AHFS Class:

• Salicylates 28:08.04.24

Generic Name(s):

• Salicylamide

Salicylamide, the amide of salicylic acid, is an analgesic agent that is not hydrolyzed to salicylate in vivo and is therefore not considered a true salicylate.

Salicylamide is used in the treatment of minor aches and pains. The drug has also been used as an antipyretic†. However, because the efficacy of salicylamide (particularly in the usually recommended dosage) has not been clearly established, some clinicians recommend that the drug no longer be used. Acetaminophen and aspirin are more effective analgesics and antipyretics than salicylamide.

In 2 double-blind, placebo-controlled studies in patients with nonspecific pain secondary to cancer or rheumatic disease, the analgesic effect of salicylamide (600 mg every 4 hours) did not differ from that of placebo. Salicylamide has been reported to be an effective analgesic in patients with pain secondary to rheumatic disease, but dosages of 6-24 g daily in divided doses were apparently necessary for such an effect; the safety of such dosages has not been clearly established.

There is some evidence that salicylamide is an effective antipyretic†, but a dosage of 1 g every 4 hours appears to be necessary for antipyresis in adults; further studies are needed to determine the safety of such dosages. In one study in children, the antipyretic effect of aspirin or acetaminophen was greater than that of salicylamide.

Salicylamide is commercially available in various analgesic-antipyretic combination preparations. There are insufficient data to date to determine the safety and efficacy of salicylamide in these preparations. However, based on the pharmacokinetics of salicylamide and controlled studies performed to date with the drug as a single agent, salicylamide is unlikely to produce an analgesic or antipyretic effect in the amounts (approximately 200-400 mg) contained in various combination preparations.

Administration

Salicylamide is administered orally, preferably with food or a large quantity (240 mL) of water or milk to minimize gastric irritation.

Dosage

The usual adult dosage of salicylamide for the treatment of minor aches and pains is 325-650 mg 3-4 times daily; however, higher dosages have been used. (See Uses.) Salicylamide should not be used in adults for self-medication of pain for longer than 10 days, unless directed by a physician, since pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.

For the treatment of minor aches and pains† or fever† in children, some clinicians have recommended a daily dosage of 65 mg/kg or 1.5 g/m², administered in 6 equally divided doses.

Adverse Effects

Dose-related GI and CNS disturbances are the most common adverse effects of salicylamide. GI disturbances may include nausea, vomiting, heartburn, anorexia, or diarrhea. CNS disturbances may include dizziness, drowsiness, lightheadedness, faintness, or headache. Flushing, hyperventilation, sweating, dry mouth, rash, and thrombocytopenic purpura have also been reported. Adverse GI and CNS effects occur infrequently with salicylamide doses of 325-650 mg but occur often with higher doses. Tinnitus, ecchymoses, hemorrhagic lesions, leukopenia, or thrombocytopenia may also occur with high doses.

Salicylamide apparently does not cause occult GI bleeding. The drug can probably be used safely in patients in whom aspirin or another nonsteroidal anti-inflammatory agent precipitates urticaria, angioedema, bronchospasm, severe rhinitis, or shock.

Precautions

Although it has not been established that salicylamide shares all the toxic potentials of the salicylates, the usual precautions of salicylate administration should probably be observed since salicylamide is structurally and pharmacologically related to the salicylates. (See Cautions in the Salicylates General Statement 28:08.04.24.)

Pediatric Precautions

Safety and efficacy of salicylamide in children for self-medication have not been established.

Pregnancy and Lactation

Pregnancy

Safe use of salicylamide during pregnancy has not been established.

Lactation

Safe use of salicylamide during lactation has not been established.

There is some evidence that concomitant administration of salicylamide with aspirin may result in increased plasma concentrations of salicylamide and salicylate. There is also some evidence that concomitant administration of salicylamide with acetaminophen may result in increased plasma concentrations of salicylamide and acetaminophen. Salicylamide and salicylate appear to mutually inhibit the formation of their respective glucuronide conjugates and salicylate may also inhibit formation of the sulfate conjugate of salicylamide. Similarly, salicylamide and acetaminophen appear to mutually inhibit the formation of their respective sulfate conjugates and possibly their respective glucuronide conjugates. However, the clinical importance of the interactions between salicylamide and salicylate or acetaminophen remains to be established.

Drug interactions usually associated with salicylates have not been reported to date with salicylamide.

Acute Toxicity

Pathogenesis

Little information is available on the acute toxicity of salicylamide. Salicylamide is generally considered to be less toxic than salicylates in overdosage but unequivocal evidence in humans is lacking; in animals, salicylamide and salicylates appear to be equitoxic. The acute lethal dose of salicylamide is estimated to be 0.5-5 g/kg.

Manifestations

In contrast to salicylates, salicylamide overdosage produces CNS depression, hypotension, and eventually respiratory arrest, but does not produce excitement, seizures, metabolic acidosis, or hypoprothrombinemia.

Treatment

In acute salicylamide overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal and a saline cathartic. Supportive and symptomatic treatment should be initiated.

Pharmacology

Salicylamide reportedly has analgesic and antipyretic effects similar to those of salicylates; however, these effects are not consistently produced, possibly because the drug is rapidly and extensively metabolized during absorption. It has not been established whether salicylamide has anti-inflammatory effects. In animals, the drug produces hypotensive effects, possibly by dilating peripheral blood vessels, and depresses the CNS.

Pharmacokinetics

Absorption

Salicylamide is rapidly and almost completely absorbed from the GI tract following oral administration in fasting individuals. Following oral administration of usual doses, salicylamide is almost completely metabolized to inactive metabolites during absorption and on first pass through the liver (see Pharmacokinetics: Elimination); only trace amounts of unchanged salicylamide are detected in plasma. In one study in fasting healthy adults who received single 650-mg, 1.3-g, 1.95-g, and 2.6-g oral doses of salicylamide (as 325-mg tablets), peak plasma concentrations of unchanged salicylamide were attained within 30-60 minutes and averaged less than 1 mcg/mL, 2 mcg/mL, 4 mcg/mL, and 7 mcg/mL, respectively; peak total plasma concentrations of salicylamide and its metabolites were attained within 1.5-2 hours and averaged 8 mcg/mL, 18 mcg/mL, 25 mcg/mL, and 35 mcg/mL, respectively. Peak plasma concentrations of unchanged salicylamide are higher in patients with cirrhosis than in healthy individuals, apparently because patients with cirrhosis have a decreased ability to metabolize the drug on first pass through the liver.

Distribution

Salicylamide is rapidly and widely distributed into most tissues including muscle, liver, and brain. In vitro, salicylamide is 40-55% bound to serum proteins at concentrations of 20-500 mcg/mL. It is not known if salicylamide or its metabolites cross the placenta or are distributed into milk.

Elimination

In one study in healthy adults, the apparent elimination half-life of salicylamide and its metabolites was determined indirectly to be 1.2 hours based on urinary excretion data.

Salicylamide is not hydrolyzed to salicylate. Salicylamide is apparently metabolized principally to an inactive glucuronide conjugate in adults and to an inactive sulfate conjugate in children. In oral doses up to 1 g, salicylamide is almost completely metabolized to these inactive conjugates in the GI mucosa during absorption and on first pass through the liver. The formation of the sulfate conjugate is a capacity-limited process that appears to be saturated with single oral doses of 600 mg to 1 g of salicylamide. In addition to the formation of glucuronide and sulfate conjugates, salicylamide is partially metabolized by hydroxylation to form gentisamide, which is also conjugated with glucuronic acid.

Salicylamide and its metabolites are rapidly excreted in urine. In patients with normal hepatic and renal function, 90-100% of a single oral dose of the drug is excreted in the urine in 24 hours. Following a single oral dose of 150 mg to 1 g of salicylamide in adults, approximately 40-70% of the dose is excreted in urine as salicylamide glucuronide, 25-50% as salicylamide sulfate, 5-10% as gentisamide glucuronide, and less than 5% as unchanged salicylamide.

Chemistry and Stability

Chemistry

Salicylamide, the amide of salicylic acid, is an analgesic agent. Although salicylamide is structurally and pharmacologically related to the salicylates, the drug is not hydrolyzed to salicylate in vivo and is therefore not considered a true salicylate.

Salicylamide occurs as a white, almost odorless, crystalline powder, is slightly soluble in water and soluble in alcohol, and has a pK_a of 8.2. The drug may have a slightly bitter taste or cause a sensation of warmth on the tongue.

Stability

Salicylamide preparations generally should be stored in well-closed containers at a temperature less than 40°C, preferably between 15-30°C.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.