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Introduction

VA Class:OP300

ATC Class:M01AB05

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Diclofenac, a phenylacetic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,5

Uses

[Section Outline]

Actinic Keratoses !!navigator!!

Diclofenac sodium is used topically for the treatment of actinic keratoses.1,2,3,4 Efficacy of topical diclofenac sodium 3% gel was evaluated in 3 controlled clinical trials in patients with a minimum of 5 actinic keratosis lesions in 1-3 major body areas (5 cm × 5 cm regions of the scalp, forehead, face, forearm or hand) who received therapy with diclofenac sodium 3% gel or placebo (gel vehicle) for 30-90 days.1,7 Efficacy was defined as complete clearing of the actinic keratosis lesions 30 days after completion of therapy.1 In 2 trials that evaluated therapy for 90 days, 47 and 34% of diclofenac-treated patients had complete clearing of actinic keratosis lesions; 19 and 18% of vehicle-treated patients had complete clearing in these trials.1 Complete clearing of lesions in the scalp, forehead, face, arm/forearm, or back of hand was reported in 25, 57, 53, 33, and 38% of diclofenac-treated patients, respectively, in one trial and in 33, 47, 80, 63, and 6% of patients in the second trial.1 In another trial, complete clearing occurred in 31 or 14% of patients who received diclofenac for 60 or 30 days, respectively; complete clearing occurred in 10 or 4%, respectively, of vehicle-treated patients.1,7 Complete clearing of lesions in the scalp, forehead, face, or back of hand was reported in 43, 42, 53, or 25% of patients, respectively, who received diclofenac for 60 days.1

Superficial Thrombophlebitis !!navigator!!

Topical or oral diclofenac has been used for the symptomatic treatment of infusion-related superficial thrombophlebitis.8,9 In a controlled clinical trial in a limited number of patients, symptoms of thrombophlebitis improved in 60% of patients receiving either topical diclofenac (as a gel applied to the affected area every 8 hours) or oral diclofenac (75 mg every 12 hours) for 48 hours compared with 20% of those receiving placebo.8,9

For systemic uses of diclofenac, see 28:08.04.92.

Dosage and Administration

[Section Outline]

General !!navigator!!

Diclofenac sodium is applied topically to actinic keratosis lesions as a 3% gel.1

Actinic Keratoses

A sufficient amount (usually 0.5 g for each 5 cm × 5 cm lesion) of diclofenac sodium 3% gel should be applied and rubbed gently onto the lesions twice daily for 60-90 days.1 The patient should avoid exposure to sunlight while receiving diclofenac sodium gel.1 Complete healing of the lesions or optimal therapeutic response may not occur until 30 days after cessation of therapy.1 Lesions that do not respond to therapy should be carefully re-evaluated and management should be reconsidered.1

Special Populations !!navigator!!

No special population dosage recommendation at this time.1

Cautions

[Section Outline]

Contraindications !!navigator!!

Known hypersensitivity to diclofenac or any ingredient in the formulation.1

In the setting of coronary artery bypass graft (CABG) surgery.1

Warnings/Precautions !!navigator!!

Warnings

Cardiovascular Thrombotic Effects

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.1,500,502

Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.1,500,502,505,506 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.1,500,502,506

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.1,505 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).1,500,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.1,511 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Diclofenac sodium 3% gel should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if diclofenac sodium gel is used in such patients, the patient should be monitored for cardiac ischemia.1

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following CABG surgery, the incidence of myocardial infarction and stroke was increased.1 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.1

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.26,27,28,30,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

To minimize the potential risk of adverse cardiovascular events, NSAIAs should be used at the lowest effective dosage and for the shortest possible duration of therapy.1,500 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.1,500

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,24,502

Other Warnings and Precautions

Heart Failure and Edema

Data from observational studies indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.1,500,504,507 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.1,500,504 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.1,500,501 Fluid retention and edema also have been observed in some patients receiving NSAIAs.1 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).1

The manufacturer states that use of diclofenac sodium 3% gel should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if diclofenac sodium gel is used in such patients, the patient should be monitored for worsening heart failure.1 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507

Sensitivity Reactions

Sensitivity reactions, including anaphylaxis, are possible in patients without prior exposure to diclofenac.1 Use with caution in patients with the aspirin triad.1 (See Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.)

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 Symptoms may resemble those of an acute viral infection.1 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1 If such signs or symptoms develop, diclofenac sodium gel should be discontinued and the patient evaluated immediately.1

GI Effects

Use diclofenac sodium 3% gel with caution in patients with active GI ulceration or bleeding.1

Topical Use

For external use only; contact with the eyes should be avoided.1 Diclofenac sodium 3% gel should not be applied to open skin wounds, infected lesions, or exfoliative dermatitis.1

Safety and efficacy of concomitant use of diclofenac sodium 3% gel with other topical products (e.g., sunscreens, cosmetics, other topical medications) is unknown.1

Specific Populations

Pregnancy

Safety of diclofenac sodium 3% gel has not been established during pregnancy.1

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1,1200 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1,1200 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1,1200 (See Advice to Patients.)

Known effects of NSAIAs on the human fetus during the 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

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1,1200 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1,1200 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1,1200 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1,1200 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1,1200 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1 In animal studies, inhibitors of prostaglandin synthesis, such as diclofenac, were associated with increased pre- and post-implantation losses.1 Prostaglandins also have an important role in fetal kidney development.1 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1

No evidence of teratogenicity was observed in reproduction studies in mice, rats, or rabbits at diclofenac doses at least 15 times the maximum recommended human dose of diclofenac sodium 3% gel.1 In rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weight and growth, and reduced fetal survival.1

The effects of diclofenac on labor and delivery in pregnant women are unknown.1

Lactation

Discontinue nursing or the drug because of potential risk in nursing infants.1

Pediatric Use

Safety and efficacy not established in children.1 Actinic keratoses generally are not seen in the pediatric population; diclofenac sodium 3% gel should not be used by children.1

Geriatric Use

Individuals 65 years of age or older were included in clinical trials since actinic keratoses occur frequently in an older patient population.1 No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Renal Impairment

Use with caution in patients with severe renal impairment.1

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.1

Common Adverse Effects !!navigator!!

Local Effects

Dermatologic and application site reactions occurred in 82% of patients receiving diclofenac sodium 3% gel in clinical trials compared with 75% of vehicle-treated patients.1 Approximately 18% of patients receiving diclofenac sodium gel discontinued therapy, mainly due to skin irritation or related cutaneous reactions.1 Contact dermatitis, rash, dry skin, or exfoliation (scaling) was reported in 19-33, 35-46, 25-27, or 6-24% of patients, respectively.1

Drug Interactions

The manufacturer states that specific drug interaction studies between diclofenac sodium 3% gel and other topical or oral agents have not been performed.1

Nonsteroidal Anti-inflammatory Agents

Although absorption of diclofenac is low following use of diclofenac sodium 3% gel as recommended, there is some systemic exposure to the drug.1 Therefore, concomitant use with oral NSAIAs, including aspirin, may result in increased adverse effects.1 Concurrent use of NSAIAs and aspirin increases the risk of serious adverse GI events.1

Other Information

Description

Diclofenac, a phenylacetic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,5 Diclofenac is structurally related to meclofenamate sodium and meclofenamic acid5 and has pharmacologic actions similar to those of other prototypical NSAIAs.3,5 While the mechanism(s) of the topical effects of diclofenac in the treatment of actinic keratoses has not been established,1,2,3 the drug has inhibited angiogenesis and induced neovascular regression in inflammatory tissue in animal models.2,3 It has been suggested that NSAIAs, including diclofenac, may inhibit angiogenesis through inhibition of substance P or by blocking the angiogenic effects of prostaglandin E2 (PGE2).2 For topical use in the treatment of actinic keratoses, diclofenac sodium is commercially available as a 3% gel with benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water.1 The contribution of individual vehicle components to the efficacy of diclofenac sodium gel remains to be established.1

Diclofenac is absorbed into the epidermis following topical application of diclofenac sodium 3% gel.1,2,3 Some systemic absorption of diclofenac occurs following topical administration to the skin.1,3 Following topical application of 0.5 g of diclofenac sodium 3% gel (15 mg of diclofenac sodium) to up to 3 actinic keratosis lesion areas (5 cm × 5 cm) twice daily for up to 105 days, serum concentrations of diclofenac averaged 20 ng/mL or less.1,7 In contrast, peak plasma concentrations following oral administration of a single 50-mg dose of diclofenac sodium (delayed-release tablet) generally averaged 1417 ng/mL.6 The effect of occlusive dressings on absorption of diclofenac sodium 3% gel has not been established.1

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1

Risk of adverse dermal effects, including irritant or allergic contact dermatitis, exfoliation, dry skin, and rash.1 Importance of reporting signs and symptoms of adverse dermal reactions.1 Necessity of interrupting therapy if severe dermal reactions occur.1 Avoid exposure to sunlight and use of sunlamps.1

Importance of monitoring and follow-up evaluation.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription, OTC, or herbal products.1 Safety and efficacy of use with other topical products (e.g., sunscreens, cosmetics, other topical medications) are unknown.1

Risk of serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS).1 Advise patients to discontinue use immediately if they develop any type of rash or fever and to promptly contact their clinician.1

Risk of serious cardiovascular toxicity (e.g., myocardial infarction, stroke) with NSAIAs.1 Importance of seeking immediate medical attention if signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) occur.1

Risk of heart failure or edema with NSAIAs; importance of reporting dyspnea, unexplained weight gain, or edema.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of avoiding use of NSAIAs, including diclofenac sodium 3% gel, beginning at 20 weeks' gestation unless otherwise advised by a clinician and of avoiding use beginning at 30 weeks' gestation because of risk of premature closure of the fetal ductus arteriosus; advise pregnant women that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1,1200

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Diclofenac Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

3%*

Diclofenac Sodium Gel

Solaraze®

PharmaDerm

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

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions December 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. PharmaDerm. Solaraze® (diclofenac sodium 3%) topical gel prescribing information. Melville, NY; 2021 Apr.

2. Rivers JK, McLean DI. An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses. Arch Dermatol . 1997; 133:1239-42. [PubMed 9382562]

3. Peters DC, Foster RH. Diclofenac/Hyaluronic acid. Drugs Aging . 1999; 14:313-9. [PubMed 10319244]

4. McEwan LE, Smith JG. Topical diclofenac/hyaluronic acid gel in the treatment of solar keratoses. Australas J Dermatol . 1997; 38:187-9. [PubMed 9431711]

5. Hamor GH. Nonsteroidal anti-inflammatory drugs. In: Foye WO, ed. Principles of medicinal chemistry. 3rd ed. Philadelphia: Lea & Febiger; 1989:503-30.

6. Novartis Pharmaceuticals. Cataflam® diclofenac potassium (immediate-release tablets), Voltaren® diclofenac sodium (delayed-release tablets), Voltaren®-XR diclofenac sodium (extended-release tablets) prescribing information (dated 2000 May). In Physicians' desk reference. 55th ed. Montvale, NJ: Medical Economics Company; 2001:2151-5.

7. Bioglan Pharma, Malvern, PA: Personal communication.

8. Buller HR, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest . 2004; 126(Suppl):401S-28S. [PubMed 15383479]

9. Becherucci A, Bagilet D, Marenghini J et al. Effect of topical and oral diclofenac on superficial thrombophlebitis caused by intravenous infusion. Med Clin (Barc) . 2000; 114:371-3. [PubMed 10786346]

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

26. 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]

27. 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. [PubMedCentral][PubMed 16740558]

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

30. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: [Web].

500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22. [Web]

501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet . 2013; 382:769-79. [PubMedCentral][PubMed 23726390]

502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site [Web]

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ . 2011; 342:c7086. [PubMedCentral][PubMed 21224324]

504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med . 2009; 169:141-9. [PubMed 19171810]

505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation . 2011; 123:2226-35. [PubMed 21555710]

506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med . 2011; 8:e1001098. [PubMedCentral][PubMed 21980265]

507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013; 62:e147-239. [PubMed 23747642]

511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation . 2012; 126:1955-63. [PubMed 22965337]

512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One . 2013; 8:e54309.

516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med . 2011; 124:614-20. [PubMedCentral][PubMed 21596367]

1200. US Food and Drug Administration. FDA drug safety communication: FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. 2020 Oct 15. From the FDA website. [Web]

1202. Actavis Pharma. Sulindac tablets prescribing information. Parsippany, NJ; 2020 Oct 20.