Drug class: Salicylates
VA class: CN103
CAS number: 552-94-3

Medically reviewed by Drugs.com on Nov 19, 2024. Written by ASHP.

Introduction

Prototypical NSAIA; salicylate ester of salicylic acid.^{a b}

Uses for Salsalate

Consider potential benefits and risks of salsalate therapy as well as alternative therapies before initiating therapy with the drug.^b Use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.^b

Inflammatory Diseases

Symptomatic treatment of rheumatoid arthritis, osteoarthritis, and related inflammatory conditions.^{a b}

Salsalate Dosage and Administration

General

• Consider potential benefits and risks of salsalate therapy as well as alternative therapies before initiating therapy with the drug.^b

Administration

Oral Administration

Administer orally.^b Administration with food or a full glass of water or milk (240 mL) may minimize adverse GI effects.^{a c}

Dosage

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.^b Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^b

Adults

Inflammatory Diseases

Rheumatoid Arthritis, Osteoarthritis, or Other Inflammatory Conditions

Oral

1.5 g twice daily or 1 g 3 times daily.^b

Special Populations

Geriatric Patients

Dosage reduction may be needed.^b

Cautions for Salsalate

Contraindications

• Known hypersensitivity to salsalate or any ingredient in the formulation.^b

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^b

• Treatment of perioperative pain in the setting of CABG surgery.^b

Warnings/Precautions

Warnings

Reye's Syndrome

Risk of Reye's syndrome in individuals with varicella (chickenpox), influenza, or flu symptoms. ^{b c} (See Pediatric Use under Cautions.)

Cardiovascular Effects

Selective COX-2 inhibitors have been associated with increased risk of cardiovascular events (e.g., MI, stroke) in certain situations.^d Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.^{e f g} Current data insufficient to assess risk associated with salsalate.^{e f g}

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dosage for the shortest duration necessary.^b

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).^d

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{b d} (See Specific Drugs and Laboratory Tests under Interactions.)

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^b Use with caution in patients with hypertension; monitor BP.^b Impaired response to certain diuretics may occur.^b (See Specific Drugs and Laboratory Tests under Interactions.)

Fluid retention and edema reported.^b Caution in patients with fluid retention or heart failure.^b

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.^{b c}

For patients at high risk for complications from NSAIA-induced GI ulcerations (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{i j k z} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., lansoprazole, omeprazole)^{i j k} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).^k

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^b

Potential for overt renal decompensation.^b Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{b h} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.^b Immediate medical intervention and discontinuance for anaphylaxis.^b

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^b

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.¹²⁰² Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).¹²⁰² Symptoms may resemble those of acute viral infection.¹²⁰² Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹²⁰² If signs or symptoms of DRESS develop, discontinue the NSAIA and immediately evaluate the patient.¹²⁰²

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur without warning.^b Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^b

Major Toxicities

Otic Effects

Dose-related tinnitus and hearing loss reported.^c

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^b

Elevations of serum ALT or AST reported.^b

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^b Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.^b

Hematologic Effects

Anemia reported rarely.^b Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.^b

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.^b

May mask certain signs of infection.^b

Obtain CBC and chemistry profile periodically during long-term use.^b

Monitor plasma salicylate concentrations during long-term use.^b

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{1200 1202}

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.¹²⁰²

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.^{1200 1202} (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.^{1200 1202} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{1200 1202} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1200 1202} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1200 1202} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1200 1202} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.¹²⁰² Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹²⁰²

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.¹²⁰² In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.¹²⁰²

No adequate and well-controlled studies of salsalate in pregnant women.¹²⁰¹ No evidence of developmental abnormalities in animal studies.¹²⁰¹

Effects of salsalate on labor and delivery not known.¹²⁰¹ In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.¹²⁰¹ Other salicylates associated with prolonged gestation and labor, maternal and neonatal bleeding sequelae, potentiation of opiate and barbiturate effects (respiratory or cardiac arrest in the mother), delivery problems, and stillbirth.¹²⁰¹

Lactation

Salicylate is distributed into human milk in concentrations approximating maternal blood level.^b Caution advised.^b

Fertility

NSAIAs may be associated with reversible infertility in some women.¹²⁰³ Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.¹²⁰³

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.¹²⁰³

Pediatric Use

Safety and efficacy not established.^b

Salicylates should not be used in children and teenagers with varicella or influenza, unless directed by a clinician.^{l m n o q r s t u v w x y} Generally avoid salicylates in children and teenagers with suspected varicella or influenza and during presumed outbreaks of influenza, since accurate diagnosis of these diseases may be impossible during the prodromal period;^l do not use salicylates in the management of viral infections in children or adolescents, since the infection may be one associated with an increased risk of Reye’s syndrome.^p

Geriatric Use

Caution.^b Fatal adverse GI effects reported more frequently in geriatric patients than younger patients.^b

Lower dosage may be needed.^b

Renal Impairment

Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.^b

Common Adverse Effects

Tinnitus, nausea, hearing impairment, rash, vertigo.^b

Drug Interactions

Protein-bound Drugs

Potential for salicylate to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.^{b c}

Specific Drugs and Laboratory Tests

Salsalate Pharmacokinetics

Absorption

Bioavailability

Salsalate is insoluble in gastric acid fluids, but readily soluble in small intestine.^{a b} Salsalate is absorbed from the small intestine.^a

Food

Food delays absorption of salsalate and decreases peak plasma salicylate concentrations.^{a b}

Plasma Concentrations

Plasma salicylate concentrations of 30–100 mcg/mL produce analgesia and antipyresis; the concentration required for anti-inflammatory effect is 150–300 mcg/mL; toxicity noted at 300–350 mcg/mL.^c

Distribution

Extent

Rapidly and widely distributed into most body tissues and fluids, including synovial fluid.^{a c}

Not known whether salsalate is distributed into milk.^b Salicylate distributes into human milk in concentrations approximating the maternal blood level.^b

Plasma Protein Binding

Salicylate: 90–95% bound at plasma salicylate concentrations <100 mcg/mL; 70–85% bound at concentrations of 100–400 mcg/mL; 25–60% bound at concentrations >400 mcg/mL.^c

Elimination

Metabolism

Partially hydrolyzed to 2 molecules of salicylate by esterases in GI mucosa, liver, plasma, blood, and other tissues and fluids.^{a b}

Salicylate is metabolized in the liver by the microsomal enzyme system.^c

Elimination Route

Excreted in urine (7–13% as salsalate glucuronide, < 1% as unchanged salsalate, the remainder as salicylate and its metabolites). ^{a b} Urinary excretion of salicylate is pH dependent; as urine pH increases from 5 to 8, urinary excretion of salicylate is greatly increased.^c

Half-life

Salsalate: 1 hour.^{a b}

Half-life of salicylate increases with increasing plasma salicylate concentrations; range reported is 3.5 to ≥16 hours.^b

Special Populations

Salicylate and its metabolites are readily removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.^c

Stability

Storage

Oral

Tablets

15–30°C.^b

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{b c} Exhibits anti-inflammatory and analgesic activity; does not inhibit platelet aggregation.^{b c}

Advice to Patients

• Importance of not using salsalate for chickenpox, influenza, or flu-like symptoms.^b

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.^b

• Risk of serious cardiovascular events with long-term use.^b

• Risk of GI bleeding and ulceration.^b

• Risk of serious skin reactions,^b DRESS,¹²⁰² and anaphylactoid and other sensitivity reactions.^b

• Risk of hepatotoxicity.^b

• Risk of ototoxicity.^b

• Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^b

• Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.^b

• Advise patients to stop taking the drug immediately if they develop any type of rash or fever and to promptly contact their clinician.¹²⁰² Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^b

• Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^b

• Importance of notifying clinician if ringing in the ears or hearing loss develops.^c

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^b

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.^{1200 1202}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.¹²⁰³

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^b

• Importance of informing patients of other important precautionary information.^b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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