Diclofenac (Monograph)

Brand names: Cambia, Flector, Licart, Pennsaid, Voltaren, Zipsor
Drug class: Other Nonsteroidal Anti-inflammatory Agents
Chemical name: 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt
Molecular formula: C₁₄H₁₁C₁₂NO₂•KC₁₄H₁₁C₁₂NO₂.NaC₂₀H₂₄Cl₂N₂O₃
CAS number: 15307-81-0

Medically reviewed by Drugs.com on Oct 30, 2023. Written by ASHP.

Warning

Cardiovascular Risk

Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁰ ⁵⁰² ⁵⁰⁸ Risk may occur early in treatment and may increase with duration of use.⁵⁰⁰ ⁵⁰² ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁸ (See Cardiovascular Thrombotic Effects under Cautions.)
Contraindicated in the setting of CABG surgery.⁵⁰⁸

GI Risk

Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Geriatric individuals and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA;¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁸⁹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ phenylacetic acid derivative;¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁸⁹ ²⁶² structurally related to meclofenamate sodium and mefenamic acid.²⁰³

Uses for Diclofenac

Inflammatory Diseases

Orally for symptomatic treatment of osteoarthritis,¹ ⁸¹ ⁸² ⁸³ ⁸⁴ ⁸⁵ ⁸⁶ ⁸⁹ ⁹⁰ ¹⁰⁷ ¹⁰⁸ ¹⁰⁹ ¹¹⁰ ¹¹¹ ¹¹² ¹¹³ ¹¹⁴ ¹²¹ ¹²⁵ ¹²⁶ ¹³³ ²⁷⁴ ³⁰² ³⁰³ rheumatoid arthritis,¹ ⁷⁴ ⁷⁵ ⁷⁶ ⁷⁷ ⁷⁸ ⁷⁹ ⁸⁰ ⁸⁷ ⁸⁸ ¹⁰⁷ ¹¹⁵ ¹¹⁶ ¹¹⁷ ¹¹⁸ ¹¹⁹ ¹²¹ ¹²⁵ ¹²⁶ ¹²⁹ ²⁵⁴ ³⁰² ³⁰³ and ankylosing spondylitis.¹ ⁹¹ ¹²⁰ ¹²¹ ¹²⁵ ¹²⁷ ²⁷⁴

Orally in fixed combination with misoprostol for the symptomatic treatment of osteoarthritis and rheumatoid arthritis in patients at high risk for developing NSAIA-induced gastric or duodenal ulcers and in patients at high risk for developing complications from these ulcers.²⁸⁴

Topically (as 1% gel or 1.5 or 2% solution) for the symptomatic treatment of osteoarthritis-related joint pain.³¹⁸ ³²¹ ³²⁵ ³²⁶ ³²⁷ Gel used for joints amenable to topical therapy (e.g., hands, wrists, elbows, knees, ankles, feet); has not been evaluated on joints of the spine, hip, or shoulder.³¹⁸ ³²⁵ Topical solution used for symptoms (e.g., pain) affecting knees.³²⁶ ³²⁷ American College of Rheumatology (ACR) states that topical NSAIAs may be an appropriate initial choice for pharmacologic therapy of osteoarthritis for some patients with limited disease; oral NSAIAs more appropriate for those with hip or polyarticular involvement.³³⁰

Orally for management of juvenile rheumatoid arthritis^{† [off-label]}.³ ¹²⁸ ²¹⁰

Orally for symptomatic relief of acute gouty arthritis^{† [off-label]}.¹²¹ ¹³⁰ ¹³¹ ¹³²

Orally or topically for symptomatic treatment of infusion-related superficial thrombophlebitis^{† [off-label]}.³¹⁰ ³¹¹

Pain

Orally for relief of mild to moderate acute pain, postoperative (e.g., orthopedic, gynecologic, oral) pain, and orthopedic pain (e.g., musculoskeletal sprains, traumatic joint distortions).²⁷⁶ ²⁷⁷ ²⁷⁸ ²⁷⁹ ³⁰³ ³³¹

Transdermally for relief of acute pain due to minor strains, sprains, and contusions.³¹⁷ ³¹⁹ ³²⁴

Migraine

Orally (as solution) for acute treatment of attacks of migraine 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

Dysmenorrhea

Orally for symptomatic management of primary dysmenorrhea.³⁰³

Diclofenac Dosage and Administration

General

Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.¹ ³⁰² ³⁰³ ³¹⁷

Administration

Oral Administration

Diclofenac sodium delayed-release (enteric-coated) and extended-release tablets are not recommended for relief of acute pain³ ²⁴⁸ or primary dysmenorrhea¹ because of slow onset of action.⁵³ ⁵⁴ ⁵⁶ ⁵⁷ ⁶⁰ ⁶¹

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% Gel

Apply gel 4 times daily to the affected joint.³¹⁸ ³²⁵ Use the dosing card from the manufacturer to measure the appropriate dose.³¹⁸ ³²⁵ Apply the gel within the oblong area of the dosing card up to the appropriate line (2.25- or 4.5-inch line, corresponding to 2 or 4 g of gel, respectively); then use the dosing card to apply the gel.³¹⁸ ³²⁵ Gently massage the gel into the skin; ensure gel is applied to the entire affected joint (e.g., foot [including sole, top of foot, and toes], knee, ankle, hand [including palm, back of hand, and fingers], elbow, wrist).³¹⁸

Allow application site to dry for 10 minutes before covering treated area with clothing; wait ≥60 minutes before bathing or showering.³¹⁸ Wash hands after application unless the treated joint is in the hand.³¹⁸

Do not apply to open wounds or areas of skin with cuts, infections, or rashes; avoid contact with eyes and mucous membranes.³¹⁸ ³²⁵

Do not expose treated joint to external heat or to natural or artificial sunlight; do not use occlusive dressings.³¹⁸ ³²⁵

Avoid application of sunscreens, cosmetics, lotions, moisturizers, insect repellents, or other topical agents to the same site; concomitant use with other topical agents not studied.³¹⁸ ³²⁵

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

Dosage

Available as diclofenac potassium, diclofenac sodium, or diclofenac epolamine; dosage expressed in terms of the salt.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

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.¹ ³⁰² ³⁰³ ³¹⁷ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.¹ ³⁰² ³⁰³ ³¹⁷

Based on safety reviews conducted to evaluate cardiovascular risk of diclofenac, some authorities (e.g., Health Canada) now recommend that systemic diclofenac dosage not exceed 100 mg daily (except on first day of treatment for dysmenorrhea when total dose of 200 mg may be administered).⁵²⁰ (See Cardiovascular Thrombotic Effects under Cautions.)

Different strengths and formulations of oral diclofenac are not interchangeable.³³¹ Commercially available diclofenac sodium enteric-coated 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 Diclofenac potassium liquid-filled capsules and conventional tablets are not equivalent.³³²

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 The 1% gel contains 10 mg of diclofenac sodium per 1 g of gel.³¹⁸

Adults

Inflammatory Diseases

Oral

Some authorities (e.g., Health Canada) recommend that systemic diclofenac dosage for inflammatory diseases not exceed 100 mg daily.⁵²⁰ (See Cardiovascular Thrombotic Effects under Cautions.)

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

Preparation	Dosage
Diclofenac potassium conventional tablets	100–150 mg daily, given as 50 mg 2 or 3 times daily³⁰³
Diclofenac sodium delayed-release tablets	100–150 mg daily, given as 50 mg 2 or 3 times daily or 75 mg twice daily¹
Diclofenac sodium extended-release tablets	100 mg once daily³⁰²
Diclofenac sodium (in fixed combination with misoprostol)	50 mg 3 times daily²⁸⁴

Topical (gel)

For lower extremity (i.e., knees, ankles, feet) joint pain, massage 4 g of diclofenac sodium 1% gel into the affected joint 4 times daily.³¹⁸ ³²⁵

For upper extremity (i.e., elbows, wrists, hands) joint pain, massage 2 g of diclofenac sodium 1% gel into the affected joint 4 times daily.³¹⁸ ³²⁵

If multiple joints are treated, total daily dose applied to all joints should be ≤32 g of gel daily.³¹⁸

When used for self-medication for temporary relief of arthritis pain, treat no more than 2 body areas at the same time, and apply no more than 16 g of gel daily to any single lower extremity joint and no more than 8 g of gel daily to any single upper extremity joint.³²⁵ May use for up to 21 days unless otherwise directed by a clinician; discontinue if no pain relief within 7 days.³²⁵

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

Preparation	Dosage
Diclofenac potassium conventional tablets	150–200 mg daily, given as 50 mg 3 or 4 times daily³⁰³
Diclofenac sodium delayed-release tablets	150–200 mg daily, given as 50 mg 3 or 4 times daily or 75 mg twice daily¹
Diclofenac sodium extended-release tablets	100 mg once daily; may increase to 100 mg twice daily ³⁰²
Diclofenac sodium (in fixed combination with misoprostol)	50 mg 3 or 4 times daily²⁸⁴

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 ⁹¹ ¹²⁵

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

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

Some authorities (e.g., Health Canada) recommend that dosage not exceed 100 mg daily.⁵²⁰ (See Cardiovascular Thrombotic Effects under Cautions.)

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

Some authorities (e.g., Health Canada) state that a total dose of 200 mg may be administered on the first day of treatment for dysmenorrhea but subsequent dosage should not exceed 100 mg daily.⁵²⁰ (See Cardiovascular Thrombotic Effects under Cautions.)

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis

Topical (gel)

Maximum total daily dose applied to all affected joints: 32 g of diclofenac sodium 1% gel.³¹⁸ Maximum 16 g of gel applied daily to any single lower extremity joint and 8 g applied daily to any single upper extremity joint.³¹⁸

For self-medication, treat no more than 2 body areas at the same time; maximum 16 g of gel applied daily to any single lower extremity joint and 8 g of gel applied daily to any single upper extremity joint.³²⁵ Maximum 21 days of treatment unless otherwise directed by a clinician.³²⁵

Migraine

Oral

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

Special Populations

Renal Impairment

Dosage adjustment not required.¹ ³ ⁷² ²⁴⁷ ²⁴⁸ ³⁰² ³⁰³ (See Renal Impairment under Cautions.)

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

Cautions for Diclofenac

Contraindications

Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to diclofenac or any ingredient in the formulation.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.¹ ¹⁴¹ ¹⁴⁴ ¹⁴⁵ ¹⁴⁶ ¹⁴⁷ ¹⁶⁸ ²²⁵ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
In the setting of CABG surgery.⁵⁰⁸
Diclofenac sodium in fixed combination with misoprostol: Contraindicated in pregnant women.²⁸⁴
Diclofenac epolamine transdermal system: Use on nonintact or damaged skin, regardless of etiology (e.g., exudative dermatitis, eczema, infected lesions, burns, wounds), is contraindicated.³¹⁷ ³²⁴

Warnings/Precautions

Warnings

Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.¹ ³⁰² ³⁰³ ³¹⁷ Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

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.⁵⁰⁰ ⁵⁰² ⁵⁰⁸

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information⁵⁰⁰ ⁵⁰¹ ⁵⁰² indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

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.⁵⁰⁰ ⁵⁰² ⁵⁰⁶ ⁵⁰⁸

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.⁵⁰⁰ ⁵⁰² ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁸

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.⁵⁰⁸

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.⁵⁰⁵ ⁵⁰⁸

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;⁵⁰⁰ ⁵⁰⁸ ⁵¹¹ 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.⁵⁰⁸ ⁵¹¹

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.³¹² ³¹³ ³¹⁴ ³¹⁶ ⁵⁰⁰ ⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁶ FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Findings from some meta-analyses and systematic reviews also suggest that cardiovascular risk of diclofenac, particularly at higher dosages (e.g., ≥150 mg daily), is similar to that observed with selective COX-2 inhibitors.³¹² ³¹³ ⁵⁰¹ ⁵⁰³ ⁵⁰⁶ ⁵²⁰ ⁵²¹ Some authorities (e.g., Health Canada) recommend that systemic diclofenac dosage not exceed 100 mg daily (except for first day of treatment for dysmenorrhea).⁵²⁰ (See Dosage under Dosage and Administration.)

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.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁰ ⁵⁰⁸

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.⁵⁰⁵ ⁵¹¹ ⁵¹² ⁵¹⁶ 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.⁵⁰⁸ Contraindicated in the setting of CABG surgery.⁵⁰⁸

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰² ⁵⁰⁸ (See Specific Drugs under Interactions.)

GI Effects

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.¹ ¹⁶⁷ ¹⁸¹ ¹⁸⁷ ²⁵⁶ ²⁵⁹ ²⁶⁰ ²⁶⁷ ²⁶⁸ ²⁸² ²⁹² ³⁰⁰ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

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.²⁶⁰ ²⁹² ³⁰² ³¹⁷ ³¹⁸

Other risk factors for GI bleeding include concomitant use of oral corticosteroids, anticoagulants, aspirin, or SSRIs; longer duration of NSAIA therapy (however, short-term therapy is not without risk); smoking; alcohol use; older age; poor general health status; and advanced liver disease and/or coagulopathy.²⁶⁰ ²⁹² ³⁰⁰ ³⁰²

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.¹ ¹⁶⁷ ¹⁸¹ ²⁵⁹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Frequency of NSAIA-associated upper GI ulcers, gross bleeding, or perforation is approximately 1% in patients receiving NSAIAs for 3–6 months and 2–4% at one year.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Use at lowest effective dosage for the shortest duration necessary.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Avoid use of more than one NSAIA at a time.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ (See Specific Drugs under Interactions.)

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.³⁰²

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;²⁴⁹ ²⁵⁴ ²⁸⁴ ²⁹² ²⁹³ alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)²⁴⁹ ²⁵⁴ ²⁹² or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).²⁴⁹

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.¹ ¹⁶⁷ ¹⁸¹ ²⁵⁶ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

If serious adverse GI event suspected, promptly initiate evaluation and discontinue diclofenac until serious adverse GI event ruled out.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Other Warnings and Precautions

Hepatic Effects

Severe hepatic reactions (sometimes fatal or requiring liver transplantation), including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, reported rarely with diclofenac.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ³²³

Serum ALT or AST elevations reported.¹ ⁷⁹ ¹⁵⁵ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ³²³ In one large, open-label, controlled study, ALT/AST elevations were observed more frequently with diclofenac than with other NSAIAs.³⁰² Aminotransferase elevations also observed more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.³⁰² During clinical trials, test abnormalities were observed during the first 2 months of diclofenac therapy in 82% of patients who developed marked aminotransferase elevations.³⁰²

Retrospective population-based, case-control study of drug-induced liver injury suggested current diclofenac use is associated with increased risk of liver injury (adjusted odds ratio of 4.1) compared with nonuse of the drug; findings also suggested increased risk in women compared with men and with use of higher doses (≥150 mg) and longer durations of therapy (>90 days).³⁰² ³³⁵

Monitor for symptoms and/or signs suggesting liver dysfunction.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ³²³ Measure serum aminotransferase concentrations at baseline and 4–8 weeks after initiating therapy; monitor periodically during long-term therapy.³⁰² ³¹⁷ ³¹⁸ ³²³

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).³⁰²

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.¹ ¹⁶⁴ ²⁵⁵ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ³²³

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Monitor BP during initiation of diclofenac and throughout therapy.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁸ (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁸

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.⁵⁰⁰ ⁵⁰¹ ⁵⁰⁴ ⁵⁰⁷ ⁵⁰⁸

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.⁵⁰⁸ (See Specific Drugs under Interactions.)

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.⁵⁰⁸

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Potential for overt renal decompensation.¹ ¹⁷¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ 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.¹ ¹⁶⁰ ¹⁷⁴ ¹⁸⁵ ¹⁹¹ ²⁸⁴ ³⁰² ³⁰³ ³⁰⁶ ³¹⁵ ³¹⁷ ³¹⁸ (See Renal Impairment under Cautions.)

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

Hyperkalemia

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

Hypersensitivity Reactions

Anaphylactic reactions reported.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Immediate medical intervention and discontinuance for anaphylaxis.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); in patients with asthma but without known aspirin sensitivity. monitor for changes in manifestations of asthma.³⁰² ³⁰³ ³¹⁷ ³¹⁸

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.³⁰³ Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).³⁰³ Symptoms may resemble those of acute viral infection.³⁰³ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.³⁰³ If signs or symptoms of DRESS develop, discontinue diclofenac and immediately evaluate the patient.³⁰³

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Hematologic Effects

Anemia reported rarely.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.³⁰² Determine hemoglobin concentration or hematocrit if signs or symptoms of anemia or blood loss occur.¹ ²⁴⁸ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

NSAIAs may increase the risk of bleeding.³⁰² 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.³⁰² (See Specific Drugs under Interactions.)

May inhibit platelet aggregation and prolong bleeding time.³ ⁴⁰ ⁴¹ ⁴² ⁴³ ¹⁶⁵ ¹⁶⁶

Precautions Specific to Diclofenac Sodium Topical Gel or Solution

Avoid exposure of treated areas to natural or artificial sunlight.³¹⁸ ³²⁶ ³²⁷ Topical application of diclofenac gel formulations has resulted in early onset of ultraviolet (UV) light-related skin tumors in animal studies.³¹⁸ ³²¹ The potential effects of topical diclofenac gel or solution on skin response to UV damage in humans are not known.³¹⁸ ³²⁶ ³²⁷

Application to nonintact skin may alter absorption and tolerability; apply only to intact skin.³¹⁸ ³²⁶ ³²⁷

Avoid contact with the eyes and mucous membranes.³¹⁸ ³²⁶ ³²⁷ If contact with the eyes occurs, thoroughly rinse the eyes with water or saline.³¹⁸ ³²⁶ ³²⁷ If ocular irritation persists for >1 hour, consult a clinician.³¹⁸ ³²⁶ ³²⁷

Precautions Specific to Diclofenac Epolamine Transdermal System

Avoid contact with eyes and mucous membranes.³¹⁷ ³²⁴ If contact with the eyes occurs, thoroughly rinse the eyes with water or saline.³¹⁷ ³²⁴ If ocular irritation persists for >1 hour, consult a clinician.³¹⁷ ³²⁴

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

Use of Fixed Combinations

Observe the usual cautions, precautions, and contraindications associated with misoprostol therapy when diclofenac is used in fixed combination with misoprostol.²⁸⁴

Concomitant NSAIA Therapy

Do not use multiple diclofenac-containing preparations concomitantly.¹ ³⁰² ³⁰³ Concomitant use of topical formulations of diclofenac and oral NSAIAs may increase risk of adverse effects.³¹⁷ ³¹⁸ (See Specific Drugs under Interactions.)

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.¹ ²⁴⁸ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

May mask certain signs of infection.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Obtain CBC and chemistry profile periodically during long-term use.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

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.³⁰³ ¹²⁰⁰

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

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.³⁰³ ¹²⁰⁰ (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.³⁰³ ¹²⁰⁰ Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.³⁰³ ¹²⁰⁰ Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.³⁰³ ¹²⁰⁰ In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.³⁰³ ¹²⁰⁰ Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).³⁰³ ¹²⁰⁰ Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.³⁰³ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.³⁰³

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.³⁰³ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.³⁰³

Diclofenac crosses the placenta.³⁰³ No evidence of teratogenicity in animal studies; however, fetal toxicity (e.g., reduced weight, growth, and survival) observed.³⁰⁷

Effects of diclofenac on labor and delivery not known.³⁰³ In animal studies, NSAIAs, including diclofenac, increased incidence of dystocia, delayed parturition, and increased stillbirths.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 milk; ³ ³⁰³ 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.³⁰³

Fertility

NSAIAs may be associated with reversible infertility in some women.³⁰³ 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.³⁰³

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.³⁰³

Pediatric Use

Safety and efficacy not established in children.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ³²⁴ ³²⁶ ³²⁷ ³²⁸ ³³¹

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

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects.³⁰² ³¹⁷ Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ If anticipated benefits outweigh potential risks, initiate at lower end of dosing range and monitor for adverse effects.³⁰² ³¹⁷

Diclofenac sodium 1% gel: No substantial difference in safety and efficacy in individuals ≥65 years of age compared with younger individuals; possibility of greater sensitivity to the drug in some geriatric individuals.³¹⁸

Diclofenac sodium 1.5% topical solution: No age-related differences in the 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

Use diclofenac with caution because of age-related decreases in renal function.³⁰² ³¹⁸ May be useful to monitor renal function.³⁰² ³¹⁸

Hepatic Impairment

Almost completely metabolized in the liver; reduction of oral dosage may be necessary.³⁰² ³⁰³ ³³¹

Renal Impairment

Metabolites eliminated principally via the kidney.¹ ³⁰² ³⁰³

May hasten progression of renal dysfunction in patients with preexisting renal disease.³⁰² Monitor patients with preexisting renal disease for worsening renal function.³⁰²

Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function; close monitoring of renal function advised if used.¹ ²⁴⁸ ³⁰² ³⁰³ ³⁰⁴ ³¹⁷ ³¹⁸

Common Adverse Effects

Oral diclofenac: Abdominal pain or cramps,¹ ⁷⁵ ⁸⁶ ⁹³ ¹⁰⁷ ¹¹³ ¹³⁶ ³⁰² ³⁰³ constipation,¹ ⁷⁵ ¹¹³ ¹³² ¹³⁴ ¹³⁶ ³⁰² ³⁰³ diarrhea,¹ ⁸⁴ ⁸⁶ ⁸⁷ ⁹³ ⁹⁵ ¹²⁵ ¹³⁴ ³⁰² ³⁰³ flatulence,¹ ³⁰² ³⁰³ GI bleeding,¹ ³⁰² ³⁰³ GI perforation, ¹ ³⁰² ³⁰³ peptic ulcer,¹ ³⁰² ³⁰³ vomiting, ¹ ³⁰² ³⁰³ dyspepsia,¹ ³⁰² ³⁰³ nausea,¹ ⁷⁶ ⁷⁸ ⁸⁴ ⁸⁵ ⁹³ ⁹⁵ ⁹⁶ ⁹⁷ ⁹⁸ ⁹⁹ ¹⁰⁹ ¹¹¹ ¹¹³ ¹²⁶ ¹²⁹ ¹³⁴ ¹⁶⁵ ³⁰² ³⁰³ dizziness,¹ ¹⁰² ¹⁰⁷ ¹¹³ ¹²⁵ ¹²⁹ ¹⁶⁵ ³⁰² ³⁰³ headache,¹ ⁸⁹ ⁹⁰ ⁹¹ ⁹³ ⁹⁵ ¹⁰⁷ ¹¹⁰ ¹¹³ ¹¹⁸ ¹²⁵ ¹²⁷ ¹²⁹ ¹³² ¹⁶⁵ ³⁰² ³⁰³ liver function test abnormalities,¹ ¹¹⁶ ¹²⁵ ¹⁶⁵ ¹⁸⁹ ²⁰⁹ ²²³ ²⁵⁵ ³⁰² ³⁰³ renal function abnormalities,¹ ³⁰² ³⁰³ anemia,¹ ³⁰² ³⁰³ prolonged bleeding time,¹ ³⁰² ³⁰³ pruritus,¹ ³⁰² ³⁰³ rash,¹ ³⁰² ³⁰³ tinnitus,¹ ³⁰² ³⁰³ edema.¹ ¹⁰⁹ ¹²⁵ ¹³² ¹⁵⁹ ¹⁶⁵ ³⁰² ³⁰³

Diclofenac sodium gel: Application site reactions (e.g., dermatitis).³¹⁸

Diclofenac sodium topical solution: Application site reactions (e.g., dryness; exfoliation; erythema; pruritus; contact dermatitis with erythema, induration, or vesicles).³²⁶ ³²⁷

Diclofenac epolamine transdermal system: Application site reactions (e.g., pruritus, dermatitis, irritation, erythema), nausea, altered taste.³¹⁷ ³²⁴

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

Protein-bound Drugs

Only minimally displaces other highly protein-bound drugs from binding sites; however, may be displaced from binding sites by other highly protein-bound drugs.⁵¹ ⁵² ⁵⁹ ⁶¹

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Reduced BP response to ACE inhibitor¹ ²⁴⁸ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Possible deterioration of renal function, including acute renal failure, in geriatric patients and patients with volume depletion or renal impairment³⁰² ³¹⁵	Monitor BP¹ ²⁴⁸ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter³⁰² Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function³⁰²
Angiotensin II receptor antagonists	Reduced BP response to angiotensin II receptor antagonist³⁰² ³¹⁵ Possible deterioration of renal function, including acute renal failure, in geriatric patients and patients with volume depletion or renal impairment³⁰² ³¹⁵	Monitor BP³⁰² Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter³⁰² Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function³⁰²
Antacids (magnesium- or aluminum-containing)	Delayed diclofenac absorption³ ¹⁸⁹ ²³⁸
Anticoagulants (warfarin)	Possible bleeding complications¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸	Caution advised; carefully observe for signs of bleeding¹ ³⁰² ³⁰³
β-Adrenergic blocking agents	Reduced BP response to β-blocker³⁰²	Monitor BP³⁰²
Cyclosporine	Possible increase in nephrotoxic effects of cyclosporine¹ ³⁰² ³⁰³ ³¹⁸	Monitor for worsening renal function³⁰²
Digoxin	Increased serum concentrations and prolonged half-life of digoxin³⁰²	Monitor serum digoxin concentrations³⁰²
Diuretics (furosemide, thiazides, potassium-sparing)	Reduced natriuretic effects¹ ²² ¹⁷⁹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Potassium-sparing diuretics: Possible increased serum potassium concentrations²⁸⁴ Triamterene: Reversible renal impairment reported¹⁷⁴	Monitor for worsening renal function and for adequacy of diuretic and antihypertensive effects¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Triamterene: Use with caution³ ¹⁷⁴ ²⁴⁶
Lithium	Increased plasma lithium concentrations¹ ¹⁷⁶ ¹⁸⁸ ²⁶⁵ ³⁰² ³⁰³ ³¹⁷ ³¹⁸	Monitor for lithium toxicity¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
Methotrexate	Possible increased risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction);³⁰² severe, sometimes fatal toxicity associated with increased plasma methotrexate concentrations¹⁷⁵ ³⁰⁷	Monitor for methotrexate toxicity³⁰²
NSAIAs	Concomitant NSAIAs and aspirin (analgesic dosages): Therapeutic effect not greater than that of NSAIAs alone³⁰² Concomitant NSAIAs and aspirin: Increased risk for bleeding and serious adverse GI effects³⁰² Concomitant use of oral and topical NSAIAs may result in higher incidence of hemorrhage and abnormal S_cr, urea, and hemoglobin concentrations³¹⁷ ³¹⁸ ³²⁴ ³²⁶ ³²⁷ Protein binding of NSAIAs reduced by aspirin, but clearance of unbound NSAIA not altered; clinical importance unknown³⁰² Aspirin: Decreased peak plasma concentration and AUC of diclofenac;²² ⁶¹ ¹⁸⁴ ²⁰² ³⁰² ³⁰³ limited data indicate that diclofenac does not inhibit antiplatelet effect of aspirin²⁶² No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs³⁰⁵ ³¹⁷ ³¹⁸ ⁵⁰² ⁵⁰⁸	Concomitant use of diclofenac with analgesic dosages of aspirin generally not recommended³⁰² Do not use topical diclofenac formulations with oral NSAIAs unless expected benefits outweigh risks; if used, periodic laboratory evaluations recommended³¹⁷ ³¹⁸ ³²⁴ ³²⁶ ³²⁷ Advise patients not to take low-dose aspirin without consulting clinician; closely monitor patients receiving concomitant antiplatelet agents (e.g., aspirin) for bleeding³⁰²
Pemetrexed	Possible increased risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity³⁰²	Short half-life NSAIAs (e. g., diclofenac, indomethacin): Avoid administration beginning 2 days before and continuing through 2 days after pemetrexed administration³⁰² Longer half-life NSAIAs (e.g., meloxicam, nabumetone): In the absence of data, avoid administration beginning at least 5 days before and continuing through 2 days after pemetrexed administration³⁰² Patients with Cl_cr 45–79 mL/minute: Monitor for myelosuppression, renal toxicity, and GI toxicity³⁰²
Quinolones (ciprofloxacin)	Possible increased risk of seizures¹⁸³ ¹⁹⁷ ¹⁹⁸
Serotonin-reuptake inhibitors (e.g., SSRIs, SNRIs)	Possible increased risk of bleeding due to importance of serotonin release by platelets in hemostasis³⁰²	Monitor for bleeding³⁰²
Voriconazole	Peak concentration and AUC of diclofenac increased by 114 and 78%, respectively³⁰²	Dosage adjustment may be required³⁰²

Diclofenac Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.¹ ³ ⁵¹ ⁵² ⁵³ ⁵⁷ ⁶⁸ ¹⁸⁹ ³⁰² ³⁰³ Undergoes first-pass metabolism; only 50–60% of a dose reaches systemic circulation as unchanged drug.¹ ⁵² ⁵³ ⁷³ ²⁸⁴ ³⁰² ³⁰³

Peak plasma concentration usually attained within about 15 minutes (diclofenac potassium oral solution), 0.47 hours (diclofenac potassium liquid-filled capsules), 1 hour (diclofenac potassium conventional tablets), 2 hours (diclofenac sodium delayed-release tablets), or 5.25 hours (diclofenac sodium extended-release tablets).¹ ³ ⁵¹ ⁵² ³⁰² ³⁰³ ³⁰⁷ ³²⁸ ³³¹

Absorbed into systemic circulation following topical administration as gel, solution, or transdermal system; plasma concentrations generally very low compared with oral administration.³ ²²⁷ ³¹⁷ ³¹⁸ ³²⁴ ³²⁶

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

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

Following topical application of diclofenac sodium 1% gel, peak plasma concentrations occur in about 10–14 hours.³¹⁸ Moderate exercise does not alter systemic absorption.³¹⁸ Application of a heat patch for 15 minutes before application of the 1% gel did not affect systemic absorption.³¹⁸ Not established whether application of heat following gel application affects systemic absorption.³¹⁸

Onset

Single 50- or 100-mg doses of diclofenac potassium provide pain relief within 30 minutes.³⁰⁷

Duration

Pain relief lasts up to 8 hours following administration of single 50- or 100-mg doses of diclofenac potassium.³⁰⁷

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

Widely distributed in animals.³ ⁵¹ ⁵²

Following oral administration, concentrations in synovial fluid may exceed those in plasma.¹ ³ ⁶² ⁶³ ⁶⁴ ⁶⁵ ⁶⁶ ⁶⁷ ⁶⁸ ⁶⁹ ³⁰² ³⁰³

Plasma Protein Binding

>99%.¹ ³ ⁵¹ ⁵² ⁵⁸ ⁵⁹ ⁶⁶ ³⁰² ³⁰³ ³¹⁷

Elimination

Metabolism

Metabolized in the liver via hydroxylation and conjugation.¹ ³ ⁵¹ ⁵² ⁶⁸ ⁷⁰ ³⁰² ³⁰³ Some metabolites may exhibit anti-inflammatory activity.¹ ³ ²² ³⁰² ³⁰³

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%) as metabolites.¹ ³ ⁵¹ ⁵⁵ ⁵⁶ ⁷⁰ ⁷¹ ³⁰² ³⁰³

Half-life

Oral preparations: 1–2 hours.² ⁵³ ⁵⁷ ⁶⁰ ³⁰² ³⁰³ ³²⁸ ³³¹

Diclofenac epolamine transdermal system: Approximately 12 hours.³¹⁷ ³²⁴

Special Populations

In geriatric patients, pharmacokinetic profile similar to that in younger adults.³⁰⁷

In patients with renal impairment, plasma clearance not substantially altered,¹ ³ ²⁰⁸ ³⁰² ³⁰³ although clearance of metabolites may be decreased.³ ⁷²

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; consult manufacturer's labeling for specific storage recommendation.¹ ³⁰² ³⁰³ Protect from moisture.³⁰² ³⁰³

Topical

Gel

25°C (may be exposed to 15–30°C).³¹⁸ ³²⁵ Do not freeze.³¹⁸ ³²⁵

Solution

Diclofenac sodium 1.5% topical solution: Upright position at 20–25°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 are stable for up to 6 months after envelope is opened if stored at room temperature in the resealed envelope.³²⁴

Actions

Inhibits cyclooxygenase-1 (COX-1) and COX-2.²⁸⁵ ²⁸⁶ ²⁸⁷ ²⁸⁸ ²⁸⁹ ²⁹⁰
Pharmacologic actions similar to those of other prototypical NSAIAs;¹ ³ ²⁰ ²¹ ²² ²³ ²⁴ ²⁵ ²⁶ ¹⁸⁹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ exhibits anti-inflammatory, analgesic, and antipyretic activity.¹ ³ ²¹ ²² ²³ ¹⁸⁹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
Risk of serious cardiovascular events (e.g., MI, stroke).¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁰ ⁵⁰⁸ Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (e.g., chest pain, dyspnea, weakness, slurred speech) occur.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ ⁵⁰⁰ ⁵⁰⁸
Risk of GI bleeding and ulceration.¹ ¹⁶⁷ ¹⁸¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding develop.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Inform patients receiving concomitant low-dose aspirin of the increased risk of GI bleeding.³⁰³
Risk of hepatotoxicity.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (e.g., nausea, anorexia, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
Risk of serious skin reactions,¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ DRESS,³⁰³ and anaphylactic and other sensitivity reactions.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ Advise patients to stop taking diclofenac immediately if they develop any type of rash or fever and to promptly contact their clinician.³⁰³ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.⁵⁰⁸
Importance of warning patients to keep diclofenac transdermal system out of the reach of children and pets and to safely dispose of used units.³¹⁷ ³²⁴
Importance of adhering to instructions for administration of topical diclofenac formulations (gel, solution, transdermal system).³¹⁷ ³¹⁸ ³²⁴ ³²⁶ ³²⁷
Importance of avoiding or limiting exposure of skin treated with diclofenac gel or solution to natural or artificial sunlight.³¹⁸ ³²⁶ ³²⁷
If topical formulations of diclofenac come into contact with the eye(s), importance of rinsing the affected eye(s) with water or saline and of consulting a clinician if irritation persists for >1 hour.³¹⁷ ³¹⁸ ³²⁴ ³²⁶ ³²⁷
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
Advise patients receiving diclofenac topical solution to promptly contact their clinician if any type of rash develops at the application site.³²⁶
When diclofenac topical gel is used for self-medication for temporary relief of arthritis pain, importance of reviewing the product labeling and of not exceeding the recommended dosage or duration of therapy.³²⁵ Advise patients that efficacy is not established for symptomatic relief of strains, sprains, bruises, or sports injuries.³²⁵
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
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸
Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.³⁰³ ¹²⁰⁰
Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.³⁰³
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ 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.³⁰³ Advise patients not to use concomitant low-dose aspirin without consulting their clinician.³⁰³ Alert patients to the presence of NSAIAs in many OTC preparations.³⁰³
Importance of informing patients of other important precautionary information.¹ ³⁰² ³⁰³ ³¹⁷ ³¹⁸ (See Cautions.)

Preparations

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

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

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

Diclofenac Epolamine
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Topical	Transdermal System	1.3%*	Diclofenac Epolamine Transdermal System
			Flector	Pfizer
			Licart	IBSA

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

Diclofenac Potassium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	25 mg	Zipsor	Depomed
	For oral solution	50 mg*	Cambia	Assertio
			Diclofenac Potassium for Oral Solution
	Tablets	50 mg*	Diclofenac Potassium Tablets

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

Diclofenac Sodium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, delayed-release (enteric-coated)	25 mg*	Diclofenac Sodium Delayed-release Tablets
		50 mg*	Diclofenac Sodium Delayed-release Tablets
		75 mg*	Diclofenac Sodium Delayed-release Tablets
	Tablets, extended-release	100 mg*	Diclofenac Sodium Extended-release Tablets
Topical	Gel	1%*	Diclofenac Sodium Gel
			Voltaren	Endo
			Voltaren Arthritis Pain	GlaxoSmithKline
	Solution	1.5%*	Diclofenac Sodium Topical Solution
		2%	Pennsaid	Horizon

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

Diclofenac Sodium Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, delayed-release (enteric-coated core), film-coated	50 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer*	Arthrotec	Pfizer
			Diclofenac Sodium and Misoprostol Delayed-release Tablets
		75 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer*	Arthrotec	Pfizer
			Diclofenac Sodium and Misoprostol Delayed-release Tablets

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

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102. Lundstam S, Ivarsson L, Lindblad L. Diclofenac compared with a narcotic analgesic in the treatment of biliary pain. Curr Ther Res. 1987; 42:395-99.

103. Stacher G, Steinringer H, Schneider S et al. Experimental pain induced by electrical and thermal stimulation of the skin in healthy man: sensitivity to 75 and 150 mg diclofenac sodium in comparison with 60 mg codeine and placebo. Br J Clin Pharmacol. 1986; 21:35-43. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1400805&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/3947505?dopt=AbstractPlus

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520. Health Canada. Summary safety review: Diclofenac - risk of major heart and stroke related adverse events. Ottawa, ON, Canada; 2014 Oct 14. From Health Canada website. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/diclofenac-eng.php

521. European Medicines Agency. New safety advice for diclofenac: new measures aim to minimise cardiovascular risks. London, UK; 2013 Sep 25. From European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Diclofenac-containing_medicinal_products/European_Commission_final_decision/WC500155819.pdf

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. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic

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

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Diclofenac (Monograph)

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Uses for Diclofenac

Inflammatory Diseases

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Migraine

Dysmenorrhea

Related/similar drugs

Diclofenac Dosage and Administration

General

Administration

Oral Administration

Oral Solution

Topical Administration

Diclofenac Sodium 1% Gel

Diclofenac Sodium 1.5 or 2% Topical Solution

Diclofenac Epolamine Transdermal System

Dosage

Adults

Inflammatory Diseases

Oral

Osteoarthritis

Rheumatoid Arthritis

Ankylosing Spondylitis

Pain

Oral

Topical (transdermal system)

Migraine

Oral

Dysmenorrhea

Oral

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis

Migraine

Oral

Special Populations

Renal Impairment

Hepatic Impairment

Cautions for Diclofenac

Contraindications

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

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Hepatic Effects

Hypertension

Heart Failure and Edema

Renal Effects

Hyperkalemia

Hypersensitivity Reactions

Dermatologic Reactions

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Precautions Specific to Diclofenac Sodium Topical Gel or Solution

Precautions Specific to Diclofenac Epolamine Transdermal System

Medication Overuse Headache

Use of Fixed Combinations

Concomitant NSAIA Therapy

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Specific Populations

Pregnancy

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Hepatic Impairment

Renal Impairment

Common Adverse Effects

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Drugs Affecting Hepatic Microsomal Enzymes

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Diclofenac Pharmacokinetics

Absorption

Bioavailability

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Duration