Introduction

Prototypical NSAIA; phenylacetic acid derivative; structurally related to meclofenamate sodium and mefenamic acid.

Uses for Diclofenac (Systemic)

Inflammatory Diseases

Orally for symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

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

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

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

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

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

Pain

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

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

Migraine

Orally (as solution) for acute treatment of attacks of migraine with or without aura; should not be used for prophylaxis of migraine.

Safety and efficacy not established for treatment of cluster headache (an older, predominantly male population).

Dysmenorrhea

Orally for symptomatic management of primary dysmenorrhea.

Diclofenac (Systemic) Dosage and Administration

General

• Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.

Administration

Oral Administration

Diclofenac sodium delayed-release (enteric-coated) and extended-release tablets are not recommended for relief of acute pain or primary dysmenorrhea because of slow onset of action.

Oral Solution

Empty the contents of one packet containing 50 mg of buffered diclofenac potassium powder for oral solution into a cup containing 30–60 mL of water, mix well, and administer immediately. Do not use liquids other than water.

Administration with food may decrease peak plasma concentrations and reduce efficacy compared with administration on an empty stomach.

Topical Administration

Diclofenac Sodium 1% Gel

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

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

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

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

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

Diclofenac Sodium 1.5 or 2% Topical Solution

Topical 1.5% solution: Administer as drops dispensed directly onto affected knee(s); alternatively, administer into palm of hand and apply to affected knee(s). To avoid spillage, apply drops in 4 increments of 10 drops each per joint; following each incremental application, spread solution evenly around the front, back, and sides of the knee.

Topical 2% solution: Administer via pump dispenser (2 pump actuations per affected joint) into palm of hand; then evenly apply the entire volume of solution around the front, back, and sides of the knee. Pump must be primed before first use by fully depressing the pump mechanism 4 times while holding the bottle in an upright position.

Wait until treated area is dry before covering with clothing; wait ≥30 minutes before bathing or showering.

Wash hands after application.

Avoid skin-to-skin contact between other individuals and the treated area until the area is completely dry.

Do not apply to open wounds, infected or inflamed areas of skin, or areas affected with exfoliative dermatitis; avoid contact with eyes and mucous membranes.

Do not expose treated knee to external heat, and avoid exposing treated knee to natural or artificial sunlight; also avoid use of occlusive dressings.

Allow treated knee to dry completely before applying other topical preparations (e.g., sunscreen, insect repellant, lotions, moisturizers, cosmetics, other topical medications) to the same area.

Diclofenac Epolamine Transdermal System

Apply transdermal system to the most painful area once daily (Licart) or twice daily (Flector). Apply to intact skin; do not apply to damaged skin (e.g., wounds, burns, infected areas of skin, areas affected with eczema or exudative dermatitis).

Wash hands after handling the system.

Avoid contact with eyes and mucous membranes.

Do not wear the transdermal system 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. If problems with adhesion persist, a nonocclusive mesh netting sleeve (e.g., Curad Hold Tite, Surgilast Tubular Elastic Dressing) may be used when appropriate (e.g., over ankles, knees, or elbows) to secure the system.

Dosage

Available as diclofenac potassium, diclofenac sodium, or diclofenac epolamine; dosage expressed in terms of the salt.

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals. Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.

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

Different strengths and formulations of oral diclofenac are not interchangeable. Commercially available diclofenac sodium enteric-coated tablets, diclofenac sodium extended-release tablets, and diclofenac potassium immediate-release tablets are not necessarily bioequivalent on a mg-per-mg basis. Diclofenac potassium liquid-filled capsules and conventional tablets are not equivalent.

Each actuation of the pump dispenser of diclofenac sodium 2% topical solution delivers 20 mg of diclofenac sodium in 1 g of solution. The 1.5% topical solution contains diclofenac sodium 16.05 mg/mL. The 1% gel contains 10 mg of diclofenac sodium per 1 g of gel.

Adults

Inflammatory Diseases

Oral

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

Osteoarthritis

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.

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

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

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

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

Diclofenac sodium 1.5% topical solution: 40 drops (approximately 1.2 mL) applied to each affected knee 4 times daily.

Diclofenac sodium 2% topical solution: 40 mg (2 pump actuations) applied to each affected knee twice daily.

Rheumatoid Arthritis

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.

Ankylosing Spondylitis

100–125 mg daily (as diclofenac sodium delayed-release tablets); administer as 25 mg 4 times daily, with 5th dose at bedtime as needed.

Pain

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets). Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).

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

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

Topical (transdermal system)

Apply 1 transdermal system (diclofenac epolamine 1.3%) once daily (Licart) or twice daily (Flector).

Migraine

Oral

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

Dysmenorrhea

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets). Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).

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

Prescribing Limits

Adults

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

Inflammatory Diseases

Osteoarthritis

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

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

Migraine

Oral

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

Special Populations

Renal Impairment

Dosage adjustment not required. (See Renal Impairment under Cautions.)

Hepatic Impairment

Reduction of oral dosage may be necessary.

Manufacturer of diclofenac potassium liquid-filled capsules recommends initiating treatment at the lowest dosage; if efficacy is not achieved at that dosage, discontinue diclofenac and consider alternative therapy.

Contraindications

• Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to diclofenac or any ingredient in the formulation.

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.

• In the setting of CABG surgery.

• Diclofenac sodium in fixed combination with misoprostol: Contraindicated in pregnant women.

• Diclofenac epolamine transdermal system: Use on nonintact or damaged skin, regardless of etiology (e.g., exudative dermatitis, eczema, infected lesions, burns, wounds), is contraindicated.

Warnings/Precautions

Warnings

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

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.

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

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.

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

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.

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

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.

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

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

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia. Contraindicated in the setting of CABG surgery.

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

GI Effects

Serious, sometimes fatal, GI toxicity (e.g., bleeding, ulceration, perforation of esophagus, stomach, or small or large intestine) can occur with or without warning symptoms.

Risk for GI bleeding increased more than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.

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

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.

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

Use at lowest effective dosage for the shortest duration necessary.

Avoid use of more than one NSAIA at a time. (See Specific Drugs under Interactions.)

Avoid use of NSAIAs in patients at higher risk for GI toxicity unless expected benefits outweigh increased risk of bleeding; consider alternate therapies in high-risk patients and those with active GI bleeding.

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

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.

If serious adverse GI event suspected, promptly initiate evaluation and discontinue diclofenac until serious adverse GI event ruled out.

Other Warnings and Precautions

Hepatic Effects

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

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

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

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

Use at lowest effective dosage for the shortest duration necessary; use with caution in patients receiving other potentially hepatotoxic drugs (e.g., acetaminophen, certain antibiotics, anticonvulsant agents).

Discontinue immediately if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations (e.g., eosinophilia, rash) occur.

Hypertension

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

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

Heart Failure and Edema

Fluid retention and edema reported.

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

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

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.

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

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.

Potential for overt renal decompensation. Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist. (See Renal Impairment under Cautions.)

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

Hyperkalemia

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

Hypersensitivity Reactions

Anaphylactic reactions reported. Immediate medical intervention and discontinuance for anaphylaxis.

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

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs. Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Symptoms may resemble those of acute viral infection. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash. If signs or symptoms of DRESS develop, discontinue diclofenac and immediately evaluate the patient.

Dermatologic Reactions

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

Hematologic Effects

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

NSAIAs may increase the risk of bleeding. Patients with certain coexisting conditions (e.g., coagulation disorders) or receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk; monitor such patients for bleeding. (See Specific Drugs under Interactions.)

May inhibit platelet aggregation and prolong bleeding time.

Precautions Specific to Diclofenac Sodium Topical Gel or Solution

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

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

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

Precautions Specific to Diclofenac Epolamine Transdermal System

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

Do not apply to nonintact or damaged skin.

Patient should bathe or shower after removing one transdermal system and before applying a new system; the transdermal system should not be worn during bathing or showering.

Store and discard transdermal systems in a manner that avoids accidental exposure or ingestion by children or pets.

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of NSAIAs, 5-HT₁ receptor agonists, ergotamine, or opiates on a regular basis for ≥10 days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks. Detoxification, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often include transient worsening of headaches), may be necessary.

Use of Fixed Combinations

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

Concomitant NSAIA Therapy

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

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.

May mask certain signs of infection.

Obtain CBC and chemistry profile periodically during long-term use.

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.

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

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

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

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

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

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

Fixed combination of diclofenac and misoprostol: Contraindicated in pregnant women. Misoprostol exhibits abortifacient activity and can cause serious fetal harm.

Lactation

May be distributed into milk; consider the developmental and health benefits of breast-feeding along with the mother's clinical need for diclofenac and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Fertility

NSAIAs may be associated with reversible infertility in some women. Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.

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

Pediatric Use

Safety and efficacy not established in children.

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

Geriatric Use

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

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

Diclofenac sodium 1.5% topical solution: No age-related differences in the incidence of adverse effects observed.

Diclofenac epolamine transdermal system: Insufficient experience in individuals ≥65 years of age to determine whether geriatric patients respond differently than younger individuals.

Diclofenac potassium oral solution: Insufficient experience in individuals ≥65 years of age to determine whether geriatric patients respond differently than younger individuals.

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

Hepatic Impairment

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

Renal Impairment

Metabolites eliminated principally via the kidney.

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

Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function; close monitoring of renal function advised if used.

Common Adverse Effects

Oral diclofenac: Abdominal pain or cramps, constipation, diarrhea, flatulence, GI bleeding, GI perforation, peptic ulcer, vomiting, dyspepsia, nausea, dizziness, headache, liver function test abnormalities, renal function abnormalities, anemia, prolonged bleeding time, pruritus, rash, tinnitus, edema.

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

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

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

General

• Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.

Administration

Oral Administration

Diclofenac sodium delayed-release (enteric-coated) and extended-release tablets are not recommended for relief of acute pain or primary dysmenorrhea because of slow onset of action.

Oral Solution

Empty the contents of one packet containing 50 mg of buffered diclofenac potassium powder for oral solution into a cup containing 30–60 mL of water, mix well, and administer immediately. Do not use liquids other than water.

Administration with food may decrease peak plasma concentrations and reduce efficacy compared with administration on an empty stomach.

Topical Administration

Diclofenac Sodium 1% Gel

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

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

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

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

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

Diclofenac Sodium 1.5 or 2% Topical Solution

Topical 1.5% solution: Administer as drops dispensed directly onto affected knee(s); alternatively, administer into palm of hand and apply to affected knee(s). To avoid spillage, apply drops in 4 increments of 10 drops each per joint; following each incremental application, spread solution evenly around the front, back, and sides of the knee.

Topical 2% solution: Administer via pump dispenser (2 pump actuations per affected joint) into palm of hand; then evenly apply the entire volume of solution around the front, back, and sides of the knee. Pump must be primed before first use by fully depressing the pump mechanism 4 times while holding the bottle in an upright position.

Wait until treated area is dry before covering with clothing; wait ≥30 minutes before bathing or showering.

Wash hands after application.

Avoid skin-to-skin contact between other individuals and the treated area until the area is completely dry.

Do not apply to open wounds, infected or inflamed areas of skin, or areas affected with exfoliative dermatitis; avoid contact with eyes and mucous membranes.

Do not expose treated knee to external heat, and avoid exposing treated knee to natural or artificial sunlight; also avoid use of occlusive dressings.

Allow treated knee to dry completely before applying other topical preparations (e.g., sunscreen, insect repellant, lotions, moisturizers, cosmetics, other topical medications) to the same area.

Diclofenac Epolamine Transdermal System

Apply transdermal system to the most painful area once daily (Licart) or twice daily (Flector). Apply to intact skin; do not apply to damaged skin (e.g., wounds, burns, infected areas of skin, areas affected with eczema or exudative dermatitis).

Wash hands after handling the system.

Avoid contact with eyes and mucous membranes.

Do not wear the transdermal system 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. If problems with adhesion persist, a nonocclusive mesh netting sleeve (e.g., Curad Hold Tite, Surgilast Tubular Elastic Dressing) may be used when appropriate (e.g., over ankles, knees, or elbows) to secure the system.

Dosage

Available as diclofenac potassium, diclofenac sodium, or diclofenac epolamine; dosage expressed in terms of the salt.

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals. Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.

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

Different strengths and formulations of oral diclofenac are not interchangeable. Commercially available diclofenac sodium enteric-coated tablets, diclofenac sodium extended-release tablets, and diclofenac potassium immediate-release tablets are not necessarily bioequivalent on a mg-per-mg basis. Diclofenac potassium liquid-filled capsules and conventional tablets are not equivalent.

Each actuation of the pump dispenser of diclofenac sodium 2% topical solution delivers 20 mg of diclofenac sodium in 1 g of solution. The 1.5% topical solution contains diclofenac sodium 16.05 mg/mL. The 1% gel contains 10 mg of diclofenac sodium per 1 g of gel.

Adults

Inflammatory Diseases

Oral

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

Osteoarthritis

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.

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

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

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

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

Diclofenac sodium 1.5% topical solution: 40 drops (approximately 1.2 mL) applied to each affected knee 4 times daily.

Diclofenac sodium 2% topical solution: 40 mg (2 pump actuations) applied to each affected knee twice daily.

Rheumatoid Arthritis

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.

Ankylosing Spondylitis

100–125 mg daily (as diclofenac sodium delayed-release tablets); administer as 25 mg 4 times daily, with 5th dose at bedtime as needed.

Pain

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets). Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).

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

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

Topical (transdermal system)

Apply 1 transdermal system (diclofenac epolamine 1.3%) once daily (Licart) or twice daily (Flector).

Migraine

Oral

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

Dysmenorrhea

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets). Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).

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

Prescribing Limits

Adults

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

Inflammatory Diseases

Osteoarthritis

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

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

Migraine

Oral

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

Special Populations

Renal Impairment

Dosage adjustment not required. (See Renal Impairment under Cautions.)

Hepatic Impairment

Reduction of oral dosage may be necessary.

Manufacturer of diclofenac potassium liquid-filled capsules recommends initiating treatment at the lowest dosage; if efficacy is not achieved at that dosage, discontinue diclofenac and consider alternative therapy.

Metabolized by CYP isoenzymes, mainly CYP2C9. CYP3A4, uridine diphosphate-glucuronosyltransferase (UGT) 2B7, and CPY2C8 may contribute to metabolism.

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 inhibitors: Possible increased systemic exposure to diclofenac and risk of adverse effects. Dosage adjustment may be required. Examples include but are not limited to voriconazole.

CYP2C9 inducers: Possible reduced efficacy of diclofenac. Dosage adjustment may be required. Examples include, but are not limited to, rifampin.

Protein-bound Drugs

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

Specific Drugs