AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Diclofenac Potassium

• Diclofenac Sodium

• Diclofenac Epolamine

Diclofenac is a prototypical nonsteroidal anti-inflammatory agent (NSAIA)1,2,3,4,5,6,7,8,9,189,302,303,317,318 that also exhibits analgesic and antipyretic activity.1,3,21,22,23,189,302,303,317,318

Inflammatory Diseases

Diclofenac sodium and diclofenac potassium are used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis,1,74,75,76,77,78,79,80,87,88,107,115,116,117,118,119,121,125,126,129,254,262,302,303 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 ankylosing spondylitis, and other inflammatory conditions.1,91,120,121,125,127,274

Diclofenac sodium in fixed combination with misoprostol is used orally for anti-inflammatory activity and analgesic effects in the symptomatic treatment of rheumatoid arthritis and osteoarthritis in patients at high risk of developing NSAIA-induced gastric or duodenal ulcers and in patients at high risk of developing complications from these ulcers.284

Diclofenac sodium 1% gel and diclofenac sodium 1.5 or 2% topical solution are used topically for the symptomatic treatment of osteoarthritis-related joint pain.318,321,325,326,327 The gel is used for joints amenable to topical therapy (e.g., hands, wrists, elbows, knees, ankles, feet); the gel has not been evaluated for use on joints of the spine, hip, or shoulder.318,325 The topical solution is used for symptoms (e.g., pain) affecting the knees.326,327

The potential benefits and risks of diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.1,302,303 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1,302,303

Rheumatoid Arthritis and Osteoarthritis

When used in the symptomatic treatment of rheumatoid arthritis,74,75,76,77,78,79,87,88,116,117,118,119,121,126,129 oral diclofenac has relieved pain and stiffness;74,75,76,77,78,79,87,88,115,116,117,118,121,126,129 reduced swelling,75,79,117,119,121,126 tenderness,75,117,118,119,126 and the number of joints involved;75,76,77,79,117,126,129 and improved mobility74,75,76,78,87,116,121,126 and grip strength.74,75,76,116,117,126,129 In the symptomatic treatment of osteoarthritis, diclofenac has relieved pain and stiffness,81,82,84,85,86,89,108,109,111,112,113,114,121,126,133 improved knee joint function,81,82,89,109,113,126 and increased range of motion81,82,86,89,90,114,121,126,133 and functional activity.82,84,90,109,126 Diclofenac appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process.19,76,247,248

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual oral dosages of diclofenac sodium in the management of rheumatoid arthritis79,87,88,115,116,117,118,119,126,129,133 or osteoarthritis81,82,83,84,85,89,108,109,126 are greater than those of placebo79,81,83,84,85,87,108,109,110,111,117,118,126 and about equal to those of usual dosages of salicylates,75,78,79,80,81,82,114,126,274 diflunisal,82,115 ibuprofen,79,80,82,90,126 indomethacin,77,78,80,82,116,118,125,129 ketoprofen,74,133 mefenamic acid,113 naproxen,76,80,81,82,83,86,87,88,89,110,111,115,119,126,274 phenylbutazone (no longer commercially available in the US),80 piroxicam,108,109 or sulindac.82,86 In controlled clinical studies of 3 months' duration in patients with rheumatoid arthritis or osteoarthritis, diclofenac sodium dosages of 100-200 mg daily, given as delayed-release (enteric-coated) tablets, were as effective as 2.4-4.8 g of aspirin daily, 500 mg of naproxen daily, or 2.4 g of ibuprofen daily.262 Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent.12,19,83,87,249 However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.141,144,145,146,147,226 (See Contraindications under Cautions.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.249,254 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) have the potential to reduce or prevent joint damage and to preserve joint integrity and function.249,254,322 DMARD therapy should be initiated early in the disease course to prevent irreversible joint damage.249,254 (For further information on the treatment of rheumatoid arthritis, including considerations in selecting a DMARD regimen, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)

Medical management of osteoarthritis of the hip, knee, and/or hand includes both pharmacologic therapy and nonpharmacologic (e.g., educational, behavioral, psychosocial, physical) interventions to reduce pain, maintain and/or improve joint mobility, limit functional impairment, and enhance overall well-being.330 The American College of Rheumatology (ACR) strongly recommends exercise, weight loss when necessary in patients with osteoarthritis of the knee and/or hip, self-efficacy and self-management programs, tai chi, cane use, hand orthoses, knee bracing, topical NSAIAs for osteoarthritis of the knee, oral NSAIAs, and intra-articular glucocorticoid injections for osteoarthritis of the knee or hip.330 Other pharmacologic or nonpharmacologic interventions may be recommended conditionally.330 Interventions and the order of their selection are patient specific.330 Factors to consider when making decisions regarding therapy for osteoarthritis include patients' values and preferences, the presence of 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 Pharmacologic therapy should be initiated with treatments resulting in the least systemic exposure or toxicity.330 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice for pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.330

When used for the symptomatic treatment of osteoarthritis of the hand or knee, diclofenac sodium 1% gel has been more effective than vehicle (placebo) in relieving pain; however, results of clinical trials evaluating the formulation suggest that its analgesic effects may be modest.318,321

When used for the symptomatic treatment of osteoarthritis of the knee, diclofenac sodium 1.5% topical solution (formulated with dimethyl sulfoxide [DMSO] 45.5%) has been more effective than placebo (containing DMSO 2.3%) and/or vehicle (containing DMSO 45.5%) in relieving pain, improving physical function, and resulting in clinical improvement as measured by a patient global or overall health assessment tool.326 When used for the symptomatic treatment of pain associated with osteoarthritis of the knee, diclofenac sodium 2% topical solution has been more effective than vehicle (placebo) in relieving pain.327

Ankylosing Spondylitis

In the symptomatic treatment of ankylosing spondylitis, oral diclofenac appears to provide relief of spinal pain,120,127 tenderness and/or spasm,91,127 morning stiffness,120,121,127 and pain at rest (including night pain)91,121,127 and to improve motion,120,121 posture,120 chest expansion,91,120,127 and spinal mobility.91,127 The anti-inflammatory and analgesic effects of usual dosages of diclofenac in the management of ankylosing spondylitis are about equal to those of usual dosages of indomethacin91,127 or sulindac.120 In a controlled clinical study in patients with ankylosing spondylitis, diclofenac sodium dosages of 75-125 mg daily, given as delayed-release (enteric-coated) tablets, were as effective as indomethacin 75-125 mg daily.1

Juvenile Arthritis

Diclofenac has been used orally with good results in a number of children for the management of juvenile rheumatoid arthritis†.3,128,210 Results of these studies suggest that usual dosages of the drug are more effective than placebo128 and at least as effective as usual dosages of salicylates,128 naproxen,210 or tolmetin210 in decreasing the number of painful, swollen, and tender joints.128,210 Further studies are needed to evaluate the efficacy and safety of diclofenac in the management of juvenile rheumatoid arthritis. (See Pediatric Precautions under Cautions.)

Other Inflammatory Conditions

Oral diclofenac has been effective in a limited number of patients for the symptomatic relief of acute gouty arthritis†.121,130,131,132 The drug does not appear to correct hyperuricemia3,31 but has been used instead for its anti-inflammatory and analgesic effects to relieve pain, joint tenderness, and swelling associated with this condition.121,130,131,132

Oral diclofenac also has been used for the symptomatic treatment of acute painful shoulder† (bursitis and/or tendinitis),13,134,136,154,222 sciatic pain†,3,131,132 backache†,3,131,132 myositis†,3 and radiohumeral bursitis† (radiohumeral epicondylitis, tennis elbow).135 The drug has been injected locally† (a parenteral dosage form currently is not commercially available in the US) for the relief of myofascial pain† in a limited number of patients with fibrositis, but additional study is necessary.150

Oral or topical diclofenac has been used for the symptomatic treatment of infusion-related superficial thrombophlebitis†.310 In a controlled clinical trial in a limited number of patients, symptoms of thrombophlebitis improved in 60% of patients receiving diclofenac either orally (75 mg every 12 hours) or topically (as a gel applied to affected area every 8 hours) for 48 hours compared with 20% of those receiving placebo.310,311

Pain

Diclofenac potassium is used orally for symptomatic relief of mild to moderate acute pain, postoperative pain (including that associated with orthopedic, gynecologic, and oral surgery), and orthopedic pain (including musculoskeletal sprains and traumatic joint distortions).276,277,278,279,303,331 Diclofenac epolamine transdermal system is used for symptomatic relief of acute pain due to minor strains, sprains, and contusions.317,319,324

The potential benefits and risks of diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.1,302,303,317 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1,302,303,317

In patients with dental extraction or gynecologic surgery pain, single oral 50- and 100-mg doses of diclofenac potassium have been reported to be as effective as single 650-mg doses of aspirin; the duration of diclofenac potassium's analgesic effect appears to be longer than that of aspirin.307 When used to relieve postoperative orthopedic surgery pain, 50- or 100-mg doses of diclofenac potassium followed by 50 mg every 8 hours were as effective as 550 mg of naproxen sodium followed by 275 mg every 8 hours.307 When used to relieve orthopedic pain, 150 mg of diclofenac potassium daily was more effective than placebo and at least as effective as 1.2 g of ibuprofen daily or 20 mg of piroxicam daily.277,278,279

In patients with pain following bunionectomy with osteotomy, therapy with diclofenac potassium liquid-filled capsules (25 mg every 6 hours for 4 days; the initial 25-mg dose could be repeated upon patient request) was more effective than placebo in reducing pain intensity over 48 hours of inpatient treatment.331,333,334 The median time to onset of pain relief was less than 1 hour in patients receiving the liquid-filled capsules.331

Diclofenac sodium also has been used orally for symptomatic relief of postoperative92 (including that associated with dental surgery),92,93,94 postpartum,92 and orthopedic (including musculoskeletal strains or sprains) pain†,92,95,96,97 and visceral pain associated with cancer†.122,211 Because of the relatively slow onset of action of delayed-release (enteric-coated) or extended-release tablets of diclofenac sodium,53,54,56,57,60,61 other more rapid-acting NSAIAs (e.g., diclofenac potassium) may be preferred when prompt relief of acute pain is required.1,3,248 Diclofenac also has been used parenterally† (a parenteral dosage form is currently not commercially available in the US) for the relief of acute biliary99,102,123,206,221 or renal colic†,92,98,100,101,124 and for relief of postoperative pain† (including that associated with gynecologic and orthopedic surgery).151,152,153

When used to relieve mild to moderate acute pain†, single oral diclofenac sodium doses of 50-150 mg have been more effective than placebo92,94 and at least as effective as usual analgesic doses of other NSAIAs95 or mild opiate analgesics.98,103 Diclofenac sodium dosages of 75-150 mg daily have been as effective as aspirin dosages of 0.9-2.7 g daily92 or ibuprofen dosages of 1.2 g daily.92 In patients with oral surgery pain†, 50-mg doses of diclofenac sodium have been reported to be as effective as 100-mg doses of pentazocine.92

Efficacy of diclofenac epolamine transdermal system (Flector^®) for the management of pain in patients with minor strains, sprains, and contusions has been demonstrated in 2 of 4 clinical studies.317,319 In one of these studies, diclofenac epolamine transdermal system (applied twice daily for 2 weeks) was more effective than a placebo transdermal system in relieving pain due to an acute minor sports injury.317,319,320 In a 7-day clinical study in patients with ankle sprain and a 14-day study in patients with muscle contusion, diclofenac epolamine transdermal system (Licart^®, applied once daily) was more effective that placebo in reducing pain upon movement on day 3 of treatment.324

Migraine

Diclofenac potassium is used as an oral solution for the acute treatment of attacks of migraine with or without aura; diclofenac should not be used for the prophylaxis of migraine.328,329 Safety and efficacy have not been established for the treatment of cluster headache, which occurs in an older, predominantly male population.328

In 2 randomized, double-blind, placebo-controlled trials, efficacy of diclofenac potassium (50-mg dose given as an oral solution) for the acute treatment of migraine attacks was evaluated in a total of 1212 adults (85% female, 86% White, mean age of 40 years) experiencing a migraine attack causing moderate to severe pain.328,329 Greater proportions of patients receiving diclofenac compared with those receiving placebo reported freedom from headache pain at 2 hours after the dose (24-25 versus 10-13%) and reported sustained freedom from headache pain from 2-24 hours after the dose (19-22 versus 7-10%).328,329 The incidence of associated symptoms (i.e., nausea, photophobia, phonophobia) also was reduced in patients receiving diclofenac compared with those receiving placebo.328,329

Dysmenorrhea

Diclofenac potassium is used orally in the management of primary dysmenorrhea.303 In patients with primary dysmenorrhea, NSAIAs may relieve pain and reduce the frequency and severity of uterine contractions, possibly as a result of inhibition of prostaglandin synthesis.105,140,275

The potential benefits and risks of diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.1,302,303 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1,302,303

When used to relieve primary dysmenorrhea, 50- or 100-mg doses of diclofenac potassium followed by 50 mg every 8 hours were as effective as 550 mg of naproxen sodium followed by 275 mg every 8 hours.307

Diclofenac sodium as delayed-release (enteric-coated) tablets also has been used for the symptomatic relief of dysmenorrhea†.92,104,105,140 When used to relieve dysmenorrhea, diclofenac sodium (delayed-release [enteric-coated]) dosages of 50-150 mg daily were more effective than placebo92,105,140 and as effective as naproxen dosages of 250-1250 mg daily.92,104

Other Uses

Oral diclofenac sodium has been used for its antipyretic effect in the management of fever†, usually associated with infection.137,138,139 In one study, the antipyretic effect of usual dosages of diclofenac sodium as delayed-release (enteric-coated) tablets was about equal to that of usual dosages of aspirin.138 The drug, however, should not be used routinely as an antipyretic because of its potential adverse effects.186,247

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease† among patients who received an NSAIA for 2 years or longer.294,295 Similar findings have been reported from some other, but not all, observational studies.294,295,296,297,298,299

Diclofenac sodium also is used topically as an ophthalmic solution for the treatment of postoperative ocular inflammation in patients undergoing cataract extraction.264

For use of diclofenac sodium in the topical treatment of actinic keratoses, see Diclofenac Sodium 84:06.20.

Administration

The potential benefits and risks of diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.1,302,303,317

Diclofenac sodium, diclofenac sodium in fixed combination with misoprostol, and diclofenac potassium are administered orally.1,67,68,74,76,81,82,83,86,87,89,284,302,303 Diclofenac sodium also is administered topically as a solution or gel.318,325,326,327 The drug also has been administered rectally†51,52,137,139,240 and parenterally† (by IM injection),99,102,123,206,221 but commercially available dosage forms for the rectal and parenteral routes of administration currently are not available in the US. Diclofenac epolamine is administered topically as a transdermal system.317,324

Oral Administration

When diclofenac potassium powder for oral solution is used, the contents of one packet containing 50 mg of buffered diclofenac potassium for oral solution should be emptied into a cup containing 30-60 mL of water, mixed well, and swallowed immediately.328 Liquids other than water should not be used.328 Administration of the oral solution with food may decrease peak plasma concentrations of the drug and result in reduced efficacy compared with administration on an empty stomach.328

Topical Administration

Diclofenac sodium is administered topically as a 1% gel or as a 1.5 or 2% solution,318,325,326,327 and diclofenac epolamine is administered topically as a transdermal system.317,324

Patients receiving diclofenac sodium 1% topical gel should be instructed in the use of the gel and given a copy of the patient instructions provided by the manufacturer.318 Diclofenac sodium 1% gel should be applied 4 times daily to the affected joint(s).318,325 To measure the appropriate dose using the dosing card provided by the manufacturer, gel is applied within the oblong area of the dosing card up to the appropriate line (i.e., 2.25- or 4.5-inch line, corresponding to 2 or 4 g of gel, respectively); the dosing card can be used to apply the gel.318,325 The gel should be massaged gently into the skin, ensuring application to the entire joint (e.g., foot [including sole, top of foot, and toes], knee, ankle, hand [including palm, back of hand, and fingers], elbow, wrist).318 The patient should be advised to wait 10 minutes before covering the treated area with clothing and at least 60 minutes before bathing or showering.318 Hands should be washed after application of the gel unless the treated joint is in the hand.318 Diclofenac sodium gel should not be applied to open wounds or areas of skin afflicted with cuts, infections, or rashes; contact with eyes and mucous membranes should be avoided.318,325 The treated joint should not be exposed to external heat or to natural or artificial sunlight; use of occlusive dressings has not been evaluated and should be avoided.318,325 Other topical preparations (e.g., sunscreens, cosmetics, lotions, moisturizers, insect repellents, other topical medications) should not be applied to the treated joint; such use has not been evaluated.318,325

Diclofenac sodium 1.5% topical solution is administered as drops dispensed directly onto the affected knee(s) or into the palm of the hand and then applied to the affected knee(s).326 To avoid spillage, the drops should be applied in 4 increments of 10 drops each per joint; following each incremental application, the topical solution should be spread evenly around the front, back, and sides of the knee.326 Diclofenac sodium 2% topical solution is administered via pump dispenser (2 pump actuations per affected joint) into the palm of the hand and then the entire volume of solution is applied evenly around the front, back, and sides of the knee.327 The pump must be primed before first use by fully depressing the pump mechanism 4 times while holding the bottle in an upright position.327 Patients receiving therapy with diclofenac sodium 1.5 or 2% topical solution should be advised to wait until the treated area is dry before covering the area with clothing and to wait at least 30 minutes before bathing or showering.326,327 Hands should be washed after application of the topical solution.326,327 In addition, other individuals should avoid skin-to-skin contact with the treated area until the area is completely dry.326,327 Diclofenac sodium topical solution should not be applied to open wounds, infected or inflamed areas of skin, or areas affected with exfoliative dermatitis; contact with eyes and mucous membranes should be avoided.326,327 The treated knee should not be exposed to external heat, and exposure to natural or artificial sunlight should be avoided; use of occlusive dressings also should be avoided.326,327 The treated knee should be allowed to dry completely before other topical preparations (e.g., sunscreen, insect repellant, lotions, moisturizers, cosmetics, other topical medications) are applied to the same area.326,327

Diclofenac epolamine is administered by topical application of a transdermal system.317,324 Patients receiving diclofenac epolamine transdermal system should be instructed in the use of the system.317,324 The manufacturer states that the transdermal system should be applied to the most painful area once daily (Licart^®) or twice daily (Flector^®).317,324 The system should be applied to intact skin only; application to damaged skin (e.g., wounds, burns, infected areas of skin, areas affected with eczema or exudative dermatitis) should be avoided.317,324 Hands should be washed after handling the system.317,324 Contact with the eyes and mucous membranes should be avoided.317,324 The transdermal system should not be worn 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 In one study in which diclofenac epolamine transdermal system (Licart^®) was applied to the lower leg above the ankle, evaluations performed every 4 hours during the 24-hour application period indicated 90% or greater adhesion at each evaluation.324

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1,302,303,317,318 Dosage of diclofenac must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.1,302,303

Based on safety reviews conducted to evaluate available data on cardiovascular risk of diclofenac, some authorities (e.g., Health Canada) recommend that the dosage of systemically administered diclofenac not exceed 100 mg daily (except on the first day of treatment for dysmenorrhea when a total dose of 200 mg may be administered).520 (See Cardiovascular 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 conventional tablets are not necessarily bioequivalent on a mg per mg basis.1,302,303 In addition, 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

Inflammatory Diseases

Based on safety reviews conducted to evaluate cardiovascular risk of diclofenac, some authorities (e.g., Health Canada) recommend that systemic diclofenac dosage for inflammatory diseases not exceed 100 mg daily.520 (See Cardiovascular Effects under Cautions.)

Rheumatoid Arthritis and Osteoarthritis

For the symptomatic treatment of acute or chronic rheumatoid arthritis, the usual initial adult dosage of diclofenac sodium delayed-release (enteric-coated) tablets or diclofenac potassium conventional tablets is 150-200 mg daily, administered in divided doses of 75 mg (diclofenac sodium delayed-release [enteric-coated] tablets only) twice daily or 50 mg (diclofenac sodium delayed-release [enteric-coated] tablets or diclofenac potassium conventional tablets) 3 or 4 times daily.1,74,76,79,87,115,117,119,125,126,303 For the management of rheumatoid arthritis, the usual initial adult dosage of diclofenac sodium extended-release tablets is 100 mg daily.302 If dosage increase is necessary in patients receiving diclofenac sodium 100 mg daily as extended-release tablets, dosage can be increased to 100 mg twice daily.302

When diclofenac is used in fixed combination with misoprostol for the symptomatic treatment of chronic rheumatoid arthritis, the usual dosage is 50 mg of diclofenac sodium 3 or 4 times daily.284 Dosage may be changed to 50 or 75 mg of diclofenac sodium twice daily in patients who do not tolerate the usual dosa however, these dosages may be less effective in preventing NSAIA-induced ulcers.284 When therapy with diclofenac and misoprostol is required for the treatment of chronic rheumatoid arthritis, the commercially available combination of diclofenac in fixed combination with misoprostol should not be used for initial therapy.284 Instead, dosage should first be adjusted by administering each drug separately.284 If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used.284 If clinically indicated, supplemental doses of misoprostol or diclofenac as the individual component can be administered with the fixed combination.284

For the symptomatic treatment of osteoarthritis, the usual adult dosage of diclofenac sodium delayed-release (enteric-coated) tablets or diclofenac potassium conventional tablets is 100-150 mg daily, administered in divided doses of 75 mg (diclofenac sodium delayed-release [enteric-coated] tablets only) twice daily or 50 mg (diclofenac sodium delayed-release [enteric-coated] tablets or diclofenac potassium conventional tablets) 2 or 3 times daily.1,81,82,83,84,86,89,90,108,111,112,114,126,303 For the management of osteoarthritis, the recommended adult dosage of diclofenac sodium extended-release tablets is 100 mg daily.302

When diclofenac is used in fixed combination with misoprostol for the symptomatic treatment of osteoarthritis, the usual dosage is 50 mg of diclofenac sodium 3 times daily.284 Dosage may be changed to 50 or 75 mg of diclofenac sodium twice daily in patients who do not tolerate the usual dosa however, these dosages may be less effective in preventing NSAIA-induced ulcers.284 When therapy with diclofenac and misoprostol is required for the treatment of osteoarthritis, the commercially available combination of diclofenac in fixed combination with misoprostol should not be used for initial therapy.284 Instead, dosage should first be adjusted by administering each drug separately.284 If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used.284 If clinically indicated, supplemental doses of misoprostol or diclofenac as the individual component can be administered with the fixed combination.284

When diclofenac sodium 1% gel is used for the management of lower extremity (i.e., knees, ankles, feet) joint pain due to osteoarthritis, 4 g of gel is massaged into the affected joint 4 times daily.318,325 When the gel is used for the management of upper extremity (i.e., elbows, wrists, hands) joint pain, 2 g of gel is massaged into the affected joint 4 times daily.318,325 The total daily dose applied to all affected joints should not exceed 32 g of gel, with no more than 16 g of gel applied daily to any single lower extremity joint and no more than 8 g of gel applied daily to any single upper extremity joint.318 When diclofenac sodium 1% gel is used for self-medication for the temporary relief of arthritis pain, no more than 2 body areas should be treated at the same time, with no more than 16 g of gel applied daily to any single lower extremity (i.e., knees, ankles, feet) joint and no more than 8 g of gel applied daily to any single upper extremity (i.e., elbows, wrists, hands) joint.325 For self-medication , diclofenac sodium 1% gel may be used for up to 21 days unless otherwise directed by a clinician, and should be discontinued if no pain relief is obtained in 7 days.325

When diclofenac sodium 1.5% topical solution is used for the symptomatic treatment of osteoarthritis of the knee, the recommended dosage is 40 drops (approximately 1.2 mL of a 16.05-mg/mL solution) applied to each affected knee 4 times daily.326 When diclofenac sodium 2% topical solution is used for the management of knee pain due to osteoarthritis, the recommended dosage is 40 mg of diclofenac sodium (2 pump actuations) applied to each affected knee twice daily.327

Ankylosing Spondylitis

For the symptomatic treatment of ankylosing spondylitis, the usual adult dosage of diclofenac sodium delayed-release (enteric-coated) tablets is 100-125 mg daily, administered in divided doses of 25 mg 4 or 5 times daily.1,91,125 When diclofenac potassium is used for the management of ankylosing spondylitis, a dosage of 50 mg twice daily has been suggested by the manufacturers.274

Pain and Dysmenorrhea

When diclofenac potassium conventional tablets are used for relief of pain or primary dysmenorrhea, an initial dose of 50 mg is recommended, followed by 50 mg every 8 hours as needed; some patients may benefit from an initial dose of 100 mg, followed by 50 mg every 8 hours as needed.303 Based on safety reviews conducted to evaluate available data on cardiovascular risk of diclofenac, some authorities (e.g., Health Canada) now recommend that the dosage of systemically administered diclofenac not exceed 100 mg daily (except on the first day of treatment for dysmenorrhea when a total dose of 200 mg may be administered).520 (See Cardiovascular Effects under Cautions.)

When diclofenac potassium liquid-filled capsules are used for relief of mild to moderate acute pain, the recommended dosage is 25 mg 4 times daily.331

When diclofenac epolamine transdermal system is used for relief of acute pain due to strains, sprains, and contusions, the manufacturers state that one system should be applied to the most painful area once daily (Licart^®) or twice daily (Flector^®).317,324

Migraine

For the acute treatment of migraine with or without aura, the usual adult dosage of diclofenac potassium is a single 50-mg dose (contents of one packet containing diclofenac potassium for oral solution mixed with water).328 The safety and efficacy of administering a second dose have not been established.328

Dosage in Renal or Hepatic Impairment

Diclofenac dosage reductions do not appear to be necessary in patients with renal impairment.1,3,72,247,248,302,303 However, use of diclofenac should be avoided in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function.302,303,317,318 If diclofenac is used, such patients should be monitored for signs of worsening renal function.302,303,317,318 (See Renal, Electrolyte, and Genitourinary Effects under Cautions.)

Reduction of oral diclofenac dosage may be necessary in patients with hepatic impairment.1,302,303,331 The manufacturer of diclofenac potassium liquid-filled capsules states that treatment should be initiated at the lowest dosage in such patients; if efficacy is not achieved at that dosage, diclofenac should be discontinued and alternative treatment considered.331

Adverse reactions to oral diclofenac are usually mild and transient and mainly involve the upper GI tract;3,22,74,75,76,77,78,79,80,81,82,83,84,85,86,88,90,91,125,127,133,156,158 however, adverse effects may be severe enough to require discontinuance of the drug in about 1.5-2% of patients.75,81,86,87,90,91,116,127,134,135,223,256 Most diclofenac-induced adverse effects occur during the first 3-6 months of treatment.3,125 The relationship of the frequency of adverse effects to dosage remains to be established.3,79,125 Overall, the frequency and nature of adverse effects produced by diclofenac sodium delayed-release (enteric-coated) tablets, diclofenac potassium conventional tablets, and ibuprofen appear to be similar.303 When diclofenac potassium was administered short-term (2 weeks or less), the incidence of adverse effects was about 10-50% of that associated with long-term administration of the drug.303

Cardiovascular Effects

Fluid retention manifested principally as edema has occurred in up to 10% of patients receiving oral diclofenac.1,109,125,132,159,165,302,303 Edema also has been reported in 3% of patients receiving diclofenac sodium topical solution.326,327 Adverse cardiovascular effects reported occasionally in diclofenac-treated patients include congestive heart failure, hypertension,1,302,303 tachycardia,1,302,303 and syncope.1,302,303 Arrhythmia,1,302,303 myocardial infarction,1,302,303 chest pain,89 palpitations,1,89,165,302,303 vasculitis,1,302,303 thrombophlebitis,125 hypotension, 1,98,99,101,186,302,303 angina-like attack,165 and circulatory shock186 or distress125 have occurred rarely.

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500,502,508 Use of NSAIAs also is associated with an increased risk of heart failure.500,508

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.305,316,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500,502,505,506,508 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500,502,506 508 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505,508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500,508,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508,511

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.312,313,314,316,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Findings from some of these meta-analyses and systematic reviews also suggest that the cardiovascular risk associated with diclofenac, particularly at higher dosages (e.g., 150 mg or more daily), is similar to that observed with selective COX-2 inhibitors.312,313,501,503,506,520,521 (See Experience with Prototypical NSAIAs under Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.) Some authorities (e.g., Health Canada) now recommend that the dosage of systemically administered diclofenac not exceed 100 mg daily (except for the first day of treatment for dysmenorrhea).520 (See Dosage and Administration: Dosage.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.507,508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500,504,508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,302,303,305,317,318,502,508

GI Effects

Adverse GI effects, which mainly involve the upper GI tract,1,30,74,75,76,77,78,79,80,81,82,83,86,87,88,91,112,115,116,125,127,136,302,303 occur in up to 10% of patients receiving oral diclofenac.1,302,303 Adverse GI effects require discontinuance of the drug in about 3% of patients.81,86,87,91,110,119,125,127,134,256,307 Peptic ulcer, GI bleeding, and/or perforation have been reported in up to 10% of patients receiving oral diclofenac in controlled clinical studies.1,79,86,91,125,132,155,158,302,303 There is some evidence that the incidence of diclofenac-induced peptic ulcers and gastric lesions may be reduced with concomitant use of an appropriate ulcer preventive regimen.218,249,250 Nausea,1,76,78,84,85,93,95,96,97,98,99,109,111,113,126,129,134,165,302,303 diarrhea,1,84,86,87,93,95,125,134,302,303 constipation,1,75,113,132,134,136,302,303 abdominal pain or cramps,1,75,86,93,107,113,136,302,303 flatulence,1,86,113,125,302,303 vomiting,1,93,99,109,125,132,134,165,302,303 and dyspepsia1,78,88,90,96,107,109,110,112,118,119,127,132,136,158,302,303 occur in up to 10% of patients receiving oral diclofenac.1,302,303 Esophagitis,1,302,303 gastritis,1,302,303 glossitis,1,302,303 stomatitis,1,302,303 aphthous stomatitis,165 changes in appetite,1,111,165,302,303 dry mouth and mucous membranes,1,302,303 pancreatitis (with or without hepatitis),1,260,262,302,303 thirst,86 colitis,1,302,303 ulceration of the colon,256,257 and distress77,82,84,85,86,125,127,136,158 have occurred during diclofenac therapy. The incidence of abdominal pain, diarrhea, and other GI symptoms may be higher in patients receiving diclofenac in fixed combination with misoprostol than in patients receiving diclofenac without misoprostol.284 Dyspepsia, abdominal pain, flatulence, diarrhea, nausea, and constipation have occurred in 3-8% of patients receiving diclofenac sodium topical solution.326,327 Nausea,317 altered taste,317 dyspepsia,317 or other adverse GI effects (including gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth)317 have occurred in 1-3% of patients receiving diclofenac epolamine transdermal system (Flector^®). Nausea has been reported in 3% of patients receiving diclofenac potassium oral solution for acute treatment of migraine attacks compared with 2% of those receiving placebo.328

Usual oral dosages of diclofenac sodium reportedly produce fewer adverse GI effects than usual anti-inflammatory dosages of aspirin or naproxen.3,22,75,79,80,82,114,155,157,158 In healthy individuals, GI bleeding as determined by fecal blood loss was less in individuals receiving 150 mg of diclofenac sodium daily than in those receiving 3000, 750, or 150 mg of aspirin, naproxen, or indomethacin daily, respectively, for 3 weeks.80,155,307 In healthy adults, the frequency of GI mucosal lesions observed with endoscopic examination was lower with diclofenac than with naproxen.38,155,307 However, the clinical importance of these findings is not known since currently there is no evidence to indicate that diclofenac is less likely to produce serious GI lesions during chronic therapy than other prototypical NSAIAs.307

Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.1,167,181,187,256,259,267,268,282,302,303,317,318 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1,302,303,317,318 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.1,167,181,256,302,303,317,318 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.302 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.1,167,181,302,303,317,318 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.1,302,303,317,318

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.167,181,292 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.1,302,303,317,318 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.1,302,303,317,318 However, short-term therapy is not without risk.1,302,303,317,318 High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.167,181,267 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.1,167,181,302,303

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold increased risk of developing GI bleeding than patients without these risk factors.260,292,302,317,318 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies 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 a and poor general health status.260,292,300,302 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.302 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.249,260,292 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.1,167,181,259,302,303,317,318

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.249,254,284,292,293 (See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.249,254,292 In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.292 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.292 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.249,292 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than prototypical NSAIAs.249 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.301,309 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.301,309

Nervous System Effects

Headache1,89,90,91,93,95,107,110,113,118,125,127,129,132,165,302,303 or dizziness1,102,107,113,125,129,165,302,303 has been reported in up to 10% of patients receiving oral diclofenac.1,302,303 Anxiety,1,302,303 asthenia,1,76,93,302,303 confusion,1,302,303 depression,1,302,303 abnormal dreams,1,302,303 drowsiness,1,98,302,303 insomnia,1,113,132,302,303 malaise,1,302,303 nervousness,1,302,303 paresthesia,1,165,302,303 somnolence,1,76,111,132,165,302,303 tremors,1,302,303 irritability,97,132 and vertigo1,78,96,118,132,302,303 have occurred occasionally in patients receiving the drug.1,302,303 Tingling sensation,86 dreams,86 myoclonus,220 and migraine125 have occurred rarely. Headache,317 paresthesia,317 somnolence,317 or other adverse nervous system effects (including hypoesthesia, dizziness, and hyperkinesias)317 have occurred in 1% of patients receiving diclofenac epolamine transdermal system (Flector^®).317 Paresthesia also has occurred in 2% of patients receiving diclofenac sodium topical solution.326,327 Dizziness has been reported in 1% of patients receiving diclofenac potassium oral solution for acute treatment of migraine attacks compared with 0.5% of those receiving placebo.328 Although a causal relationship to diclofenac has not been established, seizures,1,302,303 coma,1,302,303 hallucinations, 1,302,303 and meningitis1,302,303 have been reported during therapy with the drug.

Renal, Electrolyte, and Genitourinary Effects

Diclofenac has caused impairment of renal function, resulting in acute renal failure,160,162,185,212 interstitial nephritis,1,159,185,212,302,303 nephrotic syndrome,160,215 increased BUN32,159 and serum creatinine concentrations,84,159 and renal papillary necrosis1,162,302,303 in patients receiving the drug.1,302,303 In at least one patient receiving oral diclofenac, acute renal failure became chronic.160 Cystitis,1,302,303 dysuria,1,302,303 hematuria,1,302,303 oliguria/polyuria,1,165,186,302,303 and proteinuria1,159,302,303 have been reported occasionally in patients receiving diclofenac.1,302,303 Urinary tract infection,125 renal calculi,125 and hyponatremia161 have occurred rarely. Hyperkalemia also has been reported in patients receiving NSAIAs, including in individuals without renal impairment; in those with normal renal function, this effect has been attributed to a hyporenin-hypoaldosterone state.302

Hepatic Effects

Severe hepatic reactions (sometimes fatal or requiring liver transplantation), including jaundice1,163,165,223,255,302,303,317,318,323 and fulminant hepatitis,1,164,214,255,302,303,317,318,323 liver necrosis,1,255,302,303,317,318,323 cholestasis,255 hepatic failure,1,302,303,317,318,323 asymptomatic hepatitis,79 acute hepatitis,163,255 and chronic active hepatitis,253 have been reported rarely in patients receiving diclofenac.155,255,302,317,318 Meaningful (more than 3 times the upper limit of normal) elevations of serum AST concentration have occurred in approximately 2% of patients at some time during therapy with diclofenac.1,79,302,303,317,318,323 Increased serum concentrations of bilirubin have been reported rarely in patients receiving diclofenac therapy.255

In one large, open-label, controlled study, meaningful or marked (more than 8 times the upper limit of normal) elevations of serum AST and/or ALT concentrations occurred in 4 or 1% of patients, respectively, receiving diclofenac for 2-6 months.1,79,155,302,303,318,323,317 In that open-label study, borderline, moderate, and marked elevations of ALT or AST were observed more frequently with diclofenac than with other NSAIAs.302 In addition, aminotransferase elevations were observed more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.302 Almost all meaningful elevations of aminotransferase concentrations were detected before patients became symptomatic.302 During clinical trials, test results were abnormal during the first 2 months of diclofenac therapy in 82% of patients who developed marked aminotransferase elevations.302 During postmarketing experience, cases of drug-induced hepatotoxicity have been reported during the first month of diclofenac therapy and, in some cases, during the first 2 months of therapy, but can occur at any time during treatment with the drug.302

In a retrospective population-based, case-control study of drug-induced liver injury, which included 10 cases of diclofenac-associated liver injury, current use of diclofenac was associated with an increased risk of liver injury (adjusted odds ratio of 4.1) compared with nonuse of the drug; the study findings suggested an increased risk in women compared with men and with use of higher doses (150 mg or more) and longer durations of therapy (more than 90 days).302,335

Misoprostol does not appear to exacerbate hepatic effects (e.g., increases in liver function test values) associated with diclofenac therapy.284

Diclofenac should be discontinued immediately if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur.1,255,302,303,317,318,323 (See Hepatic Precautions under Cautions.)

Dermatologic and Sensitivity Reactions

Rash1,86,115,119,125,132,134,165,223,302,303 or pruritus1,86,115,125,165,302,303 occurs in up to 10% of patients receiving oral diclofenac.1 Other adverse dermatologic reactions, including alopecia,1,302,303 photosensitivity,1,302,303 and excessive perspiration,1,86,302,303 have occurred occasionally. Bullous eruption,216 Stevens-Johnson syndrome,1,7,169,302,303 erythema multiforme,1,125,135,217,302,303 exfoliative dermatitis,1,302,303 toxic epidermal necrolysis,1,302,303 urticaria,1,302,303 and angioedema,1,302,303 1 have occurred rarely.1,302,303

Sensitivity reactions, including anaphylaxis; swelling of the eyelids, tongue, lips, pharynx, or larynx; urticaria; asthma; bronchospasm; laryngeal edema; dyspnea; chest tightness; wheezing; anaphylactoid reactions; eosinophilic pneumonitis and angioedema, sometimes with concomitant, potentially severe hypotension, have been reported in patients receiving diclofenac.168,223,261,280,302,303 Anaphylactic reactions have been reported in patients with or without known hypersensitivity to the drug, as well as in patients with aspirin-sensitivity asthma.302

In clinical studies that evaluated diclofenac sodium 1% gel, the most common adverse effect reported was dermatitis at the application site; this adverse effect has been reported in 4-11% of patients receiving the gel.318 Application site pruritus, erythema, paresthesia, dryness, vesicles, irritation, or papules also have occurred in patients receiving diclofenac gel.318

In clinical studies that evaluated diclofenac sodium 2% topical solution, dryness at the application site has been reported in 22% of patients receiving the topical solution, while application site exfoliation, erythema, pruritus, pain, induration, and rash have been reported in 2-7% of patients, and scabbing has been reported in less than 1% of patients.327 In clinical studies that evaluated diclofenac sodium 1.5% topical solution, dryness at the application site has been reported in 32% of patients receiving the topical solution, while contact dermatitis characterized by skin erythema and induration, contact dermatitis with vesicles, and pruritus have been reported in 2-9% of patients.326,327 Other application site reactions (e.g., paresthesia, vasodilation, acne, urticaria) have occurred in patients receiving diclofenac sodium topical solution.326,327 Rash, pruritus, and dry skin that are not localized to the application site also have occurred in 2-3% of patients receiving diclofenac sodium topical solution.326,327

Application site reactions (i.e., pruritus, dermatitis, burning, dryness, irritation, erythema, atrophy, discoloration, hyperhidrosis, vesicles) have been reported in 11% of patients receiving therapy with diclofenac epolamine transdermal system (Flector^®) in clinical studies.317 Rash also has been reported in patients receiving diclofenac epolamine transdermal system.320 Skin infection developed in one individual after the diclofenac system that had been applied to the foot was subjected to prolonged exposure to wetness.320 Edema and abnormal sensation at the treated site and allergic skin reactions also have been reported.317 Pruritus or other reactions (i.e., irritation, erythema, rash, inflammation, blister) at the application site have occurred in approximately 1% of patients receiving therapy with diclofenac epolamine transdermal system (Licart^®) in clinical studies.324

Otic and Ocular Effects

Tinnitus has occurred in up to 10% of patients receiving oral diclofenac.1,75,302,303

Adverse ocular effects132 (including blurred vision1,302,303 and conjunctivitis)1,302,303 and hearing impairment1,302,303 have occurred in diclofenac-treated patients.

Hematologic Effects

Anemia1,74,83 has been reported in up to 10% of patients receiving oral diclofenac1 and may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.302 Leukopenia,1,125,302,303 thrombocytopenia,1,155,225,302,303 purpura,1,302,303 ecchymosis,1,302,303 eosinophilia,1,302,303 melena,1,302,303 and rectal bleeding1,302,303 have occurred occasionally in patients receiving diclofenac.1,302,303 Ecchymosis has been reported in 2% of patients receiving diclofenac sodium topical solution.326,327 Agranulocytosis,1,302,303 lymphadenopathy,1,302,303 hemolytic anemia,1,189,225,302,303 aplastic anemia,1,207,302,303 and pancytopenia1,302,303 have been reported rarely in diclofenac-treated patients.1,302,303 Bruising in the extremities and abdomen,219,258 spontaneous bleeding,165,166 and hematoma formation166 also have been reported rarely in patients receiving the drug.165,166,219 Diclofenac may inhibit platelet aggregation1,3,40,41,42,43 and prolong bleeding time.3,40,41,42,43,165,166,258,302,303 However, administration of diclofenac sodium 1.5% topical solution at the maximum recommended dosage for 7 days in healthy individuals resulted in no substantial change in platelet aggregation.326 Diclofenac usually does not affect platelet count, prothrombin time, partial thromboplastin time, or thrombin time.1,166,302,303

Respiratory Effects

Asthma1,84,302,303 or dyspnea1,302,303 has been reported occasionally in patients receiving diclofenac.1,302,303 Respiratory tract infection (e.g., pneumonia, pharyngitis, bronchitis) 1,125,302,303 or respiratory depression has been reported rarely.1,302,303

Other Adverse Effects

Fever,1,302,303 infection,1,302,303,326,327 and sepsis1,302,303 have occurred in patients receiving diclofenac.1,302,303 Back, leg, or joint pain and hyperglycemia have occurred rarely.125 Although a causal relationship to diclofenac has not been established, weight changes1,86,125,302,303 have occurred in patients receiving the drug.1,302,303

Precautions and Contraindications

Multiple diclofenac-containing preparations should not be used concomitantly.1,302,303 Concomitant use of topical formulations of diclofenac with oral NSAIAs may result in increased adverse effects.317,318

When diclofenac sodium is used in fixed combination with misoprostol, the cautions, precautions, and contraindications associated with misoprostol must be considered in addition to those associated with diclofenac.284

Patients should be advised that diclofenac, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.1,167,181,302,303,305,317,318,500,508

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1,302,303,317,318

Cardiovascular Precautions

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.1,302,303,312,313,314,316,317,318,500,502,508 (See Cardiovascular Effects under Cautions.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.1,302,303,317,318,500,508 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.1,302,303,317,318,500,508 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.1,302,303,317,318,500,508 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, the patient should be monitored for cardiac ischemia.508

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,302,303,317,318,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.1,302,303,317,318 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.1,302,303,317,318 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.1,302,303,317,318,508 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.1,302,303,317,318

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that diclofenac should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if diclofenac is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)

GI Precautions

The risk of potentially serious adverse GI effects should be considered in patients receiving diclofenac, particularly in patients receiving chronic therapy with the drug.1,167,181,302,303,317,318 (See GI Effects under Cautions.) Because peptic ulceration and/or GI bleeding have been reported in patients receiving the drug,1,167,181,267,282,302,303,317,318 patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.1,302,303,304,317,318

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.1,302,303,317,318 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.) In addition, use of NSAIAs should be avoided in patients at higher risk (see GI Effects under Cautions) unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.302

Concomitant use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration; therefore, NSAIAs should be used with caution when used concomitantly with corticosteroids.266,273

Hepatic Precautions

Because severe hepatotoxic effects may develop without symptoms of liver dysfunction, serum aminotransferase concentrations should be measured at baseline and monitored periodically during long-term therapy with diclofenac.1,189,255,302,303,317,318,323 While the optimum timing of aminotransferase determinations during diclofenac therapy has not been determined, serum aminotransferase values should be obtained 4-8 weeks after therapy with the drug is initiated.302,317,318,323 Diclofenac should be discontinued 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 (See Hepatic Effects under Cautions.) Patients receiving diclofenac should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, anorexia, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, flu-like syndrome) and the appropriate actions to take if any of these manifestations develop.1,164,302,303,317,318,323

To minimize the potential risk of adverse hepatic effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and diclofenac should be used with caution in patients receiving concomitant therapy with other potentially hepatotoxic drugs (e.g., acetaminophen, certain antibiotics, anticonvulsant agents).302

Because diclofenac is almost completely metabolized in the liver, patients with hepatic impairment may require reduced oral dosages of the drug.302,303,331

Renal Precautions

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1,302,303,317,318 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1,302,303,317,318 Patients at greatest risk of this reaction are those with impaired renal function,1,174,185,302,303,317,318 heart failure,1,185,302,303,317,318 or hepatic dysfunction;1,302,303,317,318 those with extracellular fluid depletion (e.g., patients receiving diuretics);1,185,317,318 those taking an ACE inhibitor1,302,303,317,318 or angiotensin II receptor antagonist306 concomitantly; and geriatric patients.1,160,302,303,317,318 Fluid depletion should be corrected prior to initiation of diclofenac therapy, and renal function should be monitored during diclofenac therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.302 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.1,302,303,317,318 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1,302,303,317,318

The renal effects of diclofenac may hasten the progression of renal dysfunction in patients with preexisting renal disease.302 Patients with preexisting renal disease should be monitored for worsening renal function.302

Diclofenac has not been evaluated in patients with severe renal impairment, and the manufacturers state that use of the drug should be avoided in patients with advanced renal disease unless the benefits of therapy are expected to outweigh the risk of worsening renal function.1,302,303,317,318 If diclofenac is used in patients with advanced renal disease, close monitoring of renal function is recommended.1,302,303,317,318

Precautions Related to Dermatologic or Hypersensitivity Reactions

Anaphylactic reactions have been reported in patients receiving diclofenac.1,302,303 Patients receiving diclofenac should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.1,302,303,317,318

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving diclofenac.1,302,303,317,318 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.1,302,303,317,318 Diclofenac should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1,302,303,317,318

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.303 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.303 Symptoms may resemble those of an acute viral infection.303 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.303 If such signs or symptoms develop, diclofenac should be discontinued and the patient evaluated immediately.303

Precautions Related to Transdermal or Other Topical Use

When topical diclofenac preparations (e.g., diclofenac sodium topical gel or topical solution, diclofenac epolamine transdermal system) are used, patients should be advised to avoid contact with the eyes or mucous membranes.317,318,324,326,327 If the topical preparation does come in contact with the eyes, the eyes should be thoroughly rinsed with water or saline.317,318,324,326,327 Patients should be advised to consult a clinician if ocular irritation persists for longer than one hour.317,318,324,326,327

Patients receiving diclofenac sodium 1% gel for self-administration should be advised that the gel should not be used in larger dosages or for longer periods of time than recommended and should not be used for symptomatic relief of strains, sprains, bruises, or sports injuries.325 Up to 7 days of use may be required for relief of osteoarthritis joint pain; if no relief is obtained within 7 days, self-administration of the 1% gel should be discontinued.325

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

Patients receiving therapy with diclofenac epolamine transdermal system should be advised to bathe or shower after removing one system but before applying a new system; patients should not wear the system while bathing or showering.317,324

Patients should be advised to store and discard diclofenac epolamine transdermal systems in a manner that avoids accidental exposure or ingestion by children or pets.317,324

Hematologic Precautions

Diclofenac should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), since the drug may inhibit platelet function.1,3,40,41,42,43,302,303,317,318

NSAIAs, including diclofenac, may increase the risk of bleeding.302 Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk and should be monitored for signs of bleeding.302 (See Drug Interactions.)

If signs and/or symptoms of anemia occur during therapy with diclofenac, hemoglobin concentration and hematocrit should be determined.1,302,303,317,318

Other Precautions

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.1,302,303,317,318

Some clinicians state that NSAIAs should be used with caution in patients with systemic lupus erythematosus (SLE) since serious adverse CNS effects (e.g., aseptic meningitis)229,230,231,241,243 and possible activation of SLE occasionally have been observed in patients with SLE receiving NSAIAs.232,233

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during diclofenac therapy should have an ophthalmologic examination.247,248

The possibility that the antipyretic and anti-inflammatory effects of diclofenac may mask the usual signs and symptoms of infection or other diseases should be considered.247,248,317,318

Diclofenac is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency.1,302,303,317,318 Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions.1,302,303,317,318 If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.1,302,303,317,318

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of NSAIAs, serotonin type 1 [5-HT₁] receptor agonists, ergotamine, or opiate analgesics on a regular basis for 10 or more 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 Patients should be encouraged to record the frequency of migraine headaches and medication use and to contact their clinician if the frequency of migraine attacks increases.328

Contraindications

The manufacturers state that diclofenac is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation.1,302,303,317,318 In addition, NSAIAs, including diclofenac, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.1,141,144,145,146,147,168,225,302,303,317,318 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization.143,144,145,146,147 Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving diclofenac should be monitored for changes in manifestations of asthma.302,303,317,318 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.1,302,303,317,318 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

NSAIAs are contraindicated in the setting of CABG surgery.508

Use of diclofenac epolamine transdermal system on nonintact or damaged skin, regardless of the etiology (e.g., exudative dermatitis, eczema, infected lesions, burns, wounds), is contraindicated.317,324

Pediatric Precautions

The manufacturers state that safety and efficacy of diclofenac in children have not been established.1,302,303,317,318,324,326,327,328,331 However, oral diclofenac has been used with good results for the management of juvenile rheumatoid arthritis† in a limited number of children 3-16 years of age.3,128,210 Further studies are needed to establish the optimum dosages and indications for use in children.128

Geriatric Precautions

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.302,317 Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.1,302,303,317,318 If the anticipated benefits of diclofenac therapy outweigh the potential risks, diclofenac should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects.302,317

Of the total number of patients studied in clinical trials of diclofenac sodium 1% topical gel, 498 were 65 years of age or older.318 Although no overall differences in safety or efficacy were observed between geriatric individuals and younger adults in these studies, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.318

In phase 3 clinical trials of diclofenac sodium 1.5% topical solution, 49% of patients receiving the drug were 65 years of age or older.326,327 In an open-label, long-term safety study, 42% of patients receiving diclofenac sodium 1.5% topical solution were 65 years of age or older, while 13% were 75 years of age or older.326,327 No age-related differences in the incidence of adverse effects were observed in these studies.326,327

Clinical trials of diclofenac epolamine transdermal system or diclofenac potassium oral solution did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adults.317,324,328 Other clinical experience has not identified differences in response between geriatric and younger patients.317,324

Diclofenac is substantially excreted by the kidneys, and the risk of toxicity may be greater in patients with renal impairment.302,318 Because geriatric patients are more likely to have decreased renal function, diclofenac should be used with caution; it may be useful to monitor renal function in such patients.302,318

Mutagenicity and Carcinogenicity

No evidence of diclofenac sodium-induced mutagenicity was seen with several in vitro test systems, including the microbial (Ames test) and mammalian (mouse lymphoma) test systems.307 Also, there was no evidence of mutagenicity when diclofenac sodium was tested with in vitro and in vivo mammalian tests, including dominant lethal and male germinal epithelial chromosomal tests in mice and nucleus anomaly and chromosome aberration tests in Chinese hamsters.307

No evidence of carcinogenic potential was seen in rats receiving oral diclofenac sodium dosages up to 2 mg/kg daily (12 mg/m² daily; about the maximum recommended human dosage) for 2 years.247,307 In addition, no evidence of oncogenic potential was seen in male and female mice receiving diclofenac sodium dosages up to 0.3 (0.9 mg/m²) and 1 mg/kg (3 mg/m²) daily, respectively, for 2 years.307 There was an increase, however, in benign mammary fibroadenomas in female rats receiving oral diclofenac sodium dosages of 0.25-2 mg/kg for 2 years.247,307

Animal photocarcinogenicity studies indicate a shortened time to skin tumor formation following application of diclofenac sodium gel in a concentration up to 0.035%.318,321

Pregnancy, Fertility, and Lactation

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.303,1200 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.303,1200 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.303,1200 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.303,1200

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

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.303,1200 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.303,1200 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.303,1200 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.303,1200 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.303,1200 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.303 These limitations preclude establishing 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, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.303

Diclofenac crosses the placenta in mice, rats, and humans.303 Reproduction studies in rabbits, rats, and mice receiving oral diclofenac sodium dosages up to 10, 10, and 20 mg/kg daily, respectively, have not revealed evidence of teratogenicity; however, these dosages produced maternal (e.g., dystocia, prolonged gestation) and fetal (e.g., reduced weight, growth, and survival) toxicity.307

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. 303 In animal studies, inhibitors of prostaglandin synthesis, such as diclofenac, were associated with increased pre- and post-implantation losses.303 Prostaglandins also have an important role in fetal kidney development.303 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.303

The effects of diclofenac on labor and delivery in humans currently are not known.1,302,303 In animal studies, NSAIAs, including diclofenac, inhibit prostaglandin synthesis, delay parturition, and increase the incidence of stillbirth.303

Diclofenac sodium in fixed combination with misoprostol is contraindicated in women who are pregnant because misoprostol exhibits abortifacient activity and can cause serious fetal harm.284 In addition, it is recommended that diclofenac in fixed combination with misoprostol be used in women of childbearing 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 (See Cautions: Pregnancy, Fertility, and Lactation, in Misoprostol 56:28.28.)

Fertility

Use of NSAIAs, including diclofenac, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.302 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.302 Therefore, withdrawal of diclofenac should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.302

Reproduction studies in male and female rats using diclofenac sodium dosages up to 4 mg/kg (24 mg/m²) daily have not revealed evidence of impaired fertility.307

Lactation

Diclofenac may be distributed into milk.302 While diclofenac was not detectable in breast milk in 12 women who received diclofenac 100 mg orally daily for 7 days or a single 50-mg IM dose administered in the immediate postpartum period, the drug was detected in breast milk at a concentration of 100 mcg/L (equivalent to an infant dose of about 0.03 mg/kg daily) in one woman receiving a diclofenac salt at a dosage of 150 mg daily.302

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for diclofenac and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.302

Drugs Affecting Hepatic Microsomal Enzymes

Diclofenac is metabolized by cytochrome P-450 (CYP) isoenzymes, mainly by CYP2C9.302 Concomitant use of CYP2C9 inhibitors (e.g., voriconazole) may increase systemic exposure to diclofenac and the risk of adverse effects; conversely, concomitant use of CYP2C9 inducers (e.g., rifampin) may reduce efficacy of diclofenac.302 Concomitant administration of voriconazole (inhibitor of CYP isoenzymes 2C9, 2C19, and 3A4) increased the peak concentration and area under the concentration-time curve (AUC) of diclofenac by 114 and 78%, respectively.302 Dosage adjustment may be required when diclofenac is used concomitantly with CYP2C9 inhibitors or inducers.302

Protein-bound Drugs

Because diclofenac is highly protein bound, it could be displaced from binding sites by, or it theoretically could displace from binding sites, other protein-bound drugs.248 In vitro studies suggest that diclofenac only minimally displaces from protein binding sites other highly protein-bound drugs (e.g., prednisolone, salicylates, tolbutamide, warfarin),51,52,307 although diclofenac may be displaced from binding sites by high doses of ionized protein-bound drugs (e.g., salicylates).51,52,59,61 When NSAIAs were administered with aspirin, protein binding of the NSAIAs was reduced, although clearance of the free (unbound) NSAIAs was not altered; the clinical relevance of this interaction has not been established.302

Antacids

Concomitant administration of diclofenac and an aluminum and magnesium hydroxides antacid may result in delayed diclofenac absorption;3,189,238 however, extent of absorption is not affected.3,189,238

Because magnesium-containing antacids may increase the incidence of misoprostol-induced diarrhea, concomitant administration of diclofenac in fixed combination with misoprostol with a magnesium-containing antacid is not recommended.284 Antacids and food appear to decrease the oral bioavailability of misoprostol.284 (See Drug Interactions: Food and Antacids, in Misoprostol 56:28.28.)

Antihypertensive Agents

Concomitant use of NSAIAs 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.1,302,303,315,317,318 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.302

Concomitant use of diclofenac with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function, including possible acute renal failure; such patients should be monitored for signs of worsening renal function.302 Patients receiving concomitant therapy with diclofenac and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.302

Anticoagulants

The effects of warfarin and NSAIAs on GI bleeding are synergistic.1,302,303,317,318 Concomitant use of diclofenac and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.1,302,303,317,318

In short-term controlled studies in patients receiving maintenance doses of coumarin derivatives, diclofenac did not substantially alter the hypothrombinemic effect of these anticoagulants when the drugs were administered concomitantly.3,7,201,307 However, because diclofenac may cause GI bleeding,1,79,86,91,132,302,303 inhibit platelet aggregation,1,3,40,41,42,43,302,303 and prolong bleeding time,3,40,41,42,43 the drug should be used with caution and with careful monitoring for signs of bleeding in patients receiving any anticoagulant (e.g., warfarin).272,302

Cyclosporine

Concomitant administration of diclofenac and cyclosporine may increase the nephrotoxic effects of cyclosporine; this interaction may be related to inhibition of renal prostaglandin (e.g., prostacyclin) synthesis.1,302,303,318 Patients should be monitored for signs of worsening renal function.302

Digoxin

Concomitant use of diclofenac and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.302 Serum digoxin concentrations should be monitored.302

Diuretics

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs, including diclofenac.1,16,174,199,200,302,303,317,318 (See Renal Precautions under Cautions.) In addition, NSAIAs may interfere with the natriuretic response to diuretics with activity that depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., furosemide, thiazides).1,22,179,302,303,317,318 In patients with hypertension, the antihypertensive effect of hydrochlorothiazide was attenuated by diclofenac.3,173 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for worsening renal function and for adequacy of diuretic and antihypertensive effects.1,302,303,317,318

Concomitant use of diclofenac and potassium-sparing diuretics may be associated with increased serum potassium concentrations.284

Concomitant administration of diclofenac and triamterene has resulted in reversible impairment of renal function.174 Similar adverse renal effects have been reported with concomitant use of triamterene and other NSAIAs (e.g., indomethacin), progressing to acute renal failure in some patients.3,244,252 Therefore, diclofenac and triamterene should be used concomitantly with caution.3,174,246 The mechanism of this interaction has not been determined, but it has been postulated that NSAIAs may inhibit triamterene-mediated renal vasoconstriction.244,255

Lithium

Diclofenac increases plasma lithium concentrations and reduces renal lithium clearance.1,176,180,265,302,303,317,318 The mechanism involved in the reduction of lithium clearance by NSAIAs (including diclofenac) is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.283 With concomitant NSAIA use, the mean increase in trough lithium concentrations is 15% and renal clearance is decreased by approximately 20%.302 In one study in healthy women, plasma lithium concentration was increased by 26% and renal clearance was reduced by 23%.176,265 In a patient receiving 1 g of lithium daily together with diclofenac sodium dosages of 75 mg daily, plasma lithium concentrations increased about fivefold;188 manifestations of lithium intoxication developed but resolved following discontinuance of both diclofenac and lithium.188 If diclofenac and lithium are administered concurrently, the patient should be closely observed for signs of lithium toxicity1,176,302,303,317,318 and plasma lithium concentrations should be monitored carefully during the initial stages of combined therapy or subsequent dosage adjustment.236,237 In addition, appropriate adjustment of lithium dosage may be required when therapy with diclofenac is discontinued.236,238

Methotrexate

Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).302 Severe, sometimes fatal,175 toxicity has occurred following concomitant administration of diclofenac and methotrexate.175,307 The toxicity was associated with elevated serum concentrations of methotrexate.175,307 Patients at greatest risk of this reaction are those with renal impairment and those receiving relatively high (e.g., antineoplastic) dosages of methotrexate.248,307 Patients receiving concomitant diclofenac and methotrexate therapy should be monitored for methotrexate toxicity.302 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)

Nonsteroidal Anti-inflammatory Agents

In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.302 However, concomitant use of aspirin and an NSAIA increases the risk for bleeding and serious GI events.302 Because of the potential for increased adverse effects, concomitant use of diclofenac with other NSAIAs or with analgesic dosages of aspirin generally is not recommended.302

Concomitant use of oral and topical NSAIAs may result in a higher incidence of hemorrhage and abnormal values for creatinine, urea, and hemoglobin.317,318,324,326,327 Incidences of rectal hemorrhage and abnormal creatinine, urea, and hemoglobin concentrations were greater in patients receiving concomitant therapy with diclofenac sodium 1.5% topical solution and oral diclofenac (3, 12, 20, and 13%, respectively) compared with those receiving oral diclofenac alone (less than 1, 7, 12, and 9%, respectively); however, no difference in the incidence of aminotransferase elevations was observed.326,327 Topical diclofenac formulations (e.g., gels, solutions, transdermal systems) should not be used concomitantly with oral NSAIAs unless expected benefits outweigh risks and periodic laboratory evaluations are performed.317,318,324,326,327

Patients receiving diclofenac should be advised not to take low-dose aspirin without consulting their clinician.302 Diclofenac is not a substitute for low-dose aspirin therapy for prophylaxis of cardiovascular events, and patients receiving antiplatelet agents such as aspirin concomitantly with diclofenac should be monitored closely for bleeding.302 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.302,305,317,318,502,508

While multiple-dose administration of ibuprofen may inhibit the cardioprotective effects of aspirin, limited data indicate that administration of diclofenac sodium delayed-release tablets (75 mg twice daily) does not inhibit the antiplatelet effect of aspirin (81 mg daily).262

Following concomitant administration of diclofenac and aspirin in healthy individuals, protein binding of diclofenac is decreased, biliary excretion of diclofenac may be increased, and peak plasma concentrations and AUC of diclofenac are reduced.1,22,61,184,202,302,303 Pretreatment with diclofenac for 14 days before administration of aspirin appeared to enhance renal elimination of salicylate.184 The clinical importance of these pharmacokinetic interactions remains to be determined.22,40,184

Pemetrexed

Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.302 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.302 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.302 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant diclofenac and pemetrexed therapy.302

Quinolones

It has been suggested that concomitant use of ciprofloxacin and an NSAIA (e.g., diclofenac) could increase the risk of CNS stimulation (e.g., seizures),183,197,198 but additional study and experience are necessary.197

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.302 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.302 Patients receiving concomitant therapy with diclofenac and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.302

Other Drugs

Concomitant use of ulcerogenic drugs such as corticosteroids during NSAIA therapy may increase the risk of GI ulceration.266 Concomitant administration of more than one diclofenac-containing product should be avoided.1,302,303

Acute Toxicity

Limited information is available on the acute toxicity of diclofenac.22,307

Pathogenesis

The acute lethal dose of diclofenac sodium in humans is not known. Individuals have survived reported ingestions of up to 4 g of the drug.307 The oral LD₅₀ of diclofenac sodium is 55-240, 500, and 3200 mg/kg in rats,22,247,307 dogs,307 and monkeys,307 respectively. Hydroxylated metabolites of the drug have exhibited less toxic potential than did the unchanged drug in LD₅₀ studies in rats.22

Acute diclofenac overdosage produces manifestations that are mainly extensions of adverse effects of the drug.172,182,196,234,307 Loss of consciousness, increased intracranial pressure, and aspiration pneumonitis were reported in a 17-year-old male, who died 2 days after ingesting 5 g of diclofenac.307 No signs or symptoms of toxicity were observed in a few patients who ingested 3.75-4 g of diclofenac.307 However, vomiting and drowsiness occurred in an adolescent who ingested 2.37 g of the drug.307 Several other adults who ingested overdosages of diclofenac along with other drugs, including CNS depressants, developed confusion, hypotonia, and loss of consciousness (requiring intubation and ventilation).196,234 In one of these patients, plasma diclofenac concentrations were 60.1 and 0.19 mcg/mL 7 and 15 hours after ingestion, respectively.196

In acute diclofenac overdosage, general measures should include immediately emptying the stomach by inducing emesis or by gastric lavage, followed by initiation of symptomatic and supportive treatment.1,3,302,303 Administration of activated charcoal after emesis or gastric lavage may be useful in minimizing absorption of diclofenac and reabsorption of enterohepatically recirculated drug.1 Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be beneficial in enhancing elimination of diclofenac, because the drug is highly protein bound.1,235,302,303 If forced diuresis is used in an attempt to enhance urinary excretion of the drug, fluid and electrolyte balance should be monitored carefully, since potentially serious electrolyte disturbances and fluid retention may occur.235

Pharmacology

Diclofenac has pharmacologic actions similar to those of other prototypical NSAIAs.1,3,20,21,22,23,24,25,26,189,302,303,317,318 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,3,21,22,23,189,317,318 The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.1,20,21,22,23,26,189,302,303,317,318 Diclofenac inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.285,286,287,288,289,290 Diclofenac, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.285,286,287,288,289,290 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.285,286,287,288,289,290

Anti-inflammatory, Analgesic, and Antipyretic Effects

The anti-inflammatory, analgesic, and antipyretic effects of diclofenac and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis.1,11,12,13,14,15,17,26,285,286,287,288,289,290,302,303,317,318 While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.285,286,287,288,289,290

High concentrations of diclofenac have been reported to inhibit formation of other arachidonic acid metabolites, including leukotrienes and 5- hydroxyeicosatetraenoic acid (5-HETE).3,20,21,23 Diclofenac may inhibit the migration of leukocytes, including polymorphonuclear leukocytes, into inflammatory sites.3,20,21,23 However, inhibition of leukotriene formation and migration of leukocytes do not appear to result from direct diclofenac-induced inhibition of lipoxygenase.21,23 Diclofenac also inhibits lysosomal enzyme release from polymorphonuclear leukocytes3,21,23 and may inhibit superoxide production and chemotaxis of polymorphonuclear leukocytes.3,27,28

On a weight basis, the anti-inflammatory potency of diclofenac has been shown to be less than that of piroxicam, and to be about 2.5, 10, 24, 80, or 430 times that of indomethacin, naproxen, phenylbutazone, ibuprofen, or aspirin, respectively, as determined by inhibition of carrageenan-induced paw edema in rats.3,22 In adjuvant-induced arthritis in rats, the anti-inflammatory activity of diclofenac is similar to that of indomethacin, and about 30, 95, or 380 times that of naproxen, phenylbutazone, or ibuprofen, respectively.3,22 The anti-inflammatory activity of topically applied 4% diclofenac sodium is similar to that of topically applied 2-4% ibuprofen or indomethacin and 10% meclofenamic acid, mefenamic acid, or phenylbutazone, as determined by inhibition of UV light-induced erythema in animals.24

On a weight basis, as determined by antagonism of phenylbenzoquinone-induced writhing in mice, the analgesic potency of diclofenac was similar to that of indomethacin and about 5, 10, 22, or 38 times that of naproxen, ibuprofen, phenylbutazone, or aspirin, respectively.3,22 On a weight basis in human studies, the analgesic effect of diclofenac was similar to that of codeine and about 3-8, 8-16, and 12-18 times that of naproxen, ibuprofen, and aspirin, respectively.3,92,103,104

Tolerance to the analgesic effect of diclofenac apparently does not occur during long-term administration.3,75,79,80,81,107,125,126,129

Diclofenac lowers body temperature in animals with antigen-induced fever.3,21,22 Although the mechanism of antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.12,193 In rats, the antipyretic activity of diclofenac 0.5 mg/kg was similar to that of 1.2, 24, 35, 55, or 185 mg/kg of indomethacin, ibuprofen, phenylbutazone, naproxen, or aspirin, respectively.3,21,22

Genitourinary and Renal Effects

Diclofenac has relieved symptoms associated with primary dysmenorrhea,104,105 probably by inhibiting the synthesis and/or actions of prostaglandins.105 Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.291

Diclofenac has been reported to adversely affect renal function.1,3,32,84,159,160,162,185,212,215,302,303 (See Renal, Electrolyte, and Genitourinary Effects under Cautions.) Although the exact mechanism of adverse renal effects of NSAIAs has not been determined, the effects may be related to inhibition of renal prostaglandin synthesis.15,16,17,34

Diclofenac exhibited an antiproteinuric effect in a limited number of patients with glomerulonephritis and normal renal function.3,33 The mechanism(s) of this decreased proteinuria remains to be established.33

Diclofenac does not appear to have uricosuric activity when administered in usual dosages.3,31

GI Effects

Diclofenac can cause gastric mucosal damage, which may result in ulceration and/or bleeding.1,3,22,35,36,37,38,40,50,167,181,187,259,267,268,269,270,281,302,303,317,318 These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.285,286,287,292 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.287,292

Misoprostol, a synthetic prostaglandin E₁ analog, inhibits gastric acid secretion and protects the mucosa from irritant and/or other (e.g., pharmacologic) effects of certain drugs (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]).284 (See Pharmacology, in Misoprostol 56:28.28.)

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.289 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.289

Hematologic Effects

Diclofenac can inhibit platelet aggregation and may prolong bleeding time.3,40,41,42,43,165,166 Like other prototypical NSAIAs,12,15 these effects of diclofenac appear to be associated with inhibition of the synthesis of prostaglandins produced by COX-1.44,289 In a study in healthy individuals, the drug did not substantially affect collagen-induced platelet aggregation, platelet count, prothrombin time, or bleeding time.3,39,40 Administration of diclofenac sodium 1.5% topical solution at the maximum recommended dosage for 7 days in healthy individuals resulted in no substantial change in platelet aggregation.326 Reports of the effect of parenterally administered diclofenac on bleeding time have been equivocal.3,41,195 However, parenterally administered diclofenac has produced a dose-dependent increase in bleeding time in healthy adults when administered by IV infusion.41

Other Effects

Diclofenac may increase free fatty acid concentrations3,47 and plasma post-heparin lipoprotein lipase activity.3,47 In healthy men, diclofenac does not appear to alter substantially plasma concentrations of follicle-stimulating hormone, luteinizing hormone, or thyrotropin (thyroid-stimulating hormone, TSH) but has decreased plasma prolactin concentrations.224

Like some other NSAIAs,48,49 diclofenac inhibits prostaglandin synthesis in the conjunctiva and uvea following topical application to the eye and thereby may prevent and/or decrease disruption of the blood-aqueous humor barrier.46

Pharmacokinetics

Absorption

Diclofenac sodium and diclofenac potassium are almost completely absorbed from the GI tract;1,3,51,52,53,57,68,189,302,303 however, the drugs undergo extensive first-pass metabolism in the liver,1,3,302,303 with only about 50-60% of a dose of diclofenac sodium or diclofenac potassium reaching systemic circulation as unchanged drug.1,52,53,73,262,284,302,303 Diclofenac also is absorbed into systemic circulation following rectal administration3,51,52,240,242 and percutaneously following topical application to the skin as a gel, solution, or transdermal system.3,227,317,318,324,326

Measurable plasma concentrations of diclofenac have been observed in some fasting individuals within 10 minutes of receiving diclofenac potassium conventional tablets and within 5 minutes of receiving diclofenac potassium oral solution.303,328 Onset of absorption is delayed when diclofenac sodium is administered orally as delayed-release (enteric-coated) tablets, but the extent of absorption does not appear to be affected.52,53,54,56,57,60,61 Peak plasma concentrations of diclofenac generally occur within 1 hour (range: 0.33-2 hours) or 2-3 hours (range: 1-4 hours)1,3,51,52,303 after oral administration of diclofenac potassium conventional tablets or delayed-release (enteric-coated) diclofenac sodium tablets, respectively. Peak plasma concentrations occur within 10-30 minutes after administration of an oral solution of diclofenac sodium and in approximately 15 minutes in fasting individuals receiving diclofenac potassium oral solution.3,52,328 Following oral administration of a single 25-mg dose as diclofenac potassium liquid-filled capsules under fasting conditions, peak diclofenac concentrations of approximately 1.1 mcg/mL occur at a mean of 0.47 hours.331 Following oral administration of a single 25-, 50-, 75-, or 150-mg dose as delayed-release (enteric-coated) diclofenac sodium tablets in healthy adults, average peak plasma diclofenac concentrations of 0.5-1, 1-1.5, 2, and 2.5 mcg/mL, respectively, occur within about 1.5-3 hours.51,52,284,307 The area under the plasma concentration-time curve (AUC) increases linearly with single diclofenac sodium doses of 25-150 mg.3,52,284,307 There is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage,53,54,55,62 and onset of absorption is variable secondary to differing dissolution of the enteric coating of diclofenac sodium delayed-release tablets.57 Following oral administration of a single 100-mg dose of diclofenac sodium as an extended-release tablet, mean peak plasma concentrations of 417 ng/mL generally occur within 5-6 hours.307 Following rectal administration of a single 25-, 50-, or 100-mg diclofenac sodium suppository in healthy adults, peak plasma diclofenac concentrations of approximately 0.6, 0.7, or 1.8 mcg/mL, respectively, occur within about 1 hour.51,52 The relationship between plasma diclofenac concentrations and therapeutic effect has not been established.247

Food decreases the rate of absorption of conventional tablets of diclofenac potassium and of delayed-release (enteric-coated) tablets of diclofenac sodium, resulting in delayed and decreased peak plasma concentrations; however, the extent of absorption is not affected substantially.1,54,303 When diclofenac potassium conventional tablets are administered with food, time to achieve peak plasma concentrations of the drug is increased and peak plasma concentrations of the drug are decreased by approximately 30%.303 Administration of diclofenac potassium oral solution after a high-fat meal did not substantially alter the extent of diclofenac absorption, but reduced peak plasma concentrations by approximately 70%.328 Food decreases the rate of absorption of diclofenac potassium liquid-filled capsules, resulting in a 47% decrease in peak concentration and a twofold increase in the time to peak concentration; the extent of absorption is not affected substantially.331 When single doses of diclofenac sodium delayed-release (enteric-coated) tablets are taken with food, the onset of absorption usually is delayed by 1-4.5 hours but may be delayed up to 12 hours in some patients.1,54 These food-induced alterations in GI absorption of the drug result from delayed transit of the delayed-release (enteric-coated) tablets to the small intestine, the site of dissolution.3,54 When diclofenac sodium extended-release tablets are taken with food, onset of absorption is delayed 1-2 hours and peak plasma concentrations are increased two-fold; however, extent of absorption is not substantially affected.302 Absorption of diclofenac does not appear to be affected substantially by the presence of food following continuous dosing of the drug.3,55 Antacids also may decrease the rate but not the extent of absorption of diclofenac.3,189,239

Peak plasma diclofenac concentrations attained following administration of the drug may be reduced in patients with rheumatoid arthritis compared with those in healthy adults;3,60,68 however, AUCs appear to be similar.3,60 Peak plasma concentrations and AUCs of the drug in geriatric individuals may be increased up to about fourfold and twofold those, respectively, observed in younger individuals,3,228 although a lack of substantial age-related alterations also has been reported.56,57,73 No differences in pharmacokinetic values for diclofenac have been detected in patients with renal impairment relative to healthy adults.1,72,302,303

Diclofenac is absorbed into systemic circulation following topical application, but plasma concentrations generally are very low compared with oral administration.317,318,324 Following application of a single diclofenac epolamine transdermal system (Flector^®) to intact skin on the upper arm, peak plasma diclofenac concentrations of 0.7-6 ng/mL occur in 10-20 hours.317 Following application of the system twice daily for 5 days, plasma diclofenac concentrations of 1.3-8.8 ng/mL have been reported.317 No difference in systemic absorption was observed between healthy individuals at rest and those engaging in moderate exercise.317

Following application of diclofenac epolamine transdermal system (Licart^®) to the anterior thigh once daily for 4 days, peak plasma diclofenac concentrations of 0.4-2.9 ng/mL occur in 4-20 hours; the mean plasma diclofenac concentration during the 24-hour application period is 0.5-0.9 ng/mL.324 On average, when the system is applied to the medial aspect of the upper arm for 24 hours, about 7 mg of diclofenac is released from the system.324 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 4 g of diclofenac sodium 1% gel 4 times daily to one knee, mean peak plasma diclofenac concentrations of 15 ng/mL occur in about 14 hours.318 Following application of the gel to both knees and both hands 4 times daily (48 g of gel), mean peak plasma diclofenac concentrations of 53.8 ng/mL occur in about 10 hours.318 Systemic exposure to the drug at these dosage levels (16 or 48 g of gel daily) is about 6 or 20%, respectively, of the systemic exposure attained when diclofenac sodium is administered orally at a dosage of 50 mg 3 times daily.318 Application of a heat patch for 15 minutes before application of the gel did not affect systemic absorption.318 It has not been established whether application of a heat patch following gel application affects systemic absorption of the drug.318 Moderate exercise did not affect systemic absorption of the drug.318

Following topical application of the maximum recommended dosage of diclofenac sodium 1.5% solution to both knees (40 drops per knee) 4 times daily for 7 days, mean peak plasma diclofenac concentrations of 19.4 ng/mL were achieved about 4 hours after a dose.326 Following topical application of diclofenac sodium 2% solution (40 mg per knee) twice daily for 7.5 days, mean peak plasma diclofenac concentrations at steady state on day 8 were 25.3 ng/mL; studies have not established whether application of heat, occlusive dressings, or exercise following application of the topical solution affects systemic absorption of the drug.327

Distribution

Distribution of diclofenac into human body tissues and fluids has not been fully characterized.1,3,51,52,302,303 Following IV administration of diclofenac in rats, the drug is widely distributed, achieving highest concentrations in bile, liver, blood, heart, lungs, and kidneys and lower concentrations in adrenals, thyroid glands, salivary glands, pancreas, spleen, muscles, brain, and spinal cord.3,51,52

Like other NSAIAs, diclofenac is distributed into synovial fluid,1,3,62,63,64,65,66,67,68,69,302,303 achieving peak synovial fluid concentrations about 60-70% of those attained in plasma following oral administration;3,64,68 however, synovial fluid concentrations of the drug and its metabolites substantially exceed those in plasma after 3-6 hours.3,62,63,64,65,68 Following oral administration of a single 75-mg dose of diclofenac sodium, peak synovial fluid concentrations of approximately 225 ng/mL occur within about 4 hours,64,68 but there is considerable interindividual variation in synovial concentrations attained with a given dosage of the drug.62,63 Diclofenac appears to be eliminated from synovial fluid less rapidly than from plasma.63,64,65,67

The apparent total volume of distribution of diclofenac reportedly averages about 1.3-1.4 L/kg.1,302,303

Diclofenac is extensively but reversibly bound to plasma proteins, mainly albumin.1,3,51,52,58,66,302,303 At plasma diclofenac concentrations of 0.15-105 mcg/mL, the drug is 99-99.8% protein bound in vitro.1,3,51,52,58,59,66,302,303 Two binding sites have been identified, a high-affinity, low capacity site and a low-affinity, high capacity site.3,58,59 In patients with rheumatoid arthritis, protein binding of diclofenac in synovial fluid appears to be lower than in plasma.66

Diclofenac and its metabolites cross the placenta in mice and rats.3,307 While substantial distribution of the drug into the milk of lactating women does not appear to occur with oral diclofenac sodium dosages of 100 mg daily, milk diclofenac concentrations of approximately 100 ng/mL were achieved in at least one woman receiving 150 mg of the drug daily.3

Elimination

Plasma concentrations of diclofenac appear to decline in a triphasic manner.53,61 Following IV administration of diclofenac sodium in healthy adults, the half-life of diclofenac reportedly averages about 3 minutes in the initial distribution phase, about 16 minutes in the intermediate (redistribution) phase, and about 1-2 hours in the terminal (elimination) phase.53,61 Following oral administration of delayed-release (enteric-coated) diclofenac sodium tablets in healthy individuals53,57 or in patients with rheumatoid arthritis,60 the elimination half-life of the drug was approximately 1.2-2 hours.2,53,57,60 Following application of diclofenac epolamine transdermal system, the elimination half-life of diclofenac is approximately 12 hours.317,324 The elimination half-life of diclofenac in patients with moderate renal impairment appears to be similar to that in patients with normal renal function;1,3,72,302,303 however, half-life may be prolonged with severe renal impairment.3,72

The exact metabolic fate of diclofenac has not been fully elucidated, but the drug is rapidly and extensively metabolized in the liver.1,3,51,52,70,302,303 Diclofenac undergoes extensive hydroxylation and subsequent conjugation with glucuronic acid, taurine amide, sulfuric acid, and other biogenic ligands.1,51,52,68,70 Conjugation of unchanged drug also may occur.70,302,303 Hydroxylation of the dichlorophenyl aromatic ring results in formation of 4'-hydroxydiclofenac (the principal metabolite of diclofenac) and 3'-hydroxydiclofenac, both of which subsequently undergo conjugation.1,51,52,68,70,302,303 Diclofenac also may undergo hydroxylation of the phenylacetic acid ring and subsequent conjugation to form conjugates of 5-hydroxydiclofenac and 4',5-dihydroxydiclofenac.1,51,52,68,70,302,303 Formation of 4'-hydroxydiclofenac is mediated mainly by cytochrome P-450 (CYP) isoenzyme 2C9, while formation of the minor metabolites 5-hydroxydiclofenac and 3'-hydroxydiclofenac is mediated by CYP3A4.302 Uridine diphosphate-glucuronosyltransferase (UGT) 2B7 and CYP2C8 may mediate acyl glucuronidation and oxidation reactions, respectively.302 Conjugation with glucuronic acid and taurine usually occurs at the carboxyl group of the phenylacetic ring, while conjugation with sulfuric acid mainly occurs at the 4' hydroxyl group of the dichlorophenyl aromatic ring;70 3'- and/or 4'-hydroxydiclofenac may undergo further 4'- O -methylation to form 3'-hydroxy-4'-methoxydiclofenac.177

Studies in animals indicate that on a weight basis, 4'-hydroxydiclofenac has about 3% of the anti-inflammatory potency of diclofenac3,22 and about 6 times the anti-inflammatory potency of aspirin.22 3'-Hydroxydiclofenac also may have some anti-inflammatory activity,22 but other metabolites of the drug appear to be pharmacologically inactive.3,22,177

Following oral or IV administration, diclofenac is excreted in urine and feces, with only minimal amounts being excreted unchanged.1,3,51,55,56,70,71,302,303 Fecal excretion of the drug occurs mainly via biliary elimination.1,51,52,70,71,302,303 Conjugates of unchanged diclofenac are excreted principally in bile, while hydroxylated metabolites are excreted in urine.52 Although there is evidence from animal studies that diclofenac undergoes enterohepatic circulation,3,22,51,52,71 such recirculation is minimal in humans.3,22,52,71

Following oral or IV administration of diclofenac in healthy adults, about 50-70% of a dose is excreted in urine and about 30-35% is excreted in feces within 96 hours.1,3,51,70,302,303 About 20-30% of a dose is excreted in urine as conjugates of 4'-hydroxydiclofenac, 10-20% as conjugates of 5-, 3'-, and 4',5-dihydroxydiclofenac, 5-10% as conjugates of unchanged diclofenac, 2% as unconjugated metabolites, 1.4% as an unidentified metabolite (with an elimination half-life of 80 hours), and less than 1% as unchanged drug.3,51,56,70,71,75,307 Approximately 10-20% of a dose is excreted in bile as conjugates of 4'-hydroxydiclofenac, 1-5% as conjugates of unchanged diclofenac, and about 5-6% total as conjugates of the other 3 major metabolites.51,71,307

Following IV administration of diclofenac in healthy individuals, plasma clearance of the drug averages about 263-350 mL/minute.3,53 Plasma clearance of diclofenac does not appear to be affected by renal impairment,1,3,208,302,303 although clearance of metabolites may be decreased.72

The degree of accumulation of metabolites of diclofenac in patients with renal failure has not been systematically evaluated.1,302,303 Metabolites of diclofenac may accumulate in patients with severe renal impairment.3,72 In these patients, steady-state plasma metabolite concentrations may be up to four times higher than those observed in healthy individuals.3,72

It is not known whether diclofenac is removed from systemic circulation by hemodialysis, hemoperfusion, or peritoneal dialysis.247

Chemistry and Stability

Chemistry

Diclofenac, a phenylacetic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,5,6,7,8,9,189,302,303 The drug is structurally related to meclofenamate sodium and mefenamic acid, but unlike these anthranilic acid (2-aminobenzoic) acid derivatives,203 diclofenac is a 2-aminobenzeneacetic acid derivative.5

Diclofenac is commercially available as diclofenac sodium delayed-release (enteric-coated) tablets, diclofenac sodium extended-release tablets, diclofenac potassium conventional tablets, diclofenac potassium liquid-filled capsules, and diclofenac potassium powder for oral solution.1,302,303,328,331 Diclofenac also is commercially available as a fixed combination of diclofenac sodium in an enteric-coated core and misoprostol in an outer shell.284 Diclofenac sodium also is commercially available as a topical gel or topical solution.318,326,327 Diclofenac epolamine is commercially available as a transdermal system.317,324 The transdermal system consists of an adhesive material containing diclofenac epolamine (13 mg of drug per g of adhesive) that is applied to a polyester felt backing and is covered with a polypropylene liner; the liner is removed prior to application to the skin.317,324 Each transdermal system measures 10 × 14 cm and contains 180 mg (Flector^®) or 182 mg (Licart^®) of diclofenac epolamine in an aqueous base.317,324

Diclofenac sodium and diclofenac potassium occur as faintly yellowish white to light beige, practically odorless, slightly hygroscopic crystalline powders307 and, at 25°C, have a pK_a of approximately 4.9,10,22,53,58

Stability

Diclofenac sodium delayed-release (enteric-coated) tablets, diclofenac sodium extended-release tablets, diclofenac potassium tablets, and diclofenac potassium liquid-filled capsules should be protected from moisture and stored in tight containers at room temperature; the manufacturer's labeling should be consulted for specific storage temperatures.1,263,302,303,331 Diclofenac potassium powder for oral solution should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.328 Diclofenac sodium and misoprostol tablets should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.284 Diclofenac sodium delayed-release (enteric-coated) tablets have an expiration date of 2 years following the date of manufacture.247

Diclofenac sodium 1% gel should be stored at 20-25°C and should not be frozen.318,325 Diclofenac sodium 1.5% topical solution should be stored in an upright position at 20-25°C.326 Diclofenac sodium 2% topical solution should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C.327 Diclofenac epolamine transdermal system should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C;317,324 once an envelope containing diclofenac epolamine transdermal systems (Licart^®) has been opened, the systems are stable for up to 6 months if stored at room temperature in the resealed envelope.324

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.

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