Brand names: Cambia, Flector, Licart, Voltaren, Zipsor
Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Aug 10, 2025. Written by ASHP.

Introduction

NSAIA; also exhibits analgesic and antipyretic activity.¹

Uses for Diclofenac (Systemic, Local)

Inflammatory Diseases

Orally for symptomatic treatment of osteoarthritis (diclofenac sodium delayed-release tablets and extended-release tablets; diclofenac potassium tablets).^{1 81 82 84 85 86 89 90 108 109 111 112 113 114 126 133 302 303 336}

Topically (as 1.5 or 2% solution) for the symptomatic treatment of osteoarthritis of the knee.^{326 327 337 342 343 344 345}

Topically (as 1% gel) for self-medication for temporary relief of arthritis pain in the hand, wrist, elbow, foot, ankle, or knee.^{318 321 340 341 353}

American College of Rheumatology (ACR) recommends topical/oral NSAIAs for treatment of osteoarthritis, among other interventions.³³⁰ Therapy selection is patient-specific; factors to consider include patients' values and preferences, risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.³³⁰

Orally for symptomatic treatment of rheumatoid arthritis (diclofenac sodium delayed-release tablets and extended-release tablets; diclofenac potassium tablets).^{1 74 75 76 77 78 79 80 87 88 115 116 117 118 119 125 126 129 133 302 303 336 354 356 361}

Guidelines on the treatment of rheumatoid arthritis from ACR recommend initiation of a disease-modifying antirheumatic drug (DMARD) for most patients; role of NSAIAs not discussed.²⁰⁰¹

Orally for symptomatic treatment of ankylosing spondylitis (diclofenac sodium delayed-release tablets).^{1 120 127 338}

Continuous NSAIA treatment is considered first-line for active ankylosing spondylitis in current guidelines.²⁰⁰⁸ On-demand NSAIAs are recommended for stable ankylosing spondylitis.²⁰⁰⁸ No preference is given to one NSAIA over another.²⁰⁰⁸

Diclofenac sodium also commercially available in an oral fixed-combination preparation with misoprostol for symptomatic treatment of rheumatoid arthritis and osteoarthritis in adults at high risk of developing NSAIA-induced gastric and duodenal ulcers and their complications.²⁸⁴ See full prescribing information for use of this combination product.²⁸⁴

Orally for management of juvenile rheumatoid arthritis^{† [off-label]}.^{128 210}

Orally for symptomatic relief of gout^{† [off-label]2006} and acute painful shoulder^{† [off-label]} .^{134 136 154 222 346}

Pain

Orally for relief of mild to moderate pain (diclofenac potassium tablets and capsules).^{277 278 279 303 331 333 334 336 358}

Transdermally for relief of acute pain due to minor strains, sprains, and contusions (diclofenac epolamine transdermal systems).^{317 320 324}

American College of Physicians recommends topical NSAIAs (with or without menthol gel) as first-line therapy to reduce or relieve symptoms (including pain) and improve physical function in patients with non-low back pain musculoskeletal injury.²⁰¹⁰ Oral NSAIAs and acetaminophen also suggested to reduce pain and (for NSAIAs) improve physical function.²⁰¹⁰

Current guidelines on postoperative pain management recommend a multimodal approach to analgesia.²⁰¹³ NSAIAs recommended as part of multimodal analgesia in patients without contraindications.²⁰¹³ When selecting therapy for a specific patient, consider potential risks associated with NSAIAs.²⁰¹³

Diclofenac sodium also has been used for symptomatic relief of oral surgery pain^{† [off-label]92 352} and low back pain^{† [off-label]} .⁹²

Migraine

Orally (as diclofenac potassium solution) for acute treatment of migraine attacks with or without aura; should not be used for prophylaxis of migraine.^{328 329}

Safety and efficacy not established for treatment of cluster headache (an older, predominantly male population).³²⁸

Agents with established efficacy in adults with acute migraine include triptans, ergotamine derivatives, gepants, lasmiditan, NSAIAs (aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen), and the combination of acetaminophen, aspirin, and caffeine.¹²²³ Nonspecific analgesic therapies such as NSAIAs and acetaminophen/aspirin/caffeine are used for mild-to-moderate attacks, while migraine-specific therapies (e.g., triptans, ergotamine derivatives, gepants, lasmiditan) are used for moderate-to-severe attacks or mild-to-moderate attacks that respond poorly to non-specific therapy.¹²²³ Selection of an agent for acute treatment should be based on patient-specific factors such as comorbid disease states, individual treatment history, and concomitant medications.¹²²³

Dysmenorrhea

Orally for symptomatic management of primary dysmenorrhea (diclofenac potassium tablets).^{303 336 359 360}

Diclofenac sodium also has been used for symptomatic management of primary dysmenorrhea.^{92 104 105 140}

First-line treatment options for primary dysmenorrhea include combined oral contraceptives, progesterone-only contraceptives, and NSAIAs; treatment selection should be based on patient-specific considerations (e.g., comorbidities, desire/need for contraception).^{2012 2015} The American College of Obstetricians and Gynecologists does not address specific role for diclofenac in primary dysmenorrhea.²⁰¹²

Other Uses

Diclofenac sodium ophthalmic solution used for treatment of postoperative ocular inflammation in patients undergoing cataract extraction and for temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.²⁶⁴

Diclofenac (Systemic, Local) Dosage and Administration

General

Pretreatment Screening

• Verify pregnancy status in women of reproductive potential before initiating diclofenac sodium in fixed combination with misoprostol (Arthrotec).²⁸⁴

• Measure serum aminotransferase concentrations at baseline.^{1 302 303 317}

• Correct dehydration and hypovolemia before initiating therapy.^{1 284 302 303}

Patient Monitoring

• Monitor blood pressure closely when initiating diclofenac and throughout therapy.^{1 302 303 317}

• Obtain serum aminotransferase values 4–8 weeks after therapy with the drug is initiated and monitor periodically during long-term therapy.^{1 302 303 317}

• Concomitant use of nonsteroidal anti-inflammatory agents (NSAIAs), such as diclofenac, with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent; therefore, monitoring of blood pressure is recommended with concomitant use of these drugs.^{1 302 303 317}

• Perform a CBC and chemistry profile periodically in patients receiving long-term NSAIA therapy.^{1 302 303 317}

• Monitor renal function during therapy in patients with preexisting renal or hepatic impairment, heart failure, dehydration, or hypovolemia.^{1 302 303 317}

• Monitor patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) for the possible development of cardiovascular events throughout therapy.^{1 302 303 317}

• Monitor patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis closely for evidence of GI bleeding.^{1 302 303}

Dispensing and Administration Precautions

• The 2023 American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults includes diclofenac on the list of PIMs that are best avoided by older adults in most circumstances or under specific situations, such as certain diseases, conditions, or care settings.⁹⁹⁹ The criteria are intended to apply to adults 65 years of age and older in all ambulatory, acute, and institutional settings of care, except hospice and end-of-life care settings.⁹⁹⁹ For non-COX-2-selective oral NSAIAs such as diclofenac, the Beers Criteria Expert Panel specifically recommends that chronic use be avoided unless other alternatives are not effective and the patient can take a gastroprotective agent (proton-pump inhibitor or misoprostol).⁹⁹⁹ Additionally, short-term scheduled use should be avoided in combination with oral or parenteral corticosteroids, anticoagulants, or antiplatelet agents unless other alternatives are not effective and the patient can take a gastroprotective agent.⁹⁹⁹

Other General Considerations

• Because patients may have aspirin-sensitive asthma, patients with asthma but without known aspirin sensitivity who are receiving diclofenac should be monitored for changes in manifestations of asthma.^{1 302 303 317}

• To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.^{1 302 303 317}

• Use of NSAIAs should be avoided in patients at higher risk of bleeding unless the benefits of therapy are expected to outweigh the increased risk of bleeding.^{1 302 303 317} Higher risk patients include those with a history of ulcer disease or other factors that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective-serotonin reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older age; poor general health status; advanced liver disease; and/or coagulopathy.^{1 302 303 317}

• Diclofenac 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 is used in such patients, they should be monitored for cardiac ischemia.^{1 302 303}

Administration

Oral Administration

Oral Solution

Empty the contents of one packet containing 50 mg of buffered diclofenac potassium powder for oral solution into a cup containing 30–60 mL of water, mix well, and administer immediately.³²⁸ Do not use liquids other than water.³²⁸

Administration with food may decrease peak plasma concentrations and reduce efficacy compared with administration on an empty stomach.³²⁸

Topical Administration

Diclofenac Sodium 1.5 or 2% Topical Solution

Topical 1.5% solution: Administer as drops dispensed directly onto affected knee(s); alternatively, administer into palm of hand and apply to affected knee(s).³²⁶ To avoid spillage, apply drops in 4 increments of 10 drops each per joint; following each incremental application, spread solution evenly around the front, back, and sides of the knee.³²⁶

Topical 2% solution: Administer via pump dispenser (2 pump actuations per affected joint) into palm of hand; then evenly apply the entire volume of solution around the front, back, and sides of the knee.³²⁷ Pump must be primed before first use by fully depressing the pump mechanism 4 times while holding the bottle in an upright position.³²⁷

Wait until treated area is dry before covering with clothing; wait ≥30 minutes before bathing or showering.^{326 327}

Wash hands after application.^{326 327}

Avoid skin-to-skin contact between other individuals and the treated area until the area is completely dry.^{326 327}

Do not apply to open wounds, infected or inflamed areas of skin, or areas affected with exfoliative dermatitis; avoid contact with eyes and mucous membranes.^{326 327}

Do not expose treated knee to external heat, and avoid exposing treated knee to natural or artificial sunlight; also avoid use of occlusive dressings.^{326 327}

Allow treated knee to dry completely before applying other topical preparations (e.g., sunscreen, insect repellant, lotions, moisturizers, cosmetics, other topical medications) to the same area.^{326 327}

Diclofenac Epolamine Transdermal System

Apply transdermal system to the most painful area once daily (Licart) or twice daily (Flector).^{317 324} Apply to intact skin; do not apply to damaged skin (e.g., wounds, burns, infected areas of skin, areas affected with eczema or exudative dermatitis).^{317 324}

Wash hands after handling the system.^{317 324}

Avoid contact with eyes and mucous membranes.^{317 324}

Do not wear the transdermal system while bathing or showering.^{317 324}

If a system should begin to peel off during the period of use, the edges of the system may be taped to the skin.^{317 324} If problems with adhesion persist, a nonocclusive mesh netting sleeve (e.g., Curad Hold Tite, Surgilast Tubular Elastic Dressing) may be used when appropriate (e.g., over ankles, knees, or elbows) to secure the system.^{317 324}

Ophthalmic Administration

Apply 0.1% ophthalmic solution topically as an eye drop.²⁶⁴

Avoid use in patients with soft contact lenses (except for bandage hydrogel soft contact lenses during the first 3 days following refractive surgery).²⁶⁴

Dosage

Available as diclofenac potassium, diclofenac sodium, or diclofenac epolamine.^{1 302 303 317}

Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{1 302 303 317} Adjust dosage based on individual requirements and response.^{1 302 303 317}

Different strengths and formulations of oral diclofenac are not interchangeable.³³¹ Commercially available diclofenac sodium delayed-release tablets, diclofenac sodium extended-release tablets, and diclofenac potassium immediate-release tablets are not necessarily bioequivalent on a mg-per-mg basis.^{1 302 303 336} In addition, the frequency of administration may vary across available products; diclofenac potassium liquid-filled capsules are administered 4 times daily, while diclofenac potassium conventional tablets are administered 2–4 times daily.^{331 336}

Each actuation of the pump dispenser of diclofenac sodium 2% topical solution delivers 20 mg of diclofenac sodium in 1 g of solution.³²⁷ The 1.5% topical solution contains diclofenac sodium 16.05 mg/mL.³²⁶

Each mL of 0.1% diclofenac sodium ophthalmic solution delivers 1 mg of diclofenac sodium.²⁶⁴

Pediatric Patients

Acute Pain

Oral

Pediatric patients ≥12 years of age: Diclofenac potassium liquid-filled capsules: 25 mg 4 times daily.³³¹

Topical (transdermal system)

Pediatric patients ≥6 years of age: Apply 1 transdermal system (diclofenac epolamine 1.3%) twice daily (Flector).³¹⁷

Adults

Cataract Surgery

Ophthalmic

Apply 1 drop of 0.1% solution 4 times daily starting 24 hours after cataract surgery; continue for 2 weeks postoperatively.²⁶⁴

Corneal Refractive Surgery

Ophthalmic

Apply 1–2 drops of 0.1% solution to the operative eye 1 hour prior to surgery.²⁶⁴ Within 15 minutes after surgery, apply 1–2 drops to affected eye and continue 4 times daily for up to 3 days.²⁶⁴

Inflammatory Diseases

Osteoarthritis

Oral

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.²⁸⁴

Topical (solution)

Diclofenac sodium 1.5% topical solution: 40 drops (approximately 1.2 mL) applied to each affected knee 4 times daily.³²⁶

Diclofenac sodium 2% topical solution: 40 mg (2 pump actuations) applied to each affected knee twice daily.³²⁷

Rheumatoid Arthritis

Oral

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.²⁸⁴

Ankylosing Spondylitis

Oral

100–125 mg daily (as diclofenac sodium delayed-release tablets); administer as 25 mg 4 times daily, with 5th dose at bedtime as needed.¹

Pain

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets).³⁰³ Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).^{303 336}

25 mg 4 times daily (as diclofenac potassium liquid-filled capsules) for mild to moderate acute pain.³³¹

Topical (transdermal system)

Apply 1 transdermal system (diclofenac epolamine 1.3%) once daily (Licart) or twice daily (Flector).^{317 324}

Migraine

Oral

Single 50-mg dose (contents of one packet containing diclofenac potassium for oral solution mixed with water).³²⁸ Safety and efficacy of administering a second dose not established.³²⁸

Dysmenorrhea

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets).³⁰³ Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).^{303 336}

Special Populations

Hepatic Impairment

Reduction of oral dosage may be necessary.^{1 302 303 331}

Manufacturer of diclofenac potassium liquid-filled capsules recommends initiating treatment at the lowest dosage; if efficacy is not achieved at that dosage, discontinue diclofenac and consider alternative therapy.³³¹

Monitoring of renal function recommended in patients with hepatic impairment.^{284 302 303}

Renal Impairment

Reduction of oral dosage does not appear to be necessary.^{1 302 303}

Avoid use of diclofenac in advanced renal disease unless benefits are expected to outweigh risks of therapy.^{284 302 303 317} If diclofenac administered, monitor patients for signs of worsening renal function.^{284 302 303 317}

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac.^{1 284 302 303} Monitoring of renal function recommended, especially with concomitant ACE inhibitors of angiotensin II receptor antagonists,²⁸⁴ or in patients with heart failure, dehydration, or hypovolemia.^{1 302 303}

Geriatric Patients

Increased risk of NSAIA-associated serious cardiovascular, gastrointestinal, and/or renal adverse effects compared to younger adults.^{1 284 302 303} Risk possibly increased in patients with renal impairment or those receiving concomitant ACE inhibitor or angiotensin II receptor antagonists.²⁸⁴ If potential benefits outweigh potential risks, initiate therapy at the lower end of the dosage range and monitor for adverse effects.^{1 302 303}

Avoid diclofenac in fixed combination with misoprostol in geriatric patients with cardiovascular and/or renal risk factors.²⁸⁴ If use cannot be avoided, use the lowest recommended dosage for the shortest possible duration with additional monitoring for cardiac and renal adverse effects.²⁸⁴ Monitor renal function in geriatric patients receiving diclofenac in fixed combination with misoprostol, particularly during concomitant therapy with an ACE inhibitor or angiotensin II receptor antagonist.²⁸⁴

Cautions for Diclofenac (Systemic, Local)

Contraindications

• Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to diclofenac or any ingredient in the formulation.^{1 264 284 302 303 317 324 326 327 328 331 336}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{1 302 303 317 324 326 327 328 331 336}

• In the setting of CABG surgery.^{1 284 302 303 317 324 326 327 328 331 336}

• Diclofenac sodium in fixed combination with misoprostol: Active GI bleeding.²⁸⁴

• Diclofenac sodium in fixed combination with misoprostol: Pregnancy.²⁸⁴

• Diclofenac potassium liquid-filled capsules: Hypersensitivity to bovine protein.³³¹

• Diclofenac epolamine transdermal system: Use on nonintact or damaged skin, regardless of etiology (e.g., exudative dermatitis, eczema, infected lesions, burns, wounds).^{317 324}

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease (see Boxed Warning).^{1 302 303}

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but 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.^{1 302 303}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{1 302 303}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.^{1 302 303}

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{1 302 303}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{1 302 303}

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.^{1 302 303 317}

Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.^{1 302 303} Contraindicated in the setting of CABG surgery.^{1 302 303}

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{1 302 303 317}

GI Bleeding, Ulceration, and Perforation

Serious, sometimes fatal, GI toxicity (e.g., bleeding, ulceration, perforation of esophagus, stomach, or small or large intestine) can occur with or without warning symptoms (see Boxed Warning).^{1 302 303 317}

Risk for GI bleeding increased more than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.^{1 302 317}

Other risk factors for GI bleeding include concomitant use of oral corticosteroids, anticoagulants, aspirin, or SSRIs; longer duration of NSAIA therapy; smoking; alcohol use; older age; poor general health status; and advanced liver disease and/or coagulopathy.^{1 302 303 317}

Use at lowest effective dosage for the shortest duration necessary.^{1 302 303 317}

Avoid use of more than one NSAIA at a time.^{1 302 303 317}

Avoid use of NSAIAs in patients at higher risk for GI toxicity unless expected benefits outweigh increased risk of bleeding; consider alternate therapies in high-risk patients and those with active GI bleeding.^{1 302 303 317}

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.^{1 302 303 317}

If serious adverse GI event suspected, promptly initiate evaluation and discontinue diclofenac until serious adverse GI event ruled out.^{1 302 303 317}

Other Warnings and Precautions

Heart Failure and Edema

Fluid retention and edema reported.^{1 302 303 317}

NSAIAs increase the risk of MI, hospitalization for heart failure, and death.^{1 302 303 317}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.^{1 302 303 317}

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.^{1 302 303 317}

Hepatotoxicity

Monitor for symptoms and/or signs suggesting liver dysfunction.^{1 302 303 317}

Measure serum aminotransferase concentrations at baseline and 4–8 weeks after initiating therapy; monitor periodically during long-term therapy.^{1 302 303 317}

Use at lowest effective dosage for the shortest duration necessary; use with caution in patients receiving other potentially hepatotoxic drugs (e.g., acetaminophen, certain antibiotics, anticonvulsant agents).^{1 302 303 317}

Discontinue immediately if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations (e.g., eosinophilia, rash) occur.^{1 302 303 317}

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{1 302 303 317}

Monitor BP during initiation of diclofenac and throughout therapy.^{1 302 303 317}

Impaired response to ACE inhibitors and certain diuretics may occur.^{1 302 303 317}

Renal Toxicity and Hyperkalemia

Potential for overt renal decompensation.^{1 302 303 317} 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.^{1 302 303 317}

Correct fluid depletion prior to initiating diclofenac; monitor renal function during therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.^{1 302 303 317}

Hyperkalemia reported with NSAIAs, even in some patients without renal impairment; in such patients, effects attributed to a hyporenin-hypoaldosterone state.^{1 302 303 317}

Anaphylactic Reactions

Anaphylactic reactions reported in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma.^{1 302 303 317}

Exacerbation of Asthma Related to Aspirin Sensitivity

Patients with asthma can have aspirin-sensitive asthma, which manifests principally as chronic rhinosinusitis with severe (possibly fatal) bronchospasm and usually nasal polyps.^{1 302 303 317}

Avoid in patients with cross-sensitivity to aspirin.^{1 302 303 317} In patients with asthma but without known aspirin sensitivity, monitor for changes in manifestations of asthma.^{1 302 303 317}

Serious Skin Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{1 302 303 317} Fixed drug eruption (FDE), or more severe, potentially life-threatening generalized bullous fixed drug eruption (GBFDE) can occur.^{1 302 303 317}

Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^{1 302 303 317}

Drug Reaction with Eosinophilia and Systemic Symptoms

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.^{1 302 303 317} Clinical presentation 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).^{1 302 303 317} Symptoms may resemble those of acute viral infection.^{1 302 303 317} Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in absence of rash.^{1 302 303 317} If signs or symptoms of DRESS develop, discontinue diclofenac and immediately evaluate the patient.^{1 302 303 317}

Fetal/Neonatal Morbidity and Mortality

NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus, and use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios, and in some cases, neonatal renal impairment.^{1 302 303 317}

Avoid NSAIAs in pregnant women at about ≥30 weeks of gestation; if NSAIA therapy necessary between about 20−30 weeks of gestation, use lowest effective dosage and for shortest possible duration.^{1 302 303 317}

Fixed combination of diclofenac and misoprostol: Contraindicated in pregnant women.²⁸⁴ Misoprostol exhibits abortifacient activity and can cause serious fetal harm.²⁸⁴ Use in women of reproductive potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.²⁸⁴

Verify pregnancy status in women of reproductive potential within 2 weeks of initiating diclofenac sodium in fixed combination with misoprostol.²⁸⁴

Hematologic Toxicity

Anemia reported.^{1 302 303 317} May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.^{1 302 303 317} Determine hemoglobin concentration or hematocrit if signs or symptoms of anemia or blood loss occur.^{1 302 303 317}

NSAIAs may increase the risk of bleeding.^{1 302 303 317} Patients with certain coexisting conditions (e.g., coagulation disorders) or receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk; monitor such patients for bleeding.^{1 302 303 317}

Masking of Inflammation and Fever

Antipyretic and anti-inflammatory effects of diclofenac may mask usual signs and symptoms of infection.^{1 302 303 317}

Laboratory Monitoring

Monitor CBC and chemistry profile periodically in patients receiving long-term therapy.^{1 302 303 317}

Precautions Specific to Transdermal or Other Topical Use

Avoid exposure of treated areas to natural or artificial sunlight.^{326 327} The potential effects of topical diclofenac gel or solution on skin response to UV damage in humans are not known.^{326 327}

Application to nonintact skin may alter absorption and tolerability; apply only to intact skin.^{326 327}

Avoid contact with the eyes and mucous membranes.^{326 327} If contact with the eyes occurs, thoroughly rinse the eyes with water or saline.^{326 327} If ocular irritation persists for >1 hour, consult a clinician.^{326 327}

Do not apply to nonintact or damaged skin.^{317 324}

Patient should bathe or shower after removing one transdermal system and before applying a new system; the transdermal system should not be worn during bathing or showering.^{317 324}

Store and discard transdermal systems in a manner that avoids accidental exposure or ingestion by children or pets.^{317 324}

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of NSAIAs, 5-HT₁ receptor agonists, ergotamine, or opiates on a regular basis for ≥10 days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.³²⁸ Detoxification, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often include transient worsening of headaches), may be necessary.³²⁸

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.^{1 302 303 317}

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.^{1 302 303 317}

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.^{1 302 303 317} Oligohydramnios is often, but not always, reversible following NSAIA discontinuance.^{1 302 303 317} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1 302 303 317} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1 302 303 317} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1 302 303 317} 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 risk of adverse fetal and neonatal outcomes with maternal NSAIA use.^{1 302 303 317} Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants uncertain.^{1 302 303 317}

Effects of diclofenac on labor and delivery not known.^{1 302 303} In animal studies, NSAIAs, including diclofenac, increased incidence of dystocia, delayed parturition, and increased stillbirths.^{1 302 303}

Fixed combination of diclofenac and misoprostol: Contraindicated in pregnant women.²⁸⁴ Misoprostol exhibits abortifacient activity and can cause serious fetal harm.²⁸⁴

Lactation

May be distributed into human milk; consider the developmental and health benefits of breast-feeding along with the mother's clinical need for diclofenac and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.^{1 302 303 317}

Females and Males of Reproductive Potential

NSAIAs may be associated with reversible infertility in some women.^{1 302 303 317} 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.^{1 302 303 317}

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.^{1 302 303 317}

Pediatric Use

Safety and efficacy of diclofenac epolamine transdermal system (Flector) established in pediatric patients ≥6 years of age; safety comparable between pediatric patients and adults.³¹⁷

Safety and efficacy of diclofenac epolamine transdermal system (Flector) not established in pediatric patients <6 years of age.³¹⁷

Safety and efficacy of diclofenac potassium liquid-filled capsules established in pediatric patients 12−17 years of age; plasma concentrations of diclofenac similar to those observed in adult patients.³³¹

Safety and efficacy of other formulations of diclofenac not established in children.^{1 302 303 324 326 327 328 336}

Good results with oral diclofenac obtained in a limited number of children 3–16 years of age for the management of juvenile rheumatoid arthritis^† .^{128 210}

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects.^{1 302 303 317} Risk of these adverse effects may be increased in geriatric patients with renal impairment or who are receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy.²⁸⁴ Many of the spontaneous fatal adverse GI effects in patients receiving NSAIAs involve geriatric patients.^{1 302 303 317} If anticipated benefits outweigh potential risks, initiate at lower end of dosing range and monitor for adverse effects.^{1 302 303 317}

Diclofenac sodium 1.5% topical solution: No age-related differences in incidence of adverse effects observed.^{326 327}

Diclofenac epolamine transdermal system: Insufficient experience in individuals ≥65 years of age to determine whether geriatric patients respond differently than younger individuals.^{317 324}

Diclofenac potassium oral solution: Insufficient experience in individuals ≥65 years of age to determine whether geriatric patients respond differently than younger individuals.³²⁸

Diclofenac sodium in fixed combination with misoprostol: Avoid in geriatric patients with cardiovascular and/or renal risk factors.²⁸⁴

Use diclofenac with caution because of age-related decreases in renal function.^{302 303} May be useful to monitor renal function.^{302 303}

Hepatic Impairment

Almost completely metabolized in the liver; reduction of oral dosage may be necessary.^{1 302 303}

Diclofenac oral solution should only be used in patients with hepatic impairment if benefits outweigh risks.³²⁸

Diclofenac epolamine transdermal system: Pharmacokinetics not evaluated in hepatic impairment.^{317 324}

Renal Impairment

No differences in diclofenac pharmacokinetics observed in patients with renal insufficiency.^{1 302 303} Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.^{1 302 303}

Diclofenac epolamine transdermal system: Pharmacokinetics not evaluated in renal impairment.²⁸⁴

Common Adverse Effects

Diclofenac sodium delayed-release tablets, diclofenac potassium conventional tablets, or other NSAIAs (reported in 1–10% of patients): GI effects (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers, and vomiting).^{1 303} Additionally, abnormal renal function, anemia, dizziness, edema, elevations in hepatic transaminases, headaches, increased bleeding time, pruritic, rashes, and tinnitus.^{1 303}

Diclofenac in fixed combination with misoprostol (reported in ≥2% of patients): Abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, increases in ALT, and decreases in hematocrit.²⁸⁴

Diclofenac epolamine transdermal system (Flector): Pruritis (5%) and nausea (3%) reported.³¹⁷ The most common adverse effects in pediatric patients were headache (9%) and application site pruritis (7%).³¹⁷ Application site pruritis and application site reactions also common adverse effects in patients receiving diclofenac epolamine transdermal system (Licart).³²⁴

Diclofenac potassium for oral solution (reported in ≥1% of patients): Nausea and dizziness.³²⁸

Diclofenac sodium ophthalmic solution: Transient burning and stinging (15%), elevated intraocular pressure following cataract surgery (15%) and keratitis in up to 28% of patients, although keratitis was noted prior to treatment in many of these patients.²⁶⁴ Lacrimation complaints were also reported in approximately 30% of cases undergoing incisional refractive surgery.²⁶⁴ Other adverse effects reported in ≤10% of patients include abnormal vision, acute elevated intraocular pressure, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, eye pain, injection (redness), iritis, irritation, itching, lacrimation disorder, and ocular allergy.²⁶⁴

Drug Interactions

Metabolized by CYP isoenzymes, mainly CYP2C9.³⁰² CYP3A4, uridine diphosphate-glucuronosyltransferase (UGT) 2B7, and CPY2C8 may contribute to metabolism.³⁰²

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 inhibitors: Possible increased systemic exposure to diclofenac and risk of adverse effects. ³⁰² Dosage adjustment may be required.³⁰² Examples include, but are not limited to, voriconazole.³⁰²

CYP2C9 inducers: Possible reduced efficacy of diclofenac.³⁰² Dosage adjustment may be required.³⁰² Examples include, but are not limited to, rifampin.³⁰²

Specific Drugs

Diclofenac (Systemic, Local) Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.^{1 302 303} Undergoes first-pass metabolism; only 50% of a dose reaches systemic circulation as unchanged drug.^{1 302 303}

Peak plasma concentration usually attained within about 0.47 hours (diclofenac potassium liquid-filled capsules), 1 hour (diclofenac potassium conventional tablets), 2.3 hours (diclofenac sodium delayed-release tablets), or 5.3 hours (diclofenac sodium extended-release tablets).^{1 302 303 331 336}

Absorbed into systemic circulation following topical administration as gel, solution, or transdermal system; plasma concentrations generally very low compared with oral administration.^{317 324 326}

Following application of a single diclofenac epolamine transdermal system (Flector) to intact skin on the upper arm, peak plasma concentrations occur in 10–20 hours; moderate exercise does not alter absorption.³¹⁷ Plasma diclofenac concentrations similar in pediatric patients ≥6 years of age compared to adults.³¹⁷

Following application of diclofenac epolamine transdermal system (Licart) to anterior thigh, peak concentrations occur in 4–20 hours; moderate exercise, application of an occlusion dressing over the system, or moderate heat increases peak plasma concentrations and systemic exposure by approximately 20%.³²⁴

Following topical application of diclofenac sodium 1.5% solution to knees, peak plasma concentrations occur in about 4 hours.³²⁶ Not established whether occlusive dressings, application of heat, or exercise affects absorption of diclofenac sodium 2% solution.³²⁷

Food

Conventional, delayed-release, or extended-release tablets: Food delays time to reach peak plasma concentration but does not affect extent of absorption.^{1 302 303}

Diclofenac potassium oral solution: Administration after a high-fat meal reduces peak plasma concentrations by approximately 70% but does not substantially affect extent of absorption.³²⁸

Diclofenac potassium liquid-filled capsules: Food decreases rate of absorption (47% decrease in peak concentration, twofold increase in time to peak concentration) but does not substantially affect extent of absorption.³³¹

Distribution

Extent

Distributes into human milk.^{1 302 303}

Plasma Protein Binding

>99%.^{1 302 303}

Elimination

Metabolism

Metabolized in the liver via hydroxylation and conjugation.^{1 302 303} Five metabolites detected in plasma and urine.³⁰²

Formation of 4′-hydroxydiclofenac (principal metabolite) is mediated mainly by CYP2C9; formation of 5-hydroxydiclofenac and 3′-hydroxydiclofenac (minor metabolites) is mediated by CYP3A4.³⁰² UGT2B7 and CYP2C8 may mediate acyl glucuronidation and oxidation reactions, respectively.³⁰²

Elimination Route

Excreted in urine (65%) and in feces via biliary elimination (35%).³⁰²

Half-life

Diclofenac sodium: 2.3 hours.^{1 302}

Diclofenac potassium: 1.9 hours.³⁰³

Diclofenac epolamine transdermal system: Approximately 12 hours.^{317 324}

Special Populations

In patients with renal impairment, plasma clearance not substantially altered.^{1 302 303}

Stability

Storage

Oral

Capsules, Liquid-filled

Tight container at 20–25°C (may be exposed to 15–30°C).³³¹ Protect from moisture.³³¹

Powder for Oral Solution

25°C (may be exposed to 15–30°C).³²⁸

Tablets

Tight containers at room temperature (20–25°C); consult manufacturer's labeling for specific storage recommendation.^{1 302 303} Protect from moisture.^{302 303}

Diclofenac sodium in fixed combination with misoprostol: 25°C (may be exposed to 15–30°C).²⁸⁴

Topical

Solution

Diclofenac sodium 0.1% ophthalmic solution: 20–25°C protected from light.²⁶⁴

Diclofenac sodium 1.5% topical solution: 20–25°C (may be exposed to 15–30°C).³²⁶

Diclofenac sodium 2% topical solution: 25°C (may be exposed to 15–30°C).³²⁷

Transdermal System

20–25°C (may be exposed to 15–30°C).^{317 324} Licart systems stable for up to 6 months after envelope is opened if stored at room temperature in the resealed envelope.³²⁴

Actions

• NSAIA; inhibits cyclooxygenase-1 (COX-1) and COX-2.¹

• Mode of action associated principally with reduction of prostaglandin synthesis in peripheral tissues;¹ exhibits anti-inflammatory, analgesic, and antipyretic activity.^{1 317}

Advice to Patients

• Advise patients to read the medication guide for nonsteroidal anti-inflammatory agents (NSAIAs) that is provided each time the drug is dispensed.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients of the risk of serious cardiovascular thrombotic events.^{1 284 302 303 317 324 326 327 328 331} Stress importance of reporting signs and symptoms of a cardiovascular event (e.g., chest pain, shortness of breath, weakness, slurred speech) immediately to a healthcare provider.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients to report symptoms of GI bleeding and ulceration (e.g., epigastric pain, dyspepsia, melena, hematemesis) to their healthcare provider.^{1 284 302 303 317 324 326 327 328 331} Notify patients receiving concomitant low-dose aspirin of the increased risk of GI bleeding.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, anorexia, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms).^{1 284 302 303 317 324 326 327 328 331} If these occur, inform patients to stop diclofenac and seek immediate medical attention.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients of the risk of serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS).^{1 284 302 303 317 324 326 327 328 331} Advise patients to stop taking diclofenac immediately if they develop any type of rash or fever and to promptly contact their clinician.^{1 284 302 303 317 324 326 327 328 331}

• Stress importance of seeking immediate medical attention if an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat) occurs.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients of the risk of heart failure or edema, and to watch out for symptoms of heart failure such as shortness of breath, unexplained weight gain, or edema, and to contact their healthcare provider if these occur.^{1 284 302 303 317 324 326 327 328 331}

• Warn patients to keep diclofenac transdermal system out of the reach of children and pets and to safely dispose of used units.^{317 324}

• Stress importance of avoiding or limiting exposure of skin treated with diclofenac gel or solution to natural or artificial sunlight.^{326 327}

• Advise patients receiving diclofenac topical solution to avoid applying to open wounds, infections, inflammation, or exfoliative dermatitis.^{326 327}

• Advise patients receiving diclofenac topical solution to wait until the treated area is completely dry before applying sunscreen, insect repellent, lotion, moisturizer, cosmetics, or other topical medications.^{326 327}

• Advise patients receiving diclofenac topical solution to promptly contact their clinician if any type of rash develops at the application site.^{326 327}

• Advise patients receiving diclofenac topical solution that other individuals should avoid contact with the application site(s) until the site is completely dry.^{326 327}

• Inform patients that if topical formulations of diclofenac come into contact with the eye(s), to rinse the affected eye(s) with water or saline and consult a clinician if irritation persists for >1 hour.^{326 327}

• Inform patients that if diclofenac transdermal system begins peeling off that the edges of the system may be taped down.^{317 324} If problems with adhesion persist, a nonocclusive mesh netting sleeve (e.g., Curad Hold Tite™, Surgilast Tubular Elastic Dressing) may be used when appropriate (e.g., over ankles, knees, or elbows) to secure the system.^{317 324} Inform patients that Flector must not be worn when bathing or showering, and to wash hands after applying, handling, or removing the system.³¹⁷ Inform patients to only apply the system to non-damaged skin.^{317 324}

• Advise patients with migraine headaches that overuse of drugs intended for acute treatment of migraine attacks (e.g., use on ≥10 days per month) may exacerbate headaches; encourage patients to record the frequency of migraine headaches and medication use.³²⁸

• Stress importance of patients informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 284 302 303 317 324 326 327 328 331}

• Inform women of reproductive potential that Arthrotec is contraindicated in pregnancy.²⁸⁴

• Inform pregnant women to avoid 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.^{1 284 302 303 317 324 326 327 328 331}

• Advise patients who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients that diclofenac may mask the signs of an infection (e.g., fever).^{1 284 302 303 317 324 326 327 328 331}

• Inform patients receiving long-term NSAIA therapy that a CBC and chemistry profiles may be monitored periodically.^{1 284 302 303 317 324 326 327 328 331}

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 284 302 303 317 324 326 327 328 331} Advise patients that concomitant use of other NSAIAs with diclofenac provides little or no increase in efficacy but increases risk of GI toxicity, and is not recommended.^{1 284 302 303 317 324 326 327 328 331} Advise patients not to use concomitant low-dose aspirin without consulting their clinician.^{1 284 302 303 317 324 326 327 328 331} Inform patients that many OTC drugs used to treat cold, fever, or insomnia contain NSAIAs.^{1 284 302 303 317 324 326 327 328 331}

• Inform patients of other important precautionary information.^{1 284 302 303 317 324 326 327 328 331}

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.

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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