diclofenac 1.5% topical soln generic klofensaid ii

Uses

Inflammatory Diseases

Diclofenac sodium and diclofenac potassium are used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and other inflammatory conditions.

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

Diclofenac sodium 1% gel (Voltaren gel) is used topically for the symptomatic treatment of osteoarthritis-related joint pain. The gel is used for joints amenable to topical therapy (e.g., hands, knees); the gel has not been evaluated for use on joints of the spine, hip, or shoulder.

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

Rheumatoid Arthritis and Osteoarthritis

When used in the symptomatic treatment of rheumatoid arthritis, oral diclofenac has relieved pain and stiffness; reduced swelling, tenderness, and the number of joints involved; and improved mobility and grip strength. In the symptomatic treatment of osteoarthritis, diclofenac has relieved pain and stiffness, improved knee joint function, and increased range of motion and functional activity. Diclofenac appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process.

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual oral dosages of diclofenac sodium in the management of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of salicylates, diflunisal, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, phenylbutazone (no longer commercially available in the US), piroxicam, or sulindac. 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. 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. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.(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. Disease modifying antirheumatic drugs (DMARDs) (e.g., abatacept, adalimumab, anakinra, etanercept, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, rituximab, sulfasalazine) have the potential to reduce or prevent joint damage and to preserve joint integrity and function. DMARDs are used in conjunction with anti-inflammatory agents (i.e., NSAIAs, intra-articular and oral glucocorticoids) and physical and occupational therapies for the management of rheumatoid arthritis. DMARD therapy should be initiated early in the disease course to prevent irreversible joint damage. (For further information on the treatment of rheumatoid arthritis, including considerations in selecting a DMARD regimen, .) Diclofenac has been used concomitantly with gold compounds, antimalarials, penicillamine, acetaminophen, and/or corticosteroids. Use of diclofenac with aspirin is not recommended, because the risk of serious adverse GI events may be increased and the pharmacokinetics of one or both of these drugs may be altered.(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

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.

Ankylosing Spondylitis

In the symptomatic treatment of ankylosing spondylitis, oral diclofenac appears to provide relief of spinal pain, tenderness and/or spasm, morning stiffness, and pain at rest (including night pain) and to improve motion, posture, chest expansion, and spinal mobility. 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 or sulindac. 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.

Juvenile Arthritis

Diclofenac has been used orally with good results in a number of children for the management of juvenile rheumatoid arthritis. Results of these studies suggest that usual dosages of the drug are more effective than placebo and at least as effective as usual dosages of salicylates, naproxen, or tolmetin in decreasing the number of painful, swollen, and tender joints. 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

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

Oral diclofenac also has been used for the symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis), sciatic pain, backache, myositis, and radiohumeral bursitis (radiohumeral epicondylitis, tennis elbow). 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.

Oral or topical diclofenac has been used for the symptomatic treatment of infusion-related superficial thrombophlebitis. 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.

Pain

Diclofenac potassium is used orally 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). Diclofenac epolamine transdermal system is used for symptomatic relief of acute pain due to minor strains, sprains, and contusions.

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

In patients with dental extraction or gynecologic surgery pain, single oral 50- and 100-mg doses of diclofenac potassium have been reported to be as effective as single 650-mg doses of aspirin; the duration of diclofenac potassium's analgesic effect appears to be longer than that of aspirin. 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. 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.

Diclofenac sodium also has been used orally for symptomatic relief of postoperative (including that associated with dental surgery), postpartum, and orthopedic (including musculoskeletal strains or sprains) pain, and visceral pain associated with cancer. Because of the relatively slow onset of action of delayed-release (enteric-coated) or extended-release tablets of diclofenac sodium, other more rapid-acting NSAIAs (e.g., diclofenac potassium) may be preferred when prompt relief of acute pain is required. Diclofenac also has been used parenterally (a parenteral dosage form is currently not commercially available in the US) for the relief of acute biliary or renal colic , and for relief of postoperative pain (including that associated with gynecologic and orthopedic surgery).

When used to relieve mild to moderate acute pain, single oral diclofenac sodium doses of 50-150 mg have been more effective than placebo and at least as effective as usual analgesic doses of other NSAIAs or mild opiate analgesics. 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 oral surgery pain, 50-mg doses of diclofenac sodium have been reported to be as effective as 100-mg doses of pentazocine.

Efficacy of diclofenac epolamine transdermal system for the management of pain in patients with minor strains, sprains, and contusions has been demonstrated in 2 of 4 clinical studies. 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.

Dysmenorrhea

Diclofenac potassium is used orally in the management of primary dysmenorrhea. 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.

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

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.

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

Other Uses

Oral diclofenac sodium has been used for its antipyretic effect in the management of fever, usually associated with infection. 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. The drug, however, should not be used routinely as an antipyretic because of its potential adverse effects.

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. Similar findings have been reported from some other, but not all, observational studies.

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

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.

Diclofenac sodium, diclofenac sodium in fixed combination with misoprostol, and diclofenac potassium are administered orally. The drug also has been administered rectally and parenterally (by IM injection), but commercially available dosage forms for the rectal and parenteral routes of administration currently are not available in the US.

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

Diclofenac epolamine is administered by topical application of a transdermal system. Patients receiving diclofenac epolamine transdermal system (Flector) should be instructed in the use of the system and given a copy of the patient information provided by the manufacturer. The transdermal system should be applied to the most painful area twice daily. 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. Hands should be washed after handling the system. Contact with the eyes and mucous membranes should be avoided. The transdermal system should not be worn while bathing or showering. If a system should begin to peel off during the period of use, the edges of the system may be taped to the skin.

Dosage

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

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

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.

Inflammatory Diseases

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

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. For the management of rheumatoid arthritis, the usual initial adult dosage of diclofenac sodium extended-release tablets is 100 mg daily. 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.

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. 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. 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. Instead, dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. If clinically indicated, supplemental doses of misoprostol or diclofenac as the individual component can be administered with the fixed combination.

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. For the management of osteoarthritis, the recommended adult dosage of diclofenac sodium extended-release tablets is 100 mg daily.

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. 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. 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. Instead, dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. If clinically indicated, supplemental doses of misoprostol or diclofenac as the individual component can be administered with the fixed combination.

When diclofenac sodium 1% gel (Voltaren gel) is used for the management of lower extremity (i.e., knees, ankles, feet) joint pain due to osteoarthritis, 4 g of gel is massaged into the affected joint 4 times daily. When the gel is used for the management of upper extremity (i.e., elbows, wrists, hands) joint pain, 2 g of gel is massaged into the affected joint 4 times daily. The total daily dose applied to all affected joints should not exceed 32 g of gel, with no more than 16 g of gel applied daily to any single lower extremity joint and no more than 8 g of gel applied daily to any single upper extremity joint.

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. When diclofenac potassium is used for the management of ankylosing spondylitis, a dosage of 50 mg twice daily has been suggested by the manufacturers.

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

When diclofenac epolamine transdermal system (Flector) is used for relief of acute pain due to strains, sprains, and contusions, one system is applied to the most painful area twice daily.

Dosage in Renal or Hepatic Impairment

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

Reduction of oral diclofenac dosage may be necessary in patients with hepatic impairment.

Cautions

Adverse reactions to oral diclofenac are usually mild and transient and mainly involve the upper GI tract; however, adverse effects may be severe enough to require discontinuance of the drug in about 1.5-2% of patients. Most diclofenac-induced adverse effects occur during the first 3-6 months of treatment. The relationship of the frequency of adverse effects to dosage remains to be established. 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. 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.

Cardiovascular Effects

Fluid retention manifested principally as edema has occurred in up to 10% of patients receiving oral diclofenac. Adverse cardiovascular effects reported occasionally in diclofenac-treated patients include congestive heart failure, hypertension, tachycardia, and syncope. Arrhythmia, myocardial infarction, chest pain, palpitations, vasculitis, thrombophlebitis, hypotension, angina-like attack, and circulatory shock or distress have occurred rarely.

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

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. 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.

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. 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). 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.

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. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

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

Findings from some of these meta-analyses and systematic reviews also suggest that the cardiovascular risk associated with diclofenac, particularly at higher dosages (e.g., 150 mg or more daily), is similar to that observed with selective COX-2 inhibitors. Some authorities (e.g., Health Canada) now recommend that the dosage of systemically administered diclofenac not exceed 100 mg daily (except for the first day of treatment for dysmenorrhea).(See Dosage and Administration: Dosage.)

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

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

GI Effects

Adverse GI effects, which mainly involve the upper GI tract, occur in up to 10% of patients receiving oral diclofenac. Adverse GI effects require discontinuance of the drug in about 3% of patients. Peptic ulcer, GI bleeding, and/or perforation have been reported in up to 10% of patients receiving oral diclofenac in controlled clinical studies. 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. Nausea, diarrhea, constipation, abdominal pain or cramps, flatulence, vomiting, and dyspepsia occur in up to 10% of patients receiving oral diclofenac. Esophagitis, gastritis, glossitis, stomatitis, aphthous stomatitis, changes in appetite, dry mouth and mucous membranes, pancreatitis (with or without hepatitis), thirst, colitis, ulceration of the colon, and distress 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. Nausea, altered taste, dyspepsia, or other adverse GI effects (including gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth) have occurred in 1-3% of patients receiving diclofenac epolamine transdermal system.

Usual oral dosages of diclofenac sodium reportedly produce fewer adverse GI effects than usual anti-inflammatory dosages of aspirin or naproxen. 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. In healthy adults, the frequency of GI mucosal lesions observed with endoscopic examination was lower with diclofenac than with naproxen. 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.

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. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. 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. 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. 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. 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.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. 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. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. 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. 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.

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. 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. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. 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.

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. 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. 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. In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than prototypical NSAIAs. 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. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Nervous System Effects

Headache or dizziness has been reported in up to 10% of patients receiving oral diclofenac. Anxiety, asthenia, confusion, depression, abnormal dreams, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, irritability, and vertigo have occurred occasionally in patients receiving the drug. Tingling sensation, dreams, myoclonus, and migraine have occurred rarely. Headache, paresthesia, somnolence, or other adverse nervous system effects (including hypoesthesia, dizziness, and hyperkinesias) have occurred in 1% of patients receiving diclofenac epolamine transdermal system. Although a causal relationship to diclofenac has not been established, seizures, coma, hallucinations, and meningitis 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, interstitial nephritis, nephrotic syndrome, increased BUN and serum creatinine concentrations, and renal papillary necrosis in patients receiving the drug. In at least one patient receiving oral diclofenac, acute renal failure became chronic. Cystitis, dysuria, hematuria, oliguria/polyuria, and proteinuria have been reported occasionally in patients receiving diclofenac. Urinary tract infection, renal calculi, and hyponatremia have occurred rarely.

Hepatic Effects

Severe, sometimes fatal, hepatic reactions, including jaundice and fulminant hepatitis, liver necrosis, cholestasis, hepatic failure, asymptomatic hepatitis, acute hepatitis, and chronic active hepatitis, have been reported rarely in patients receiving diclofenac. 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. Liver function abnormalities associated with NSAIA therapy may progress, may remain essentially unchanged, or may be transient with continued therapy. Meaningful (more than 3 times the upper limit of normal) elevations of serum AST (SGOT) concentration have occurred in approximately 2% of patients at some time during therapy with diclofenac. In one large, open-label, controlled study, meaningful or marked (more than 8 times the upper limit of normal) elevations of serum AST and/or ALT (SGPT) concentrations occurred in 4 or 1% of patients, respectively, receiving diclofenac for 2-6 months. Increased serum concentrations of bilirubin have been reported rarely in patients receiving diclofenac therapy.

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

Diclofenac should be discontinued if signs or symptoms of a severe hepatic reaction occur.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Rash or pruritus occurs in up to 10% of patients receiving oral diclofenac. Other adverse dermatologic reactions, including alopecia, photosensitivity, and excessive perspiration, have occurred occasionally. Bullous eruption, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, urticaria, and angioedema, have occurred rarely.

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.

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

Application site reactions (i.e., pruritus, dermatitis, burning, dryness, irritation, erythema, atrophy, discoloration, hyperhidrosis, vesicles) have been reported in 11% of patients receiving therapy with diclofenac epolamine transdermal system in clinical studies. Rash also has been reported in patients receiving diclofenac epolamine transdermal system. Skin infection developed in one individual after the diclofenac system that had been applied to the foot was subjected to prolonged exposure to wetness. Edema and abnormal sensation at the treated site and allergic skin reactions also have been reported.

Otic and Ocular Effects

Tinnitus has occurred in up to 10% of patients receiving oral diclofenac.

Adverse ocular effects (including blurred vision and conjunctivitis) and hearing impairment have occurred in diclofenac-treated patients.

Hematologic Effects

Anemia has been reported in up to 10% of patients receiving oral diclofenac. Leukopenia, thrombocytopenia, purpura, ecchymosis, eosinophilia, melena, and rectal bleeding have occurred occasionally in patients receiving diclofenac. Agranulocytosis, lymphadenopathy, hemolytic anemia, aplastic anemia, and pancytopenia have been reported rarely in diclofenac-treated patients. Bruising in the extremities and abdomen, spontaneous bleeding, and hematoma formation also have been reported rarely in patients receiving the drug. Diclofenac may inhibit platelet aggregation and prolong bleeding time. Diclofenac usually does not affect platelet count, prothrombin time, partial thromboplastin time, or thrombin time.

Respiratory Effects

Asthma or dyspnea has been reported occasionally in patients receiving diclofenac. Respiratory tract infection (e.g., pneumonia, pharyngitis, bronchitis) or respiratory depression has been reported rarely.

Other Adverse Effects

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

Precautions and Contraindications

Multiple diclofenac-containing preparations should not be used concomitantly. Concomitant use of diclofenac sodium 1% gel with oral NSAIAs may result in increased adverse effects.

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.

Patients should be advised that diclofenac, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur. 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, and the drugs have a major role in the management of pain. 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.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. 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. 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.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving diclofenac should be advised not to take aspirin.

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. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.

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

The risk of potentially serious adverse GI effects should be considered in patients receiving diclofenac, particularly in patients receiving chronic therapy with the drug.(See Cautions: GI Effects.) Diclofenac should be used with caution and under close supervision in patients with a history of GI disease. Because peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.

Diclofenac should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or GI bleeding.To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.

Because severe hepatotoxic effects may develop without symptoms of liver dysfunction, serum transaminase values should be monitored periodically during long-term therapy with diclofenac. Serum transaminase values should be obtained 4-8 weeks after therapy with diclofenac is initiated. ALT (SGPT) is the recommended hepatic function marker for monitoring liver injury. Diclofenac should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).(See Cautions: Hepatic Effects.) 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.

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

Diclofenac should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), since the drug may inhibit platelet function. If signs and/or symptoms of anemia occur during therapy with diclofenac, hemoglobin concentration and hematocrit should be determined.

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, 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. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.

Diclofenac has not been evaluated in patients with severe renal impairment, and the manufacturers state that use of the drug is not recommended in patients with advanced renal disease. If diclofenac is used in patients with severe renal impairment, close monitoring of renal function is recommended.

Anaphylactoid reactions have been reported in patients receiving diclofenac. 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.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving diclofenac. 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. Diclofenac should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.

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

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

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

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

When diclofenac sodium 1% gel or diclofenac epolamine transdermal system is used, patients should be advised to avoid contact with the eyes or mucous membranes. If the gel or transdermal system does come in contact with the eyes, the eyes should be thoroughly rinsed with water or saline. Patients should be advised to consult a clinician if ocular irritation persists for longer than one hour.

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.

Topical application of diclofenac gel formulations has resulted in early onset of ultraviolet (UV) light-related skin tumors in animal studies. When diclofenac sodium 1% gel is used, it may be prudent to minimize or avoid exposure of treated areas to natural or artificial sunlight. The potential effects of topical diclofenac gel on skin response to UV damage in humans are not known.

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.

The manufacturers state that diclofenac is contraindicated in patients with known hypersensitivity to the drug. In addition, NSAIAs, including diclofenac, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, diclofenac should be used with caution in patients with asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. For a further discussion of cross-sensitivity of NSAIAs,

NSAIAs are contraindicated in the setting of CABG surgery.

Pediatric Precautions

The manufacturer states that safety and efficacy of diclofenac in children have not been established. However, oral diclofenac has been used with good results for the management of juvenile rheumatoid arthritis in a limited number of children 3-16 years of age. Further studies are needed to establish the optimum dosages and indications for use in children.

Geriatric Precautions

Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals. NSAIAs, including diclofenac, should be used with caution in geriatric patients 65 years of age or older.

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

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

Diclofenac is substantially excreted by the kidneys, and the risk of toxicity may be greater in patients with renal impairment. 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.

Mutagenicity and Carcinogenicity

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

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

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

Pregnancy, Fertility, and Lactation

Pregnancy

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

The effects of diclofenac on labor and delivery in humans currently are not known. There are no adequate and controlled studies to date using diclofenac in pregnant women. Diclofenac should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Diclofenac should not be used during late pregnancy, since inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus).

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. In addition, it is recommended that diclofenac in fixed combination with misoprostol be used in women of childbearing potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.

Fertility

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

Lactation

Because of the potential for serious adverse reactions to diclofenac in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Protein-bound Drugs

Because diclofenac is highly protein bound, it could be displaced from binding sites by, or it theoretically could displace from binding sites, other protein-bound drugs. In vitro studies suggest that diclofenac only minimally displaces from protein binding sites other highly protein-bound drugs (e.g., prednisolone, salicylates, tolbutamide, warfarin), although diclofenac may be displaced from binding sites by high doses of ionized protein-bound drugs (e.g., salicylates).

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.

Anticoagulants

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

In short-term controlled studies in patients receiving maintenance doses of coumarin derivatives, diclofenac did not substantially alter the hypothrombinemic effect of these anticoagulants when the drugs were administered concomitantly. However, because diclofenac may cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, the drug should be used with caution and the patient carefully observed if the drug is used concomitantly with any anticoagulant (e.g., warfarin).

Diuretics

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs, including diclofenac.(See Cautions: Precautions and Contraindications.) In addition, NSAIAs may interfere with the natriuretic response to diuretics with activity that depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., furosemide, thiazides). In patients with hypertension, the antihypertensive effect of hydrochlorothiazide was attenuated by diclofenac. Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.

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

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

Nonsteroidal Anti-inflammatory Agents

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving diclofenac should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

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

Following concomitant administration of diclofenac and aspirin in healthy individuals, protein binding of diclofenac is decreased, biliary excretion of diclofenac may be increased, and peak plasma concentrations and area under the plasma concentration-time curve (AUC) of diclofenac are reduced. Pretreatment with diclofenac for 14 days before administration of aspirin appeared to enhance renal elimination of salicylate. The clinical importance of these pharmacokinetic interactions remains to be determined.

Methotrexate

Severe, sometimes fatal, toxicity has occurred following concomitant administration of diclofenac and methotrexate. The toxicity was associated with elevated serum concentrations of methotrexate. Patients at greatest risk of this reaction are those with renal impairment and those receiving relatively high (e.g., antineoplastic) dosages of methotrexate. Caution is advised if methotrexate and an NSAIA are administered concomitantly.

Cyclosporine

Concomitant administration of diclofenac and cyclosporine may increase the nephrotoxic effects of cyclosporine; this interaction may be related to inhibition of renal prostaglandin (e.g., prostacyclin) synthesis. Diclofenac and cyclosporine should be used concomitantly with caution.

Lithium

Diclofenac increases plasma lithium concentrations and reduces renal lithium clearance. The mechanism involved in the reduction of lithium clearance by NSAIAs (including diclofenac) is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium. In one study in healthy women, plasma lithium concentration was increased by 26% and renal clearance was reduced by 23%. In a patient receiving 1 g of lithium daily together with diclofenac sodium dosages of 75 mg daily, plasma lithium concentrations increased about fivefold; manifestations of lithium intoxication developed but resolved following discontinuance of both diclofenac and lithium. If diclofenac and lithium are administered concurrently, the patient should be closely observed for signs of lithium toxicity and plasma lithium concentrations should be monitored carefully during the initial stages of combined therapy or subsequent dosage adjustment. In addition, appropriate adjustment of lithium dosage may be required when therapy with diclofenac is discontinued.

Quinolones

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

Antacids

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

Because magnesium-containing antacids may increase the incidence of misoprostol-induced diarrhea, concomitant administration of diclofenac in fixed combination with misoprostol with a magnesium-containing antacid is not recommended. Antacids and food appear to decrease the oral bioavailability of misoprostol.

Other Drugs

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

Pharmacokinetics

Absorption

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 50-60% of a dose of diclofenac sodium or diclofenac potassium reaching systemic circulation as unchanged drug. Diclofenac also is absorbed into systemic circulation following rectal administration and percutaneously following topical application to the skin as a gel or transdermal system.

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

Food decreases the rate of absorption of conventional tablets of diclofenac potassium and of delayed-release (enteric-coated) tablets of diclofenac sodium, resulting in delayed and decreased peak plasma concentrations; however, the extent of absorption is not affected substantially. 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%. When single doses of diclofenac sodium delayed-release (enteric-coated) tablets are taken with food, the onset of absorption usually is delayed by 1-4.5 hours but may be delayed up to 12 hours in some patients. These food-induced alterations in GI absorption of the drug result from delayed transit of the delayed-release (enteric-coated) tablets to the small intestine, the site of dissolution. 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. Absorption of diclofenac does not appear to be affected substantially by the presence of food following continuous dosing of the drug. Antacids also may decrease the rate but not the extent of absorption of diclofenac.

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

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

Following topical application of 4 g of diclofenac sodium 1% gel 4 times daily to one knee, mean peak plasma diclofenac concentrations of 15 ng/mL occur in about 14 hours. Following application of the gel to both knees and both hands 4 times daily (48 g of gel), mean peak plasma diclofenac concentrations of 53.8 ng/mL occur in about 10 hours. Systemic exposure to the drug at these dosage levels (16 or 48 g of gel daily) is about 6 or 20%, respectively, of the systemic exposure attained when diclofenac sodium is administered orally at a dosage of 50 mg 3 times daily. Application of a heat patch for 15 minutes before application of the gel did not affect systemic absorption. It has not been established whether application of a heat patch following gel application affects systemic absorption of the drug. Moderate exercise did not affect systemic absorption of the drug.

Distribution

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

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

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

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

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

Elimination

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

The exact metabolic fate of diclofenac has not been fully elucidated, but the drug is rapidly and extensively metabolized in the liver. Diclofenac undergoes extensive hydroxylation and subsequent conjugation with glucuronic acid, taurine amide, sulfuric acid, and other biogenic ligands. Conjugation of unchanged drug also may occur. Hydroxylation of the dichlorophenyl aromatic ring results in formation of 4'-hydroxydiclofenac (the principal metabolite of diclofenac) and 3'-hydroxydiclofenac, both of which subsequently undergo conjugation. Diclofenac also may undergo hydroxylation of the phenylacetic acid ring and subsequent conjugation to form conjugates of 5-hydroxydiclofenac and 4',5-dihydroxydiclofenac. Conjugation with glucuronic acid and taurine usually occurs at the carboxyl group of the phenylacetic ring, while conjugation with sulfuric acid mainly occurs at the 4' hydroxyl group of the dichlorophenyl aromatic ring; 3'- and/or 4'-hydroxydiclofenac may undergo further 4'-O-methylation to form 3'-hydroxy-4'-methoxydiclofenac.

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

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

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

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

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

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