be monitored periodically.

Hepatic Function: Disturbances of hepatic function ranging from jaundice and cases of fatal hepatitis to borderline elevations of one or more liver tests have occurred with NSAIDs. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. During long-term therapy, liver function tests should be monitored periodically especially in patients with pre-existing liver dysfunction. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred while receiving Trilisate, should be evaluated for evidence of the development of a more severe hepatic reaction. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), Trilisate should be discontinued.

Fluid and Electrolyte Balance: Trilisate should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. The possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Hematology: As with other anti-inflammatory drugs that inhibit prostaglandin biosynthesis, caution should be used in the event that Trilisate tablets are administered to persons with intrinsic coagulation defects or those on anticoagulant therapy.

The rare association of NSAIDs with blood dyscrasias (possibly serious) should be borne in mind.

Infection: As with other anti-inflammatory drugs, Trilisate may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with other nonsteroidal anti-inflammatory drugs. If such symptoms develop with Trilisate it should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Drug Interactions:

Salicylates compete for protein binding sites with a large number of drugs eg. penicillin, thiopental, phenytoin, sulfinpyrazone, warfarin and other NSAIDs as well as endogenous substances such as thyroxine, triiodothyronine and bilirubin.

In addition to displacement of other agents from protein binding, salicylates also diminish the renal excretion of methotrexate, may reduce plasma concentrations of prothrombin and may counteract the effect of uricosuric agents.

Adverse Reactions:

The most common adverse reactions encountered with most nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

In clinical studies with Trilisate the most frequently reported side effect was tinnitus with an incidence of 10.2%. Should tinnitus occur it is recommended that dosage be reduced. Other side effects reported in Trilisate clinical studies are listed below: Gastrointestinal: nausea (3.4%), heartburn (1.5%), cramps (1.1%). Less than 1% incidence: abdominal pain, indigestion, stomach ache and constipation.

CNS: Less than 1% incidence: headache, lightheadedness and dizziness.

Dermatologic: Less than 1% incidence: skin rash.

Hematologic: Less than 1% incidence: positive fecal occult blood.

Special Senses: Less than 1% incidence: hearing loss.

Symptoms And Treatment Of Overdose:

Symptoms: There are no reports to date of Trilisate overdosage in man. Signs of salicylate toxicity would be anticipated. Mild salicylate intoxication is characterized by headache, dizziness, tinnitus, hearing impairment, dimness of vision, mental confusion, lassitude, drowsiness, thirst, hyperventilation, nausea, vomiting and diarrhea. In more severe cases, CNS disturbances including EEG abnormalities, generalized convulsions and coma, skin eruption, alterations in acid-base balance, fever, hemorrhage, hypoglycemia or hyperglycemia and dehydration may also occur. In extreme cases death may result from respiratory and cardiovascular failure.Treatment

Treatment of salicylate intoxication is largely symptomatic. Absorption of salicylate from the gastrointestinal tract can be reduced by emesis, gastric lavage, or administration of activated charcoal. Hyperthermia and dehydration are the immediate threat to life and treatment should be directed at their correction together with correction of acid-base disturbances. Renal clearance of salicylate may be increased by alkaline diuresis, as consistent with the patient’s acid-base status. Hemorrhagic phenomena are treated with vitamin K.

Dosage And Administration:

For rheumatoid arthritis and more severe osteoarthritis, the recommended dose is 2 to 3 tablets (containing a total of 1 to 1.5 g salicylate content) b.i.d. or 1 to 2 tablets (total of 0.5 to 1 g salicylate) t.i.d.

For less severe osteoarthritis the recommended dose is 2 tablets (1 g salicylate) b.i.d. In some cases doses less than 2 tablets b.i.d. may achieve the desired results.

It is recommended that therapy be initiated at the lower dosage level then titrated upwards as required for optimal results. The maximum recommended daily dose is 6 tablets (3 g expressed as salicylate). The safety of doses above 3 g/day has not been investigated.

Availability And Storage:

Each scored, capsule-shaped, pale pink tablet contains: choline salicylate 293 mg combined with magnesium salicylate 362 mg to provide 500 mg of salicylate content. Tartrazine-free. Bottles of 100.

TRILISATE® Purdue Frederick Choline Magnesium Trisalicylate Anti-inflammatory–Analgesic