Diclofenac is a nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.1
Diclofenac sodium delayed-release tablets are used orally for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.1 Diclofenac sodium extended-release tablets and diclofenac potassium tablets are used orally for the symptomatic treatment of rheumatoid arthritis and osteoarthritis.302, 303, 336
Diclofenac sodium is also available in fixed combination with misoprostol for the symptomatic treatment of rheumatoid arthritis and osteoarthritis in adults at high risk of developing nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric and duodenal ulcers and their complications.284
Diclofenac potassium tablets are used orally for the treatment of primary dysmenorrhea and for relief of mild to moderate pain.303, 336 Diclofenac potassium capsules are used orally for relief of mild to moderate acute pain in adults and pediatric patients ≥12 years of age.331 Diclofenac potassium oral solution is used for the acute treatment of migraine attacks in adults.328
The potential benefits and risks of oral diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.1, 284, 302, 303, 331, 336 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1, 284, 302, 303, 328, 331, 336
Diclofenac epolamine is used topically for the treatment of acute pain due to minor strains, sprains, and contusions.317, 324 Diclofenac sodium topical solution is used for the symptomatic treatment of osteoarthritis of the knee.326, 327 When using topical diclofenac sodium or diclofenac epolamine, the lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.317, 324, 326, 327
Diclofenac sodium is also available in an over-the-counter (OTC) 1% topical gel preparation; OTC preparations are used to provide temporary relief of arthritis pain in the hand, wrist, elbow, foot, ankle, or knee.318 A prescription diclofenac sodium 3% topical gel is available, but is only indicated for the treatment of actinic keratoses; this use/preparation will not be discussed further in this monograph.227
Diclofenac sodium ophthalmic solution is indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction and for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.264
Diclofenac sodium delayed-release tablets are used orally for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.1 Diclofenac sodium extended-release tablets and diclofenac potassium tablets are used orally for the symptomatic treatment of rheumatoid arthritis and osteoarthritis.302, 303, 336
Diclofenac sodium is also available in fixed combination with misoprostol for the symptomatic treatment of rheumatoid arthritis and osteoarthritis in adults at high risk of developing nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric and duodenal ulcers and their complications.284 Consult the prescribing information for more details about the use of this fixed combination product.284
Diclofenac sodium topical solution is used for the symptomatic treatment of osteoarthritis of the knee.326, 327 Diclofenac sodium is also available in an OTC 1% topical gel preparation, which is used for self-medication for the temporary relief of arthritis pain in the hand, wrist, elbow, foot, ankle, or knee.318
Oral diclofenac also has been used for the symptomatic treatment of acute painful shoulder† (bursitis and/or tendinitis).134, 136, 154, 222, 346 NSAIAs, including oral diclofenac, have also been used in other inflammatory diseases including juvenile rheumatoid arthritis†128, 210, 2003, 2009 and gout† .2006
When used in the symptomatic treatment of rheumatoid arthritis,74, 75, 76, 77, 78, 79, 87, 88, 116, 117, 118, 119, 126, 129 oral diclofenac has relieved pain and stiffness,74, 75, 76, 77, 78, 79, 87, 88, 115, 116, 117, 118, 126, 129 reduced swelling,75, 79, 117, 119, 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, 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, 126, 133 improved knee joint function,81, 82, 89, 109, 113, 126 and increased range of motion81, 82, 86, 89, 90, 114, 126, 133 and functional activity.82, 84, 90, 109, 126
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, 354, 356, 361 or osteoarthritis81, 82, 83, 84, 85, 89, 108, 109, 126, 339, 347, 348, 349, 350, 351, 355, 357 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 acetaminophen,339 celecoxib,348 diflunisal,82, 115 ibuprofen,79, 80, 82, 90, 126 indomethacin,77, 78, 80, 82, 116, 118, 125, 129, 356, 357 ketoprofen,74, 133 mefenamic acid,113 naproxen,76, 80, 81, 82, 83, 86, 87, 88, 89, 110, 111, 115, 119, 126, 361 phenylbutazone (no longer commercially available in the US),80 piroxicam,108, 109, 351 etodolac,347, 354, 355 meloxicam,349, 350 or sulindac.82, 86
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.321, 340, 341, 353
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, 342, 343, 344 The diclofenac sodium 1.5% topical solution has demonstrated similar efficacy to oral diclofenac for pain relief and improvement in physical function in patients with knee osteoarthritis.342, 345 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, 337
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, 127 and pain at rest (including night pain)91, 127 and to improve motion,120 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 indomethacin,91, 127 celecoxib,338 or sulindac.120
Diclofenac has been used orally with good results in a number of children for the management of juvenile rheumatoid arthritis†.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.210
The American College of Rheumatology (ACR) guideline on the treatment of rheumatoid arthritis recommends initiation of a disease-modifying antirheumatic drug (DMARD) in DMARD-naïve patients; methotrexate is recommended over other DMARDs for the initial treatment of patients with moderate-to-high disease activity, while hydroxychloroquine is recommended initially for patients with low disease activity.2001 Addition of a biologic or target-specific DMARD is recommended for patients who do not attain treatment goals on methotrexate monotherapy (“treat-to-target” approach).2001 The role of NSAIAs is not discussed in the current ACR guideline on rheumatoid arthritis.2001
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
The ACR, the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network issued a joint guideline for the treatment of ankylosing spondylitis in 2019.2008 Treatments for ankylosing spondylitis include NSAIAs, conventional DMARDs (e.g., methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, secukinumab, ixekizumab), and/or targeted synthetic DMARDs (e.g., tofacitinib).2008 Specific agents for ankylosing spondylitis treatment are selected according to current disease activity, prior therapies, and the presence of comorbidities.2008 Goals of therapy in ankylosing spondylitis are to alleviate symptoms, improve functioning, maintain the ability to work, decrease complications, and prevent or slow skeletal damage.2008
Continuous NSAIA treatment is typically considered first-line for active ankylosing spondylitis, with other agents used in the treatment of NSAIA-refractory disease.2008 On-demand NSAIAs are recommended for stable ankylosing spondylitis.2008 No preference is given to one NSAIA over another.2008
Diclofenac potassium tablets are used orally for symptomatic relief of mild to moderate pain.303, 336 Diclofenac potassium capsules are used orally for relief of mild to moderate acute pain in adults and pediatric patients ≥12 years of age.331 Diclofenac epolamine transdermal systems (Flector® and Licart®) are used topically for the treatment of acute pain due to minor strains, sprains, and contusions; Flector® is indicated for use in adults and pediatric patients ≥6 years of age, but the safety and efficacy of Licart® in pediatric patients have not been established.317, 324 Diclofenac sodium also has been used orally for symptomatic relief of oral surgery pain†92, 352 , and low back pain†.92
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
A Cochrane review examined the efficacy of single-dose oral diclofenac for the treatment of acute postoperative pain and found that diclofenac potassium produces good pain relief at 25-, 50-, and 100-mg doses.358
Diclofenac sodium dosages of 75-150 mg daily have been as effective as aspirin dosages of 0.9-2.7 g daily or ibuprofen dosages of 1.2 g daily in patients with low back pain†.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 In another trial, diclofenac sodium 50 mg three times daily was as effective as ibuprofen 600 mg three times daily in patients undergoing third molar surgery.352
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 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, 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 than placebo in reducing pain upon movement on day 3 of treatment.324
A guideline from the American College of Physicians provides recommendations for the management of acute pain due to non-low back musculoskeletal injury in adults.2010 The guideline recommends topical NSAIAs (with or without menthol gel) as first-line therapy to reduce or relieve symptoms (including pain) and improve physical function.2010 Oral NSAIAs and acetaminophen are also suggested to reduce pain and (in the case of NSAIAs) improve physical function.2010
A guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists recommends a multimodal approach to treatment of postoperative pain, including both pharmacologic and nonpharmacologic interventions.2013 For most common surgeries, options for systemic pharmacologic therapy include opioids, NSAIAs and/or acetaminophen, and gabapentin or pregabalin.2013 The guideline recommends the use of NSAIAs and/or acetaminophen as part of multimodal analgesia for postoperative pain in patients without contraindications.2013 When selecting therapy for a specific patient, the potential risks associated with NSAIAs should be considered.2013
Diclofenac potassium is used as an oral solution for the acute treatment of migraine attacks with or without aura in adults; diclofenac should not be used for the prophylaxis of migraine.328 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
Guidelines on the acute treatment of migraine in adults have been published by the American Headache Society (AHS).1223 Goals of therapy in acute migraine include rapid freedom from pain and associated symptoms, as well as restored ability to function.1223 Agents with established efficacy in adults with acute migraine include triptans, ergotamine derivatives, gepants, lasmiditan, NSAIAs (aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen), and the combination of acetaminophen, aspirin, and caffeine.1223 Nonspecific analgesic therapies such as NSAIAs and acetaminophen/aspirin/caffeine are used for mild-to-moderate attacks, while migraine-specific therapies (e.g., triptans, ergotamine derivatives, gepants, lasmiditan) are used for moderate-to-severe attacks or mild-to-moderate attacks that respond poorly to non-specific therapy.1223 The AHS guideline states that selection of an agent for acute treatment should be based on patient-specific factors such as comorbid disease states, individual treatment history, and concomitant medications.1223
Diclofenac potassium tablets are used orally in the management of primary dysmenorrhea.303, 336 Diclofenac sodium as delayed-release (enteric-coated) tablets also has been used for the symptomatic relief of dysmenorrhea†.104, 105, 140
When used to relieve primary dysmenorrhea, 50- or 100-mg doses of diclofenac potassium were as effective as 550 mg of naproxen sodium.359 A placebo-controlled, double-blind, crossover study in 33 women with severe primary dysmenorrhea found that diclofenac 150 mg divided 3 times daily reduced menstrual pain intensity over the first 24 hours of menstruation compared to placebo.360 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
first-line treatment options for primary dysmenorrhea include combined oral contraceptives, progesterone-only contraceptives, and NSAIAs; treatment selection should be based on patient-specific considerations (e.g., comorbidities, desire/need for contraception).2012, 2015 The American College of Obstetricians and Gynecologists lists ibuprofen, naproxen sodium, mefenamic acid, and celecoxib as a potential NSAIAs for use in patients with primary dysmenorrhea; diclofenac is not specifically mentioned by the guideline.2012
Diclofenac sodium is used topically as an ophthalmic solution for the treatment of postoperative ocular inflammation in patients undergoing cataract extraction and for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.264
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, 284, 302, 303, 328, 331, 336 Diclofenac potassium is commercially available as a tablet (Lofena®) and as a liquid-filled capsule formulation (Zipsor®).331, 336 Diclofenac sodium also is administered topically as a solution.326, 327 Diclofenac epolamine is administered topically as a transdermal system.317, 324 Diclofenac sodium is also available as a sterile, 0.1% solution for ophthalmic administration.264
Diclofenac is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency.1, 302, 303, 317 Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions.1, 302, 303, 317 If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.1, 302, 303, 317
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
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 (20-25°C); the manufacturer's labeling should be consulted for specific storage temperatures.1, 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 is administered topically as a 1.5 or 2% solution,326, 327 and diclofenac epolamine is administered topically as a transdermal system.317, 324
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
Diclofenac sodium 1.5% topical solution should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°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
Diclofenac sodium 0.1% ophthalmic solution is administered topically as an eye drop.264 Because of the potential for adverse effects, the ophthalmic solution should not be used by patients wearing soft contact lenses, with the exception of a bandage hydrogel soft contact lens during the first 3 days following refractive surgery.264
The ophthalmic solution should be stored at 20-25°C protected from light.264
The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1, 302, 303, 317 Dosage of diclofenac must be carefully adjusted according to individual requirements and response.1, 302, 303
Different strengths and formulations of oral diclofenac are not interchangeable.331 Commercially available diclofenac sodium delayed-release tablets, diclofenac sodium extended-release tablets, and diclofenac potassium conventional tablets are not necessarily bioequivalent on a mg-per-mg basis.1, 302, 303, 336 In addition, the frequency of administration may vary across available products; diclofenac potassium liquid-filled capsules are approved for administration 4 times daily, while diclofenac potassium conventional tablets can be administered 2-4 times daily.331, 336
Each actuation of the pump dispenser of diclofenac sodium 2% topical solution delivers 20 mg of diclofenac sodium in 1 g of solution.327 The 1.5% topical solution contains diclofenac sodium 16.05 mg/mL.326
Each mL of 0.1% diclofenac sodium ophthalmic solution delivers 1 mg of diclofenac sodium.264
For the treatment of postoperative inflammation in adult patients who have undergone cataract extraction, starting 24 hours after cataract surgery, apply 1 drop of diclofenac ophthalmic solution to the affected eye 4 times daily and continue for 2 weeks postoperatively.264
For the temporary relief of pain and photophobia in adult patients undergoing corneal refractive surgery, apply 1 or 2 drops of diclofenac ophthalmic solution to the operative eye within the hour prior to surgery.264 Within 15 minutes after surgery, apply 1 to 2 drops to the affected eye and continue 4 times daily for up to 3 days.264
Rheumatoid Arthritis and Osteoarthritis
For the symptomatic treatment of acute or chronic rheumatoid arthritis, the usual initial adult dosage of diclofenac sodium delayed-release tablets or diclofenac potassium conventional tablets is 150-200 mg orally daily, administered in divided doses of 75 mg (diclofenac sodium delayed-release tablets only) twice daily or 50 mg (diclofenac sodium delayed-release tablets or diclofenac potassium conventional tablets) 3 or 4 times daily.1, 303, 336 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 dosage.284 Daily dosages of diclofenac sodium exceeding 200 mg per day are not recommended.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 tablets, diclofenac potassium conventional tablets is 100-150 mg orally daily, administered in divided doses of 75 mg (diclofenac sodium delayed-release tablets only) twice daily or 50 mg (diclofenac sodium delayed-release tablets or diclofenac potassium conventional tablets) 2 or 3 times daily.1, 303, 336 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 dosage.284 Daily dosages of diclofenac sodium exceeding 150 mg per day are not recommended.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 1.5% 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
For the symptomatic treatment of ankylosing spondylitis, the usual adult dosage of diclofenac sodium delayed-release tablets is 100-125 mg orally daily, administered in divided doses of 25 mg 4 time daily, with 5th dose at bedtime as needed.1
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, 336
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 in adults, the manufacturers state that one system should be applied to the most painful area once daily (Licart®) or twice daily (Flector®).317, 324
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
When diclofenac epolamine transdermal system (Flector®) is used for relief of acute pain due to strains, sprains, and contusions in pediatric patients ≥6 years of age, the manufacturer states that one system should be applied to the most painful area twice daily.317
When diclofenac potassium liquid-filled capsules are used for relief of mild to moderate acute pain in pediatric patients ≥12 years of age, the recommended dosage is 25 mg orally 4 times daily.331
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
The manufacturers recommend monitoring renal function in patients with hepatic impairment.284, 302, 303
Diclofenac dosage reductions do not appear to be necessary in patients with renal impairment.1, 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.284, 302, 303, 317 If diclofenac is administered, such patients should be monitored for signs of worsening renal function.284, 302, 303, 317
Volume status should be corrected in dehydrated or hypovolemic patients before initiating diclofenac.1, 284, 302, 303 Monitoring of renal function is also recommended, especially during concomitant use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists284 or in patients with heart failure, dehydration, or hypovolemia.1, 302, 303
Geriatric patients ≥65 years of age are at an increased risk for NSAIA-associated serious cardiovascular, gastrointestinal, and/or renal adverse effects compared to younger adults.1, 284, 302, 303 The risk of these adverse effects may be increased in geriatric patients with renal impairment or receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy.284 If the anticipated benefits of therapy outweigh the potential risks, it is recommended to initiate therapy at the lower end of the dosage range and monitor for adverse effects.1, 302, 303
The manufacturer states that commercially available combination of diclofenac in fixed combination with misoprostol should be avoided in geriatric patients with cardiovascular and/or renal risk factors.284 If use of the combination product cannot be avoided, the manufacturer recommends the lowest recommended dosage for the shortest possible duration, in addition to monitoring for cardiac and renal adverse effects.284 Monitor renal function in geriatric patients receiving diclofenac in fixed combination with misoprostol, particularly during concomitant therapy with an ACE inhibitor or angiotensin II receptor antagonist.284
Cardiovascular Thrombotic Effects
A boxed warning is included in the prescribing information about the increased risk of serious cardiovascular thrombotic events with diclofenac.1, 302, 303, 317 Clinical trials of nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, of up to 3 years' duration have shown an increased risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.1, 302, 303 Based on available evidence, it is unclear if the risk of cardiovascular thrombotic events is similar for selective COX-2 inhibitors and prototypical NSAIAs.1, 302, 303, 317
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.1, 302, 303, 317 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.1, 302, 303, 317
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 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 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
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 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.1, 302, 303, 317 Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.1, 302, 303 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).1, 302, 303 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.1, 302, 303 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.1, 302, 303
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.1, 302, 303 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.1, 302, 303
Gastrointestinal Bleeding, Ulceration, and Perforation
A boxed warning is included in the prescribing information concerning the increased risk of serious GI adverse effects with diclofenac.1, 302, 303, 317 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, 302, 303, 317 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1, 302, 303, 317 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, 302, 303, 317 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.1, 302, 303 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, 302, 303, 317 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
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.1, 302, 317 In addition to a history of ulcer disease, other factors that may increase the risk for GI bleeding include 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.1, 302, 303, 317 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.1, 302, 303, 317
To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.1, 302, 303, 317 In addition, use of NSAIAs should be avoided in patients at higher risk 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.1, 302, 303, 317
findings from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.1, 302, 303, 317 Results from a Danish National Registry study of patients with heart failure indicated that NSAIAs increased the risk of myocardial infarction, hospitalization for heart failure, and death.1, 302, 303, 317
Fluid retention and edema also have been observed in some patients receiving NSAIAs.1, 302, 303, 317 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists).1, 302, 303, 317
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.1, 302, 303, 317
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, 302, 303, 317 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.1, 302, 303, 317 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, 302, 303, 317 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, 302, 303, 317
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).1, 302, 303, 317
Because diclofenac is almost completely metabolized in the liver, patients with hepatic impairment may require reduced oral dosages of the drug.1, 302, 303
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 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), or ACE inhibitors.1, 302, 303, 317 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.1, 302, 303, 317
Renal Toxicity and Hyperkalemia
Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1, 302, 303, 317 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 Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor, or angiotensin II receptor antagonist concomitantly; and geriatric patients.1, 302, 303, 317 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.1, 302, 303, 317 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1, 302, 303, 317
The renal effects of diclofenac may hasten the progression of renal dysfunction in patients with preexisting renal disease.1, 302, 303, 317 Patients with preexisting renal disease should be monitored for worsening renal function.1, 302, 303, 317
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 If diclofenac is used in patients with advanced renal disease, close monitoring of renal function is recommended.1, 302, 303, 317
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.1, 302, 303, 317
Anaphylactic reactions have been reported in patients with and without known sensitivity to diclofenac and in patients with aspirin-sensitive asthma.1, 302, 303, 317 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
Exacerbation of Asthma Related to Aspirin Sensitivity
Because patients with asthma may have aspirin-sensitive asthma, patients with asthma but without known aspirin sensitivity who are receiving diclofenac should be monitored for changes in manifestations of asthma.1, 302, 303, 317 Because of cross-sensitivity between NSAIAs and aspirin in aspirin-sensitive patients, NSAIAs, including diclofenac, are generally contraindicated in such patients.1, 302, 303, 317 In patients with asthma, aspirin sensitivity is manifested principally as chronic rhinosinusitis with severe, potentially fatal, bronchospasm and usually is associated with nasal polyps.1, 302, 303, 317
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving diclofenac.1, 302, 303, 317 fixed drug eruption (FDE) can also occur, or the more severe, potentially life-threatening variant known as generalized bullous fixed drug eruption (GBFDE).1, 302, 303, 317 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 Diclofenac should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1, 302, 303, 317 Diclofenac is contraindicated in patients with previous serious skin reactions to NSAIAs.1, 302, 303, 317
Drug Reaction with Eosinophilia and Systemic Symptoms
Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1, 302, 303, 317 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1, 302, 303, 317 Symptoms may resemble those of an acute viral infection.1, 302, 303, 317 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1, 302, 303, 317 If such signs or symptoms develop, diclofenac should be discontinued and the patient evaluated immediately.1, 302, 303, 317
Fetal/Neonatal Morbidity and Mortality
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios, and in some cases, neonatal renal impairment.1, 302, 303, 317 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1, 302, 303, 317 In animal studies, NSAIAs, including diclofenac, inhibit prostaglandin synthesis, delay parturition, and increase the incidence of stillbirth.1, 302, 303
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1, 302, 303, 317 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.1, 302, 303, 317 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1, 302, 303, 317 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1, 302, 303, 317
Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1, 302, 303, 317
Administration of misoprostol, a component of Arthrotec®, during pregnancy can cause uterine rupture, abortion, preterm birth and birth defects.284 Diclofenac sodium in fixed combination with misoprostol is contraindicated in women who are pregnant.284 In addition, it is recommended that diclofenac in fixed combination with misoprostol be used in women of reproductive potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.284
It is recommended to verify pregnancy status in women of reproductive potential within 2 weeks of initiating diclofenac sodium in fixed combination with misoprostol.264
Anemia has been reported in patients receiving NSAIAs.1, 302, 303, 317 Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.1, 302, 303, 317
NSAIAs, including diclofenac, may increase the risk of bleeding.1, 302, 303, 317 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.1, 302, 303, 317 If signs and/or symptoms of anemia or blood loss occur during therapy with diclofenac, hemoglobin concentration and hematocrit should be determined.1, 302, 303, 317
Masking of Inflammation and Fever
The antipyretic and anti-inflammatory effects of diclofenac may mask the usual signs and symptoms of infection.1, 302, 303, 317
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning, patients receiving long-term NSAIA therapy should have a CBC and chemistry profile performed periodically.1, 302, 303, 317
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, 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, 324, 326, 327 Patients should be advised to consult a clinician if ocular irritation persists for longer than 1 hour.317, 324, 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
Even after diclofenac epolamine transdermal systems (Flector® or Licart®) have been used, there is a large amount of diclofenac epolamine remaining in the transdermal system (up to 170 mg).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
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 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
Use of NSAIAs during pregnancy at about ≥30 weeks' gestation can cause premature closure of the fetal ductus arteriosus, and use at about ≥20 weeks' gestation has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1, 302, 303, 317 Because of these risks, use of NSAIAs should be avoided in pregnant women at about ≥30 weeks' of gestation; if NSAIA therapy is necessary between about 20<30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1, 302, 303, 317 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1, 302, 303, 317 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<30 weeks of gestation.1, 302, 303, 317
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1, 302, 303, 317 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.1, 302, 303, 317 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1, 302, 303, 317 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1, 302, 303, 317 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1, 302, 303, 317 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1, 302, 303, 317 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1, 302, 303, 317 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1, 302, 303, 317
There are no studies evaluating the effects of diclofenac on labor and delivery in humans.1, 302, 303 In animal studies, NSAIAs, including diclofenac, inhibit prostaglandin synthesis, delay parturition, and increase the incidence of stillbirth.1, 302, 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 reproductive potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.284
Diclofenac may be distributed into human milk.1, 302, 303 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.1, 302, 303
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.1, 302, 303, 317
Females and Males of Reproductive Potential
Use of NSAIAs, including diclofenac, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1, 302, 303, 317 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.1, 302, 303, 317 Therefore, withdrawal of diclofenac should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1, 302, 303, 317
Reproduction studies in male and female rats using diclofenac sodium dosages up to 4 mg/kg (approximately 0.2 times the maximum recommended human dose [MRHD] based on body surface area) daily have not revealed evidence of impaired fertility.1, 302, 303
Safety and efficacy of diclofenac epolamine transdermal system (Flector®) have been established in pediatric patients ≥6 years of age based on quality evidence in adults and an open-label study conducted in 104 pediatric patients ≥6 years of age with minor soft tissue injuries.317 The available evidence indicates that the safety of diclofenac epolamine transdermal system (Flector®) is similar in pediatric patients compared to adults.317 Safety and efficacy of diclofenac epolamine transdermal system (Flector®) have not been established in pediatric patients <6 years of age.317
Safety and efficacy of diclofenac potassium liquid-filled capsules have been established in pediatric patients 12-17 years of age.331 Use of the drug in this age group is based on quality evidence in adults and pharmacokinetic and safety data from 2 open-label studies in a total of 125 pediatric patients ranging from 12-17 years of age.331 The plasma concentrations and safety profile of diclofenac were found to be similar in adolescents compared to healthy adults.331 Safety and efficacy of diclofenac potassium liquid-filled capsules have not been established in pediatric patients <12 years of age.331
The manufacturers state that safety and efficacy of other formulations of diclofenac in children have not been established.1, 302, 303, 324, 326, 327, 328, 336
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.128, 210
Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.1, 302, 303, 317 The risk of these adverse effects may be increased in geriatric patients with renal impairment or receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy.284 Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.1, 302, 303, 317 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.1, 302, 303, 317
Diclofenac sodium in fixed combination with misoprostol should be avoided in geriatric patients with cardiovascular and/or renal risk factors.284 In clinical trials of diclofenac sodium in fixed combination with misoprostol, 25.5% of patients were ≥65 years of age.284 No overall differences in efficacy were observed between geriatric patients and younger adults.284 Other clinical experience has not identified differences in response compared to younger adults, although a greater sensitivity to the drug cannot be ruled out in older individuals.284 No clinically meaningful differences in diclofenac and misoprostol pharmacokinetics were observed in geriatric patients compared to younger adults.284
In phase 3 clinical trials of diclofenac sodium 1.5% topical solution, 49% of patients receiving the drug were ≥65 years of age.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, while 13% were ≥75 years of age.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 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, 303 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, 303
Diclofenac is completely eliminated via hepatic metabolism, therefore patients with hepatic dysfunction may require reduced dosages of the drug.1, 302, 303
Diclofenac oral solution should only be used in patients with hepatic impairment if benefits outweigh the risks.328
The pharmacokinetics of diclofenac epolamine transdermal systems have not been evaluated in patients with hepatic impairment.317, 324
In a limited number of patients with biopsy-confirmed cirrhosis or chronic active hepatitis, plasma concentrations and urinary elimination of diclofenac following administration of 100 mg of oral solution were similar to those in healthy patients.284 In pharmacokinetic studies of misoprostol in patients with mild to moderate hepatic impairment, average misoprostol acid exposure (based on AUC) values and peak plasma concentrations were increased approximately 2-fold compared to healthy patients.284
No differences in diclofenac pharmacokinetics have been observed in patients with renal insufficiency.1, 302, 303 Diclofenac should be avoided in patients with advanced renal disease unless the benefits outweigh the risk of worsening renal function.1, 302, 303
The pharmacokinetics of diclofenac epolamine transdermal systems have not been evaluated in patients with renal impairment.317, 324
Pharmacokinetic studies evaluating a single 400 mcg misoprostol dose in patients with severe renal impairment receiving hemodialysis found that the elimination half-life, peak plasma concentration and AUC of misoprostol doubled compared to patients with normal renal function.284
Adverse effects reported in 1-10% of patients receiving diclofenac sodium delayed-release tablets, diclofenac potassium conventional tablets, or other NSAIAs, include GI effects (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers, and vomiting).1, 303 Other common adverse effects include abnormal renal function, anemia, dizziness, edema, elevations in hepatic transaminases, headaches, increased bleeding time, pruritic, rashes, and tinnitus.1, 303
Adverse effects reported in ≥2% of patients receiving diclofenac in fixed combination with misoprostol include abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, increases in ALT, and decreases in hematocrit.284
The most common adverse effects reported in adults receiving diclofenac epolamine transdermal system (Flector®) include pruritis (5%) and nausea (3%).317 The most common adverse effects in pediatric patients were headache (9%) and application site pruritis (7%).317 Application site pruritis and application site reactions were also common adverse effects in patients receiving diclofenac epolamine transdermal system (Licart®).324
Adverse effects reported with diclofenac potassium for oral solution include nausea and dizziness (≥1% of patients).328
Adverse effects reported with diclofenac sodium ophthalmic solution include transient burning and stinging (15%), elevated intraocular pressure following cataract surgery (15%) and keratitis in up to 28% of patients, although keratitis was noted prior to treatment in many of these patients.264 Lacrimation complaints were also reported in approximately 30% of cases undergoing incisional refractive surgery.264 Other adverse effects reported in ≤10% of patients include abnormal vision, acute elevated intraocular pressure, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, eye pain, injection (redness), iritis, irritation, itching, lacrimation disorder, and ocular allergy.264
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 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
When nonsteroidal anti-inflammatory agents (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
Because magnesium-containing antacids may exacerbate 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; antacids have also been shown to delay the absorption of diclofenac.284
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, 317 Therefore, blood pressure should be monitored during therapy with these concomitant agents 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
The effects of warfarin and NSAIAs on GI bleeding are synergistic.1, 302, 303, 317 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
Use diclofenac with caution and carefully monitor for signs of bleeding in patients receiving any anticoagulant (e.g., warfarin). 302
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 Patients should be monitored for signs of worsening renal function.302
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
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, 302, 303, 317, 318 In addition, NSAIAs may interfere with the natriuretic response to diuretics (e.g., furosemide, thiazides).302, 303, 317 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
Concomitant use of diclofenac and potassium-sparing diuretics may be associated with increased serum potassium concentrations.284
Diclofenac increases plasma lithium concentrations and reduces renal lithium clearance.1, 302, 303, 317 With concomitant NSAIA use, the mean increase in trough lithium concentrations is 15% and renal clearance is decreased by approximately 20%; this effect has been attributed to inhibition of renal prostaglandin synthesis.302 If diclofenac and lithium are administered concurrently, the patient should be closely observed for signs of lithium toxicity.1, 302, 303, 317
Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).302 Patients receiving concomitant diclofenac and methotrexate therapy should be monitored for methotrexate toxicity.302
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, 324 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, 324
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, 317
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
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
Diclofenac exhibits anti-inflammatory, analgesic, and antipyretic activity.1, 317 The exact mechanisms have not been clearly established, but involves the inhibition of 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2).1 The mode of action of diclofenac appears to be associated principally with the reduction of prostaglandin synthesis in peripheral tissues.1 In animal models, prostaglandins in body tissues sensitize afferent nerves and potentiate the action of bradykinin to induce pain.1 Prostaglandins also are mediators of inflammation.1
Diclofenac sodium and diclofenac potassium are almost completely absorbed from the GI tract; however, the drugs undergo extensive first-pass metabolism in the liver, with only about 50% of a dose of diclofenac sodium or diclofenac potassium reaching systemic circulation as unchanged drug.1, 302, 303 Diclofenac also is absorbed into systemic circulation following topical application to the skin as a gel, solution, or transdermal system.317, 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 Peak plasma concentrations of diclofenac generally occur within 1 hour (range: 0.33-2 hours) after oral administration of diclofenac potassium conventional tablets.303, 336 Peak plasma concentrations of delayed-release diclofenac sodium tablets occur at a mean of 2.3 hours.1 Following oral administration of a single 25-mg dose as diclofenac potassium liquid-filled capsules under fasting conditions, peak diclofenac concentrations occur at a mean of 0.47 hours.331 Following oral administration of diclofenac sodium as an extended-release tablet, mean peak plasma concentrations generally occur at 5.3 hours.302
Food decreases the rate of absorption of conventional tablets of diclofenac potassium and of delayed-release tablets of diclofenac sodium, resulting in delayed and decreased peak plasma concentrations; however, the extent of absorption is not affected substantially.1, 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 tablets are taken with food, the onset of absorption usually is delayed by 1-4.5 hours and peak plasma concentrations are decreased by <20%.1 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
Diclofenac is absorbed into systemic circulation following topical application, but plasma concentrations generally are very low compared with oral administration.317, 324 Following application of a single diclofenac epolamine transdermal system (Flector®) to intact skin on the upper arm, peak plasma diclofenac concentrations occur in 10-20 hours.317 Diclofenac concentrations in pediatric patients ≥6 years of age are similar to adults following application of the diclofenac epolamine transdermal system.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 occur in 4-20 hours.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 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 Studies have not established whether application of heat, occlusive dressings, or exercise following application of the 2% topical solution affects systemic absorption of the drug.327
Diclofenac is >99% protein bound.1, 302, 303 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 sodium and diclofenac potassium in healthy subjects is a mean of 2.3 hours and 1.9 hours, respectively.1, 302, 303
five metabolites of diclofenac have been detected in human plasma and urine, which include 4'-hydroxy- (the principal metabolite of diclofenac), 5-hydroxy-, 3'-hydroxy-, 4',5-hydroxy-, and 3'-hydroxy-4'methoxydiclofenac.302 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 Diclofenac and its metabolites undergo glucuronidation or sulfation followed by biliary excretion.302
Diclofenac is excreted in urine and feces, with only minimal amounts being excreted in the urine unchanged.302 Following oral administration of diclofenac, about 65% of a dose is excreted in urine and about 35% is excreted in feces.302 Because renal elimination is not a significant pathway for unchanged diclofenac, no dosage adjustment of diclofenac is needed in patients with mild to moderate renal impairment.302
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Transdermal System | 1.3% | Flector® | IBSA |
Licart® | IBSA |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, liquid-filled | 25 mg* | Diclofenac Potassium Capsules | |
Zipsor® | Assertio | |||
For oral solution | 50 mg* | Cambia® | Assertio | |
Diclofenac Potassium for Oral Solution | ||||
Tablets, film-coated | 25 mg* | Diclofenac Potassium Tablets | ||
Cataflam® | ||||
50 mg* | Diclofenac Potassium Tablets | |||
Cataflam® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, delayed-release | 25 mg* | Diclofenac Sodium Delayed-release Tablets | |
50 mg* | Diclofenac Sodium Delayed-release Tablets | |||
75 mg* | Diclofenac Sodium Delayed-release Tablets | |||
Tablets, extended-release | 100 mg* | Diclofenac Sodium Extended-release Tablets | ||
Topical | Gel | 3%* | Diclofenac Sodium Topical Gel | |
Solution | 1.5%* | Diclofenac Sodium Topical Solution | ||
2%* | Diclofenac Sodium Topical Solution | |||
Ophthalmic Solution | 0.1%* | Diclofenac Sodium Ophthalmic Solution |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, delayed-release (enteric-coated core), film-coated | 50 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer* | Arthrotec® | Pfizer |
Diclofenac Sodium and Misoprostol Delayed-release Tablets | ||||
75 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer* | Arthrotec® | Pfizer | ||
Diclofenac Sodium and Misoprostol Delayed-release Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Carlsbad Technology, Inc. Diclofenac sodium delayed-release tablets prescribing information. Carlsbad, CA; 2024 Jul.
74. Bendix T, Schmidt I, Rasmussen KJE et al. Diclofenac (Voltaren®) and ketoprofen (Orudis®), in rheumatoid arthritis: a randomized double-blind multicentre trial. Curr Ther Res . 1983; 33:192-9.
75. Huntwork JC. Efficacy and safety of diclofenac compared with aspirin in the treatment of rheumatoid arthritis. Curr Ther Res . 1986; 40:576-86.
76. Keiding G, Sorensen K. A randomized, double- blind, within-patient trial of diclofenac sodium (Voltaren®) and naproxen in the treatment of rheumatoid arthritis. Curr Ther Res . 1981; 29:183-92.
77. Hirsch U. Effect and tolerability of diclofenac and indomethacin administered per os and as suppositories: a comparative trial. Curr Ther Res . 1980; 28:359-66.
78. Meyers OL, Quantock OP, Joubert PG et al. A multicentre trial of Voltaren in the treatment of rheumatoid arthritis. S Afr Med J . 1974; 48:2013-7. [PubMed 4612752]
79. Caldwell JR. Efficacy and safety of diclofenac sodium in rheumatoid arthritis: experience in the United States. Am J Med . 1986; 80(Suppl 4B):43-7. [PubMed 3518432]
80. Zuckner J. International experience with diclofenac in rheumatoid arthritis. Am J Med . 1986; 80(Suppl 4B):39-42. [PubMed 3518431]
81. Ward JR. Efficacy of diclofenac in osteoarthritis. Am J Med . 1986; 80(Suppl 4B):53-7. [PubMed 3518434]
82. Altman R. International experiences with diclofenac in osteoarthritis. Am J Med . 1986; 80(Suppl 4B):48-52. [PubMed 3518433]
83. Amundsen T, Bleken L, Borkje B et al. Variation in response to naproxen and diclofenac in patients with osteoarthritis. Curr Ther Res . 1983; 33:793-801.
84. Germain BF. A placebo-controlled study of diclofenac sodium for the treatment of osteoarthritis of the hip and knee. Curr Ther Res . 1985; 37:259-68.
85. Schubiger BI, Ciccolunghi SN, Tanner K. Once daily dose treatment with a non-steroidal anti- rheumatic drug (diclofenac) in osteoarthrosis. J Int Med Res . 1980; 8:167-74. [PubMed 6989687]
86. Vetter G. A comparison of naproxen and diclofenac sodium in the treatment of osteoarthritis in elderly patients. Br J Clin Pract . 1985; 39:276-281. [PubMed 3896286]
87. Eidsaunet W, Borkje B, Larsen S et al. Response to two NSAIDs: diclofenac and naproxen in rheumatoid arthritis. Curr Ther Res . 1983; 33:966-75.
88. Lizarazo PH, Cortes MP. Single-blind parallel study comparing naproxen with sulindac and with diclofenac in rheumatoid arthritis. Curr Ther Res . 1983; 34:701-7.
89. Siraux P. Diclofenac (Voltaren®) for the treatment of osteo-arthrosis: a double-blind comparison with naproxen. J Int Med Res . 1977; 5:169-74. [PubMed 330288]
90. Crook PR, Fowler PD, Hothersall TE et al. A study of the efficacy and tolerability of diclofenac and ibuprofen in osteoarthritis of the hip. Br J Clin Pract . 1981; 35:309-12. [PubMed 7034760]
91. Calabro JJ. Efficacy of diclofenac in ankylosing spondylitis. Am J Med . 1986; 80(Suppl 4B):58-63. [PubMed 3518435]
92. Kantor TG. Use of diclofenac in analgesia. Am J Med . 1986; 80(Suppl 4B):64-9. [PubMed 2939715]
104. Ingemanson CA, Sikstrom B, Bjorkman R. Comparison between diclofenac and naproxen in the treatment of primary dysmenorrhoea. Curr Ther Res . 1984; 36:1203-09.
105. Ingemanson CA, Carrington B, Sikstrom B et al. Diclofenac in the treatment of primary dysmenorrhoea. Curr Ther Res . 1981; 30:632-9.
108. Berry H, Bloom B, Hamilton EBD. A comparative study of piroxicam (Feldene) diclofenac and placebo in osteoarthritis. Clin Trials J . 1982; 19:349-58.
109. Marcolongo R, Giordano N, Bassi GP et al. Double-blind preference and compliance multicentre study in osteoarthritis: once-a-day treatment. Clin Rheumatol . 1985; 4:267-77. [PubMed 3905218]
110. Scharf Y, Nahir M, Schapira D et al. A comparative study of naproxen with diclofenac sodium in osteoarthrosis of the knees. Rheumatol Rehabil . 1982; 21:167-70. [PubMed 7048497]
111. Car A, Jajic I, Krampac I et al. A double- blind multicentre comparison of diclofenac sodium and naproxen in osteoarthrosis of the hip. Scand J Rheumatol . 1978; Suppl 22:63-8.
112. Chiswell RJ, Grieve AP, MacDonald IR. An interim report on a multicentre general practice study of Voltarol: 2. Osteoarthritis. Br J Clin Pract . 1984; 34:207-10.
113. Aylward M, Maddock J, Lewis PA et al. Mefenamic acid and diclofenac sodium in osteoarthritis of the weight bearing joints: a double blind comparison. Br J Clin Pract . 1985; 39:135-9. [PubMed 3893502]
114. Joubert PH, Kushlick AR, McNeill WG et al. South African multicentre trial with Voltaren in osteo- arthritis of the knee. S Afr Med J . 1974; 48:1973-8. [PubMed 4608209]
115. Huskisson EC, Dieppe PA, Scott J et al. Diclofenac sodium, diflunisal and naproxen: patient preferences for anti-inflammatory drugs in rheumatoid arthritis. Rheumatol Rehabil . 1982; 21:238-42. [PubMed 7134745]
116. Kirchheiner B, Trang L, Wollheim FA. Diclophenac sodium (Voltaren®) in rheumatoid arthritis: a double-blind comparison with indomethacin and placebo. Int J Clin Pharmacol . 1976; 13:292-7.
117. Weisman MH. Double-blind randomized trial of diclofenac sodium versus placebo in patients with rheumatoid arthritis. Clin Ther . 1986; 8:427-38. [PubMed 3524843]
118. Dürrigl T, Vitaus M, Pucar I et al. Diclofenac sodium (Voltaren): results of a multi-centre comparative trial in adult-onset rheumatoid arthritis. J Int Med Res . 1975; 3:139-44. [PubMed 162669]
119. Tannenbaum H, Esdaile J, Topp JR et al. A double-blind, multicenter, controlled study on diclofenac (Voltaren®) and naproxen in patients with rheumatoid arthritis (R.A.). Curr Ther Res . 1984; 35:357-62.
120. Nahir AM, Scharf Y. A comparative study of diclofenac and sulindac in ankylosing spondylitis. Rheumatol Rehabil . 1980; 19:193-8. [PubMed 6997973]
125. Ciccolunghi SN, Chaudri HA, Schubiger BI et al. Report on a long-term tolerability study of up to two years with diclofenac sodium (voltaren). Scand J Rheumatol . 1978; 22(Suppl):86-96.
126. Caldwell JR. Diclofenac sodium in the treatment of rheumatoid arthritis and osteoarthritis. Semin Arthritis Rheum . 1985; 15:73-9. [PubMed 4081794]
127. Khan MA. A double blind comparison of diclofenac and indomethacin in the treatment of ankylosing spondylitis. J Rheumatol . 1987; 14:118-23. [PubMed 3553586]
128. Haapasaari J, Wuolijoki E, Ylijoki H. Treatment of juvenile rheumatoid arthritis with diclofenac sodium. Scand J Rheumatol . 1983; 12:325- 30. [PubMed 6361986]
129. Bijlsma A. The long-term efficacy and tolerability of Voltaren (diclofenac sodium) and indomethacin in rheumatoid arthritis. Scand J Rheumatol . 1978; 22:74-80.
133. Machtey I. Diclofenac in the treatment of painful joints and traumatic tendinitis (including strains and sprains): a brief review. Semin Arthritis Rheum . 1985; 15:87-92. [PubMed 4081796]
134. Huskisson EC, Bryans R. Diclofenac sodium in the treatment of painful stiff shoulder. Curr Med Res Opin . 1983; 8:350-3. [PubMed 6340976]
136. Famaey JP, Ginsberg F. Treatment of periarthritis of the shoulder: a comparison of ibuprofen and diclofenac. J Int Med Res . 1984; 12:238-43. [PubMed 6381167]
140. Riihiluoma P, Wuolijoki E, Pulkkinen MO. Treatment of primary dysmenorrhea with diclofenac sodium. Eur J Obstet Gynecol Reprod Biol . 1981; 12:189-194. [PubMed 7028529]
154. Valtonen EJ. A comparative short-term trial with Voltaren (diclofenac sodium) and naproxen in soft-tissue rheumatism. Scand J Rheumatol . 1978; 22:69-73.
210. Leak AM, Richter MR, Clemens LE et al. A crossover study of naproxen, diclofenac and tolmetin in seronegative juvenile chronic arthritis. Clin Exp Rheumatol . 1988; 6:157-60. [PubMed 3052965]
222. Flygare U, Seuri M, Hurme J et al. Relief of spasm with diclofenac. Clin Rheum . 1988; 7:124-5.
227. Alembic Pharmaceuticals, Inc. Diclofenac sodium 3% topical gel prescribing information. Bedminster, NJ: 2025 Jan.
264. Bausch & Lomb, Inc. Diclofenac sodium 0.1% ophthalmic solution prescribing information. Tampa, FL: 2022 Jun.
277. Morán M. Double-blind comparison of diclofenac potassium, ibuprofen and placebo in the treatment of ankle sprains. J Int Med Res . 1991; 19:121-30. [PubMed 1864448]
278. Morán M. An observer-blind comparison of diclofenac potassium, piroxicam and placebo in the treatment of ankle sprains. Curr Med Res Opin . 1990; 12:268-74. [PubMed 2127562]
279. Bahamonde LA, Saavedra H. Comparison of the analgesic and anti-inflammatory effects of diclofenac potassium versus piroxicam versus placebo in ankle sprain patients. J Int Med Res . 1990; 18:104-11. [PubMed 2111251]
284. Pfizer. Arthrotec® (diclofenac sodium and misoprostol tablets) prescribing information. New York, NY; 2024 Nov.
302. Oceanside Pharmaceuticals. Diclofenac sodium extended-release tablets prescribing information. Bridgewater, NJ; 2024 Nov.
303. Zydus Pharmaceuticals. Diclofenac potassium film-coated tablets prescribing information. Pennington, NJ; 2024 Jul.
317. IBSA Pharma. Flector® (diclofenac epolamine) topical patch prescribing information. Parsippany, NJ; 2024 Nov.
318. Haleon US Holdings LLC. Voltaren® Arthritis Pain (diclofenac sodium 1%) topical gel drug facts. Warren, NJ; 2024 Mar.
320. Galer BS, Rowbotham M, Perander J et al. Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial. J Pain Symptom Manage . 2000; 19:287-94. [PubMed 10799795]
321. Anon. Diclofenac gel for osteoarthritis. Med Lett Drugs Ther . 2008; 50:31-2.
324. IBSA Pharma. Licart® (diclofenac epolamine) transdermal system prescribing information. Parsippany, NJ; 2024 Nov.
326. Amneal Pharmaceuticals. Diclofenac sodium 1.5% topical solution prescribing information. Bridgewater, NJ; 2024 Jul.
327. Horizon Medicines. Pennsaid® (diclofenac sodium) 2% topical solution prescribing information. Deerfield, IL; 2024 Nov.
328. Assertio Therapeutics. Cambia® (diclofenac potassium) for oral solution prescribing information. Lake Forest, IL; 2024 Nov.
329. Lipton RB, Grosberg B, Singer RP et al. Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia . 2010; 30:1336-45. [PubMed 20959428]
330. Kolasinski SL, Neogi T, Hochberg MC et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol . 2020; 72:220-233. [PubMed 31908163]
331. Assertio Therapeutics. Zipsor® (diclofenac potassium) liquid-filled capsules prescribing information. Lake Forest, IL; 2024 Nov.
333. Daniels SE, Baum DR, Clark F et al. Diclofenac potassium liquid-filled soft gelatin capsules for the treatment of postbunionectomy pain. Curr Med Res Opin . 2010; 26:2375-84. [PubMed 20804444]
334. Riff DS, Duckor S, Gottlieb I et al. Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: a Phase III, multicenter, randomized, double-blind, placebo-controlled study conducted over 5 days. Clin Ther . 2009; 31:2072-85. [PubMed 19922878]
336. Carwin Pharmaceuticals Assoc. Lofena® (diclofenac potassium) film-coated tablets prescribing information. Hazlet, NJ; 2021 Jul.
337. Wadsworth LT, Kent JD, Holt RJ. Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Curr Med Res Opin. 2016;32(2):241-50.
338. Walker C, Essex MN, Li C, Park PW. Celecoxib versus diclofenac for the treatment of ankylosing spondylitis: 12-week randomized study in Norwegian patients. J Int Med Res. 2016 Jun;44(3):483-95.
339. Verkleij SP, Luijsterburg PA, Willemsen SP, Koes BW, Bohnen AM, Bierma-Zeinstra SM. Effectiveness of diclofenac versus paracetamol in knee osteoarthritis: a randomised controlled trial in primary care. Br J Gen Pract. 2015 Aug;65(637):e530-7.
340. Barthel HR, Haselwood D, Longley S 3rd, Gold MS, Altman RD. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009 Dec;39(3):203-12.
341. Altman RD, Dreiser RL, fisher CL, Chase WF, Dreher DS, Zacher J. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009 Sep;36(9):1991-9.
342. Simon LS, Grierson LM, Naseer Z, Bookman AAM, Shainhouse ZJ. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009 Jun;143(3):238-245.
343. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004 Oct 11;164(18):2017-23.
344. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskelet Disord. 2005 Aug 8;6:44.
345. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004 Oct;31(10):2002-12.
346. Heller B, Tarricone R. Oxaprozin versus diclofenac in NSAID-refractory periarthritis pain of the shoulder. Curr Med Res Opin. 2004 Aug;20(8):1279-90.
347. Liang TH, Hsu PN. Double-blind, randomised, comparative trial of etodolac SR versus diclofenac in the treatment of osteoarthritis of the knee. Curr Med Res Opin. 2003;19(4):336-41.
348. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol. 2001;30(1):11-8.
349. Goei Thè HS, Lund B, Distel MR, Bluhmki E. A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 1997 Jul;5(4):283-8.
350. Hosie J, Distel M, Bluhmki E. Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium. Br J Rheumatol. 1996 Apr;35 Suppl 1:39-43.
351. Gerecz-Simon E, Soper WY, Kean WF, Rooney PJ, Tugwell P, Buchanan WW. A controlled comparison of piroxicam and diclofenac in patients with osteoarthritis. Clin Rheumatol. 1990 Jun;9(2):229-34.
352. Esteller-Martínez V, Paredes-García J, Valmaseda-Castellón E, Berini-Aytés L, Gay-Escoda C. Analgesic efficacy of diclofenac sodium versus ibuprofen following surgical extraction of impacted lower third molars. Med Oral Patol Oral Cir Bucal. 2004 Nov-Dec;9(5):448-53; 444-8.
353. Baraf HS, Gold MS, Clark MB, Altman RD. Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sportsmed. 2010 Jun;38(2):19-28.
354. Lonauer G, Tisscher JR, Lim HG, Bijlsma JW. Double-blind comparison of etodolac and diclofenac in patients with rheumatoid arthritis. Curr Med Res Opin. 1993;13(2):70-7.
355. Grisanti AM, Vaz AA, Samara AM. Comparison of etodolac and diclofenac in osteoarthritis of the knee. Clin Ther. 1992 Nov-Dec;14(6):791-800.
356. Crowley B, Hamill JJ, Lyndon S, McKellican JF, Williams P, Miller AJ. Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment of rheumatoid arthritis: a comparative controlled clinical trial. Curr Med Res Opin. 1990;12(3):143-50.
357. Gostick N, James IG, Khong TK, Roy P, Shepherd PR, Miller AJ. Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment of osteoarthritis: a comparative controlled clinical trial in general practice. Curr Med Res Opin. 1990;12(3):135-42.
358. Derry S, Wiffen PJ, Moore RA. Single dose oral diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev. 2015 Jul 7;2015(7):CD004768.
359. Moore RA, Derry S. Diclofenac Potassium in Acute Postoperative Pain and Dysmenorrhoea: Results from Comprehensive Clinical Trial Reports. Pain Res Manag. 2018 Jan 17;2018:9493413.
360. Iacovides S, Baker FC, Avidon I. The 24-h progression of menstrual pain in women with primary dysmenorrhea when given diclofenac potassium: a randomized, double-blinded, placebo-controlled crossover study. Arch Gynecol Obstet. 2014 May;289(5):993-1002.
361. Huskisson EC, Scott DL. A clinical comparison of two leading non-steroidal anti-inflammatory drugs. Eur J Rheumatol Inflamm. 1991;11(2):4-7.
1223. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021 Jul;61(7):1021-1039.
2001. Fraenkel L, Bathon J, England B, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939.
2003. Ringold S, Angeles-Han ST, Beukelman T et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Arthritis Care Res (Hoboken). 2019; 71:717-734.
2006. fitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, Gelber AC, Harrold LR, Khanna D, King C, Levy G, Libbey C, Mount D, Pillinger MH, Rosenthal A, Singh JA, Sims JE, Smith BJ, Wenger NS, Bae SS, Danve A, Khanna PP, Kim SC, Lenert A, Poon S, Qasim A, Sehra ST, Sharma TSK, Toprover M, Turgunbaev M, Zeng L, Zhang MA, Turner AS, Neogi T. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020 Jun;72(6):744-760.
2008. Ward MM, Deodhar A, Gensler LS et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019; 71:1599-1613.
2009. Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2022 Apr;74(4):553-569.
2010. Qaseem A, McLean RM, O'Gurek D, Batur P, Lin K, Kansagara DL; Clinical Guidelines Committee of the American College of Physicians; Commission on Health of the Public and Science of the American Academy of Family Physicians; Cooney TG, Forciea MA, Crandall CJ, fitterman N, Hicks LA, Horwitch C, Maroto M, McLean RM, Mustafa RA, Tufte J, Vijan S, Williams JW Jr. Nonpharmacologic and Pharmacologic Management of Acute Pain From Non-Low Back, Musculoskeletal Injuries in Adults: A Clinical Guideline From the American College of Physicians and American Academy of Family Physicians. Ann Intern Med. 2020 Nov 3;173(9):739-748.
2012. ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. Obstet Gynecol. 2018;132(6):e249-e258.
2013. Chou R, Gordon D, de Leon-Casaola O, et al. Management of Postoperative Pain: A Clinical Practice Guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157.
2015. Ferries-Rowe E, Corey E, Archer J. Primary dysmenorrhea. Diagnosis and Therapy. Obstet Gynecol. 2020;136(5):1047-1058.