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Salsalate

Pronunciation

Class: Salicylates
VA Class: CN103
CAS Number: 552-94-3

Warning(s)

  • Cardiovascular Risk
  • Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).b Risk may increase with duration of use.b Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.b (See Cardiovascular Effects under Cautions.)

  • Contraindicated for the treatment of pain in the setting of CABG surgery.b

  • GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).b Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.b Geriatric individuals are at greater risk for serious GI events.b (See GI Effects under Cautions.)

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

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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; alternatively, consider concomitant use of a proton-pump inhibitor (e.g., lansoprazole, omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).

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

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

Category C.b Avoid use in third trimester because of possible premature closure of the ductus arteriosus.b

Lactation

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

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. 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; 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.

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

Interactions for Salsalate

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

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitorb

Monitor BPb

Acidifying agents

Drugs that decrease urine pH may decrease salicylate excretionc

Monitor urinary pHb

Alcohol

Increased risk of bleedingb c

Alkalinizing agents

Drugs that increase urine pH may increase salicylate excretionc

Monitor urinary pHb

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonisth

Monitor BPh

Aspirin

Increased risk of salicylate toxicityb

Increased risk of GI ulceration and other complicationsb

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAsb

Manufacturer states that concomitant use not recommendedb

Antidiabetic drugs (sulfonylureas)

Potential for increased hypoglycemic effectb

Monitor closelyb

Carbonic anhydrase inhibitors (acetazolamide)

Increased risk of salicylate toxicityc

Corticosteroids

Decreased plasma salicylate concentrationsc

Diuretics (furosemide, thiazides)

Reduced natriuretic effectsb

Monitor for diuretic efficacy and renal failureb

Lithium

Increased plasma lithium concentrationsb

Monitor for lithium toxicityb

Methotrexate

Potential toxicity associated with increased plasma concentrations of methotrexateb

Caution advisedb

Test for thyroid function

Possible decreased thyroxine (T4) valueb c

Warfarin

Reports of bleeding complicationsb

Caution advisedb

Uricosuric agents (probenecid, sulfinpyrazone)

Reduced uricosuric effect of uricosuric agentsb

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 Risk of 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

  • Importance of discontinuing salsalate and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.b 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 salsalate in late pregnancy (third trimester).b

  • 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.

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

Salsalate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

500 mg*

Salsalate Tablets

Caraco

750 mg*

Salsalate Tablets

Caraco

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Salsalate 500MG Tablets (AMNEAL PHARMACEUTICALS): 100/$39.99 or 300/$99.97

Salsalate 750MG Tablets (AMNEAL PHARMACEUTICALS): 60/$47.99 or 120/$71.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2007. McEvoy GK, ed. Salsalate. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2041-2.

b. Caraco Pharmaceutical Laboratories. Salsalate tablets prescribing information. Detroit, MI; 2005 Sep.

c. AHFS drug information 2007. McEvoy GK, ed. Salicylates General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2011-23.

d. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.

e. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-44. [PubMed 16968831]

f. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332: 1302-5. [PubMed 16740558]

g. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]

h. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

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