Diclofenac

AHFS Class: Other Nonsteroidal Anti-inflammatory Agents (28:08.04.92)

VA Class: MS120
Chemical Name: 2-[(2,6-Dichlorophenyl)amino]-benzeneacetic acid monopotassium salt
Chemical Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid monosodium salt
Molecular Formula: C₁₄H₁₁C₁₂NO₂•Na

View the associated Essentials monograph.

Introduction

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

Uses

Inflammatory Diseases

Diclofenac sodium and diclofenac potassium are used for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis,^{1 74 75 76 77 78 79 80 87 88 107 115 116 117 118 119 121 125 126 129 254 262 302 303} osteoarthritis,^{1 81 82 83 84 85 86 89 90 107 108 109 110 111 112 113 114 121 125 126 133 274 302 303} ankylosing spondylitis, and other inflammatory conditions.^{1 91 120 121 125 127 274}

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

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

Rheumatoid Arthritis and Osteoarthritis

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

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

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.^{249 254} Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.²⁴⁹ DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.²⁴⁹ NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.^{249 254} (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.) Diclofenac has been used concomitantly with gold compounds,^{75 76 79 87 107 125} antimalarials,^{87 125} penicillamine,^{74 75 79 125} acetaminophen,^{74 76} and/or corticosteroids.^{75 79 87 107 125 132} Use of diclofenac with aspirin is not recommended,^{1 302 303} because the risk of serious adverse GI events may be increased^{1 302 303} and the pharmacokinetics of one or both of these drugs may be altered.^{1 22 61 184 202 302 303} (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Ankylosing Spondylitis

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

Juvenile Arthritis

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

Other Inflammatory Conditions

Diclofenac has been effective in a limited number of patients for the symptomatic relief of acute gouty arthritis†.^{121 130 131 132} The drug does not appear to correct hyperuricemia^{3 31} but has been used instead for its anti-inflammatory and analgesic effects to relieve pain, joint tenderness, and swelling associated with this condition.^{121 130 131 132}

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

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

Pain

Diclofenac potassium is used for symptomatic relief of postoperative pain (including that associated with orthopedic, gynecologic, and oral surgery) and orthopedic pain (including musculoskeletal sprains and traumatic joint distortions).^{276 277 278 279 303}

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

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

Diclofenac sodium also has been used for symptomatic relief of postoperative⁹² (including that associated with dental surgery),^{92 93 94} postpartum,⁹² and orthopedic (including musculoskeletal strains or sprains) pain†,^{92 95 96 97} and visceral pain associated with cancer†.^{122 211} Because of the relatively slow onset of action of delayed-release (enteric-coated) or extended-release tablets of diclofenac sodium,^{53 54 56 57 60 61} other more rapid-acting NSAIAs (e.g., diclofenac potassium) may be preferred when prompt relief of acute pain is required.^{1 3 248} Diclofenac also has been used parenterally† (a parenteral dosage form is currently not commercially available in the US) for the relief of acute biliary^{99 102 123 206 221} or renal colic†^{92 98 100 101 124} , and for relief of postoperative pain† (including that associated with gynecologic and orthopedic surgery).^{151 152 153}

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

Dysmenorrhea

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

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

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

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

Other Uses

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

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

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

For use of diclofenac sodium in the topical treatment of actinic keratoses, see Diclofenac Sodium 84:92.

Dosage and Administration

Administration

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

Diclofenac sodium, diclofenac sodium in fixed combination with misoprostol, and diclofenac potassium are administered orally.^{1 67 68 74 76 81 82 83 86 87 89 284 302 303} The drug also has been administered rectally†,^{51 52 137 139 240} parenterally† (by IM injection),^{99 102 123 206 221} and topically,^{227 264} but commercially available dosage forms for the rectal and parenteral routes of administration currently are not available in the US.

Dosage

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

Commercially available diclofenac sodium enteric-coated tablets (Voltaren^®), diclofenac sodium extended-release tablets (Voltaren^®-XR), and diclofenac potassium conventional tablets (Cataflam^®) are not necessarily bioequivalent on a mg per mg basis.^{1 302 303}

Inflammatory Diseases

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

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

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

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

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

Pain and Dysmenorrhea

When diclofenac potassium conventional tablets are used for relief of pain or primary dysmenorrhea, an initial dose of 50 mg is recommended, followed by 50 mg every 8 hours as needed; some patients may benefit from an initial dose of 100 mg, followed by 50 mg every 8 hours as needed.³⁰³

Dosage in Renal or Hepatic Impairment

Diclofenac dosage reductions do not appear to be necessary in patients with renal impairment.^{1 3 72 247 248 302 303} However, patients with substantially impaired renal function should be monitored closely during diclofenac therapy,^{1 3 302 303} because of potential risks of NSAIA therapy in such patients.^{1 302 303} (See Cautions: Renal, Electrolyte, and Genitourinary Effects.)

Diclofenac dosage reductions may be necessary in patients with hepatic impairment.^{1 302 303}

Cautions

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

Cardiovascular Effects

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

The association between cardiovascular complications and use of nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, is an area of ongoing concern and study.^{305 316} Selective COX-2 inhibitors have been associated with an increased risk of cardiovascular events in certain situations.³⁰⁵ Several prototypical NSAIAs also have been associated with an increased risk of cardiovascular events.^{312 313 314} Data from some long-term controlled studies that have included both a prototypical NSAIA and a COX-2 inhibitor have not clearly demonstrated that the risk of serious adverse cardiovascular events is greater with use of a COX-2 inhibitor than with use of a prototypical NSAIA.³⁰⁵ Findings from a recent systematic review of controlled observational studies and a meta-analysis of published and unpublished data from randomized studies of these agents suggest that use of celecoxib (dosage exceeding 200 mg daily), diclofenac, or indomethacin is associated with an increased risk of cardiovascular events.^{312 313 314 316} The possibility exists that meloxicam and ibuprofen also are associated with increased cardiovascular risk.^{312 314} Naproxen does not appear to be associated with increased or decreased cardiovascular risk.^{312 313 314 316} Data were insufficient to assess risk associated with use of other prototypical NSAIAs.^{312 313 314} (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Short-term use of NSAIAs to relieve acute pain, especially at low dosages, does not appear to be associated with an increased risk of serious cardiovascular events (except immediately following coronary artery bypass graft [CABG] surgery).³⁰⁵

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.^{1 302 303 305}

GI Effects

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

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

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.^{1 167 181 187 256 259 267 268 282 302 303} Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.^{1 302 303} Minor upper GI effects (e.g., dyspepsia), which usually develop early, occur commonly during NSAIA therapy, but the absence of such early GI manifestations does not preclude the development of serious GI toxicity in patients receiving chronic NSAIA therapy.^{1 167 181 302 303} Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.^{1 167 181 256 302 303} In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.^{1 167 181 302 303} 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}

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

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors.^{260 292} In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.^{260 292 300} Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.^{249 260 292} In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.^{1 167 181 259 302 303}

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

Nervous System Effects

Headache^{1 89 90 91 93 95 107 110 113 118 125 127 129 132 165 302 303} or dizziness^{1 102 107 113 125 129 165 302 303} has been reported in up to 10% of patients receiving diclofenac.^{1 302 303} Anxiety,^{1 302 303} asthenia,^{1 76 93 302 303} confusion,^{1 302 303} depression,^{1 302 303} abnormal dreams,^{1 302 303} drowsiness,^{1 98 302 303} insomnia,^{1 113 132 302 303} malaise,^{1 302 303} nervousness,^{1 302 303} paresthesia,^{1 165 302 303} somnolence,^{1 76 111 132 165 302 303} tremors,^{1 302 303} irritability,^{97 132} and vertigo^{1 78 96 118 132 302 303} have occurred occasionally in patients receiving the drug.^{1 302 303} Tingling sensation,⁸⁶ dreams,⁸⁶ myoclonus,²²⁰ and migraine¹²⁵ have occurred rarely. Although a causal relationship to diclofenac has not been established, seizures,^{1 302 303} coma,^{1 302 303} hallucinations, ^{1 302 303} and meningitis^{1 302 303} have been reported during therapy with the drug.

Renal, Electrolyte, and Genitourinary Effects

Diclofenac has caused impairment of renal function, resulting in acute renal failure,^{160 162 185 212} interstitial nephritis,^{1 159 185 212 302 303} nephrotic syndrome,^{160 215} increased BUN^{32 159} and serum creatinine concentrations,^{84 159} and renal papillary necrosis^{1 162 302 303} in patients receiving the drug.^{1 302 303} In at least one patient receiving diclofenac, acute renal failure became chronic.¹⁶⁰ Cystitis,^{1 302 303} dysuria,^{1 302 303} hematuria,^{1 302 303} oliguria/polyuria,^{1 165 186 302 303} and proteinuria^{1 159 302 303} have been reported occasionally in patients receiving diclofenac.^{1 302 303} Urinary tract infection,¹²⁵ renal calculi,¹²⁵ and hyponatremia¹⁶¹ have occurred rarely.

Hepatic Effects

Severe hepatic reactions, including jaundice^{1 163 165 223 255 302 303} and fatal fulminant hepatitis,^{1 164 214 255 302 303} liver necrosis,^{1 255 302 303} cholestasis,²⁵⁵ hepatic failure (sometimes fatal),^{1 302 303} asymptomatic hepatitis,⁷⁹ acute hepatitis,^{163 255} and chronic active hepatitis²⁵³ have been reported rarely in patients receiving diclofenac.^{155 255} Borderline (1.2–3 times the upper limit of normal) or greater elevations of one or more liver function test results have occurred in about 15% of patients treated with diclofenac.^{1 116 125 165 189 209 223 255 302 303} Liver function abnormalities associated with NSAIA therapy may progress, may remain essentially unchanged, or may be transient with continued therapy.^{1 302 303} Meaningful (more than 3 times the upper limit of normal) elevations of serum AST (SGOT) concentration have occurred in approximately 2–4% of patients at some time during diclofenac therapy.^{1 79 302 303} In one large, open, controlled study, meaningful or marked (more than 8 times the upper limit of normal) elevations of serum AST and/or ALT (SGPT) concentrations occurred in 4 or 1% of patients, respectively, receiving diclofenac for 2–6 months.^{1 79 155 302 303} Increased serum concentrations of bilirubin have been reported rarely in patients receiving diclofenac therapy.²⁵⁵

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

Diclofenac should be discontinued if signs or symptoms of a severe hepatic reaction occur.^{1 255 302 303} (See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

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

Sensitivity reactions, including anaphylaxis; swelling of the eyelids, tongue, lips, pharynx, or larynx; urticaria; asthma; bronchospasm; laryngeal edema; dyspnea; chest tightness; wheezing; anaphylactoid reactions; eosinophilic pneumonitis and angioedema, sometimes with concomitant, potentially severe hypotension, have been reported in patients receiving diclofenac.^{168 223 261 280 302 303}

Otic and Ocular Effects

Tinnitus has occurred in up to 10% of patients receiving diclofenac.^{1 75 302 303}

Adverse ocular effects¹³² (including blurred vision^{1 302 303} and conjunctivitis)^{1 302 303} and hearing impairment^{1 302 303} have occurred in diclofenac-treated patients.

Hematologic Effects

Anemia^{1 74 83} has been reported in up to 10% of patients receiving diclofenac.¹ Leukopenia,^{1 125 302 303} thrombocytopenia,^{1 155 225 302 303} purpura,^{1 302 303} ecchymosis,^{1 302 303} eosinophilia,^{1 302 303} melena,^{1 302 303} and rectal bleeding^{1 302 303} have occurred occasionally in patients receiving diclofenac.^{1 302 303} Agranulocytosis,^{1 302 303} lymphadenopathy,^{1 302 303} hemolytic anemia,^{1 189 225 302 303} aplastic anemia,^{1 207 302 303} and pancytopenia^{1 302 303} have been reported rarely in diclofenac-treated patients.^{1 302 303} Bruising in the extremities and abdomen,^{219 258} spontaneous bleeding,^{165 166} and hematoma formation¹⁶⁶ also have been reported rarely in patients receiving the drug.^{165 166 219} Diclofenac may inhibit platelet aggregation^{1 3 40 41 42 43} and prolong bleeding time.^{3 40 41 42 43 165 166 258 302 303} Diclofenac usually does not affect platelet count, prothrombin time, partial thromboplastin time, or thrombin time.^{1 166 302 303}

Respiratory Effects

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

Other Adverse Effects

Fever,^{1 302 303} infection,^{1 302 303} and sepsis^{1 302 303} have occurred in patients receiving diclofenac.^{1 302 303} Back, leg, or joint pain and hyperglycemia have occurred rarely.¹²⁵ Although a causal relationship to diclofenac has not been established, weight changes^{1 86 125 302 303} have occurred in patients receiving the drug.^{1 302 303}

Precautions and Contraindications

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

Patients should be advised that diclofenac, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that, rarely, more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, can occur.^{1 167 181 302 303 305} Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases (e.g., rheumatoid arthritis), and the drugs have a major role in the management of pain.^{1 167 181 302 303} Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.^{1 167 181 268 302 303 305}

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.^{1 302 303}

NSAIAs (i.e., certain prototypical NSAIAs, selective COX-2 inhibitors) may increase the risk of serious adverse cardiovascular thrombotic events.^{1 302 303 312 313 314 316} (See Cautions: Cardiovascular Effects.) Patients with known cardiovascular disease or risk factors for cardiovascular disease may be at increased risk for NSAIA-associated cardiovascular events.^{1 302 303} 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} Clinicians and patients receiving NSAIAs (including those without previous s