Diclofenac (Topical)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Cream, Transdermal, as sodium:

EnovaRX-Diclofenac Sodium: 2.5% (120 g) [contains cetyl alcohol]

Rexaphenac: 1% (120 g) [contains isopropyl alcohol, propylene glycol]

Gel, Transdermal, as sodium:

Solaraze: 3% (100 g [DSC]) [contains benzyl alcohol, polyethylene glycol, sodium hyaluronate]

Voltaren: 1% (100 g) [contains isopropyl alcohol, propylene glycol]

Generic: 1% (100 g); 3% (100 g)

Kit, Transdermal, as sodium:

Diclo Gel: 1% [DSC] [contains isopropyl alcohol, propylene glycol]

DST Plus Pak: 1% [DSC] [contains isopropyl alcohol, propylene glycol]

Vopac MDS: 1.5% [DSC] [contains propylene glycol]

Patch, Transdermal, as epolamine:

Flector: 1.3% (5 ea, 30 ea) [contains edetate disodium, methylparaben, polysorbate 80, propylene glycol, propylparaben]

Generic: 1.3% (5 ea, 30 ea)

Solution, Transdermal, as sodium:

Klofensaid II: 1.5% (150 mL [DSC]) [contains alcohol, usp, dimethyl sulfoxide, glycerin, propylene glycol]

Pennsaid: 2% (2 g, 112 g) [contains propylene glycol]

Generic: 1.5% (150 mL)

Therapy Pack, Transdermal, as sodium:

Diclo Gel with Xrylix Sheets: 1% (1 ea [DSC]) [contains isopropyl alcohol, propylene glycol]

Diclozor: 1% (1 ea) [contains isopropyl alcohol, propylene glycol]

Lexixryl: 1.5% (1 ea [DSC]) [contains propylene glycol]

Xrylix: 1.5% (1 ea) [contains propylene glycol]

Pharmacology

Mechanism of Action

Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties

Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.

Pharmacokinetics/Pharmacodynamics

Absorption

Gel 3%: 6% to 10%

Metabolism

Hepatic; undergoes first-pass metabolism; forms several metabolites (1 with weak activity)

Excretion

Urine (~65%); feces (~35%)

Time to Peak

Serum: Patch: 10 to 20 hours; Solution 1.5%: 11 ± 6.4 hours (single application); Gel 3%: 4.5 ± 8 hours; Gel 1%: 10 to 14 hours.

Half-Life Elimination

Patch: ~12 hours; Solution 1.5%: 36.7 ± 20.8 hours (single application)

Protein Binding

>99%, primarily to albumin

Use: Labeled Indications

Gel 1%: Relief of osteoarthritis pain in joints amenable to topical therapy (eg, ankle, elbow, foot, hand, knee, wrist).

Gel 3%: Treatment of actinic keratosis in conjunction with sun avoidance.

Gel 1.16% (Voltaren Emulgel), 2.32% (Voltaren Emulgel Extra Strength) [Canadian products]: Relief of pain associated with acute, localized joint/muscle injuries (eg, sports injuries, strains) in patients ≥16 years of age (1.16% gel) or ≥18 years of age (2.32% gel).

Patch: Treatment of acute pain due to minor strains, sprains, and contusions in adults and children ≥6 years of age.

Solution: Treatment of osteoarthritis pain of the knee.

Contraindications

Hypersensitivity to diclofenac (eg, anaphylactic reaction, serious skin reactions) or any component of the formulation; history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; use in the setting of coronary artery bypass graft (CABG) surgery; use on nonintact or damaged skin, including exudative dermatitis, eczema, infected lesions, burns, or wounds.

Documentation of allergenic cross-reactivity for NSAIDs is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling):

Pennsaid: Concomitant use with other diclofenac containing products or other NSAIDS; active peptic ulcer; history of recurrent GI ulceration; active GI inflammatory disease; significant hepatic impairment or active hepatic disease; severely impaired or deteriorating renal function (CrCl <30 mL/minute); use in children; pregnancy; breastfeeding; prolonged treatment (>3 months)

Voltaren Emulgel: Concomitant use with other diclofenac-containing products or oral NSAIDS; pregnancy (last trimester)

Dosage and Administration

Dosing: Adult

Note: Solaraze gel has been discontinued in the United States for more than 1 year.

Note: Use the lowest effective dose for the shortest duration of time, consistent with individual patient treatment goals.

Actinic keratosis (AK): Topical: Apply 3% gel to lesion area twice daily for 60 to 90 days.

Acute pain (strains, sprains, contusions): Topical:

Patch: Apply 1 patch twice daily to most painful area.

Gel (Voltaren Emulgel [Canadian products]):

1.16%: Apply 2 g to 4 g to the skin over affected area(s) 3 or 4 times daily for up to 7 days

2.32%: Apply 2 g to the skin over affected area(s) twice daily for up to 7 days (maximum: 4 g/24 hours)

Osteoarthritis: Topical:

Gel: Note: Maximum total body dose of 1% gel should not exceed 32 g per day

Lower extremities: Apply 4 g of 1% gel to affected area 4 times daily (maximum: 16 g per joint per day)

Upper extremities: Apply 2 g of 1% gel to affected area 4 times daily (maximum: 8 g per joint per day)

Solution: Knee:

1.5% solution: Apply 40 drops to each affected knee 4 times daily

2% solution: Apply 2 pump actuations to each affected knee twice daily

Dosing: Geriatric

Start at lower end of dosing range. Refer to adult dosing.

Dosing: Pediatric

Pain, acute (strains, sprains, contusions): Topical: Note: Use the lowest effective dose for the shortest duration of time, consistent with individual patient treatment goals.

Patch (Flector): Children ≥6 years and Adolescents: Apply 1 patch 2 times daily to most painful area for up to 14 days; Note: Coadministration with oral NSAIDs is not recommended.

Gel (Voltaren Emulgel 1.16% [Canadian product]): Adolescents ≥16 years: Apply to skin of affected area(s) 3 or 4 times daily for up to 7 days; Note: 2 to 4 g should be adequate to treat an area 400 to 800 cm² (1 g is ~2 cm long strip of gel).

Administration

Gel: Do not apply to open wounds, eyes, or mucous membranes. Do not cover with occlusive dressings or apply heat, sunscreens, cosmetics, lotions, moisturizers, insect repellents, or other topical medications to affected area. Showering/bathing should be avoided for at least 1 hour following application. Wash hands immediately after application (unless hands are treated joint, then wait at least 1 hour to wash hands). Avoid sunlight to exposure areas. Avoid wearing clothes or gloves for ≥10 minutes after application.

1% formulation: Use dosing card to measure dose. Apply to affected area or joint and rub into skin gently, making sure to apply to entire affected area or joint.

3% formulation: Apply to lesion and smooth into skin gently.

Voltaren Emulgel [Canadian products]:

1.16% formulation: Apply to affected area and rub gently into skin; 1 g equals a strip ~2 cm long

2.32% formulation: Use dosing card to measure dose. Apply to affected area or joint and rub into skin gently, making sure to apply to entire affected area or joint.

Solution: Apply to clean, dry, intact skin; do not apply to eyes, mucous membranes, or open wounds. Wash hands before and after use. Do not shower or bathe for at least 30 minutes after applying. Allow knee to dry before applying clothing. Do not apply heat or occlusive dressing to treated knee; protect treated knee from sunlight. Cosmetics, insect repellant, lotion, moisturizer, sunscreens, or other topical medication may be applied to treated knee once solution has dried.

1.5% formulation: Apply 10 drops at a time either directly onto knee or into hand then onto knee (helps avoid spillage). Spread evenly around knee (front, back, sides). Repeat procedure until total dose applied and the knee is completely covered with solution.

2% formulation: The pump must be primed before first use. To prime, fully depress the pump 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle is required. Press the pump 2 times to deliver the solution onto the palm of the hand, and apply evenly around the front, back, and sides of the affected knee.

Patch: Apply to intact, nondamaged skin. Remove transparent liner prior to applying to skin. Wash hands after applying, handling, or removing the patch. May tape down edges of patch, if peeling occurs; if problems with adhesion persist, may overlay the patch with a mesh netting sleeve. Should not be worn while bathing or showering. Fold used patches so the adhesive side sticks to itself; dispose of used patches out of reach of children and pets.

Storage

Gel: Store between 20°C to 25°C (68°F to 77°F); do not freeze. Protect from heat. Avoid freezing.

Voltaren Emulgel [Canadian product]: Store at 15°C to 30°C (59°F to 86°F).

Solution: Store between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Patch: Store between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Keep envelope sealed when not being used.

Drug Interactions

5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Monitor therapy

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Monitor therapy

Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Management: Monitor renal function periodically in patients receiving aliskiren and any nonsteroidal anti-inflammatory agent. Patients at elevated risk of renal dysfunction include those who are elderly, are volume depleted, or have pre-existing renal dysfunction. Monitor therapy

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Monitor therapy

Apixaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Bemiparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Consider therapy modification

Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dexibuprofen: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Dexibuprofen. Avoid combination

Dexketoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Diclofenac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Seek alternatives to the combined use of diclofenac with other nonsteroidal anti-inflammatory agents (NSAIDs). Avoid the use of diclofenac/misoprostol with other NSAIDs. Consider therapy modification

Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Monitor therapy

Drospirenone: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

Edoxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Enoxaparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Felbinac: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Haloperidol: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Monitor therapy

Heparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Consider therapy modification

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed. Consider therapy modification

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Monitor therapy

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Ketorolac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Consider therapy modification

Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Consider therapy modification

Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. Avoid combination

MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Consider therapy modification

Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide. Avoid combination

Morniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Avoid combination

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pelubiprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Phenylbutazone: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation. Monitor therapy

Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Monitor therapy

Quinolones: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Monitor therapy

Rivaroxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Exceptions: Choline Magnesium Trisalicylate. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selective Serotonin Reuptake Inhibitors: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Monitor therapy

Talniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tolperisone: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Tricyclic Antidepressants (Tertiary Amine): May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Consider therapy modification

Voriconazole: May increase the serum concentration of Diclofenac (Topical). Monitor therapy

Zaltoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Adverse Reactions

Topical gel:

>10%:

Dermatologic: Pruritus (≤52%), application site rash (35% to 46%), contact dermatitis (2% to 33%), xeroderma (3% to 27%), application site pain (15% to 26%), desquamation (application site: 6% to 24%)

Hepatic: Increased serum transaminases (<3 x ULN: 15%; >3 x ULN: 2% to 4%; >8 x ULN: 1%)

1% to 10%:

Cardiovascular: Chest pain (1% to 2%), hypertension (1% to 2%)

Central nervous system: Paresthesia (≤8%), headache (7%), hyperesthesia (3%), pain (1% to 2%), migraine (1%)

Dermatologic: Skin rash (4%), vesiculobullous dermatitis (application site: 4%), skin photosensitivity (application site: 3%), alopecia (application site: 2%), dermal ulcer (1% to 2%), acne vulgaris (application site: 1%)

Endocrine & metabolic: Application site edema (3% to 4%), hypercholesterolemia (1%), hyperglycemia (1%)

Gastrointestinal: Diarrhea (2%), dyspepsia (2%), abdominal pain (1% to 2%)

Genitourinary: Hematuria (2%)

Hepatic: Increased serum alanine aminotransferase (2% to 4%), increased serum aspartate aminotransferase (2% to 4%), increased liver enzymes

Neuromuscular and skeletal: Back pain (4%), increased creatine phosphokinase in blood specimen (4%), myalgia (2% to 3%), arthralgia (2%), arthropathy (2%), asthenia (2%), hypokinesia (2%), neck pain (2%)

Ophthalmic: Conjunctivitis (2% to 4%), eye pain (2%)

Respiratory: Flu-like symptoms (10%), asthma (2%), dyspnea (2%), pneumonia (2%), sinusitis (2%)

Miscellaneous: Accidental injury (4%)

<1%, postmarketing, and/or case reports: Application site irritation, application site reaction (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation), edema, hepatic failure, hepatic necrosis, hepatitis (fulfillment; with and without jaundice), hepatotoxicity, jaundice, papule (application site), paresthesia, seborrhea, skin blister (application site), skin hypertrophy, urticaria

Topical solution:

>10%: Dermatologic: Xeroderma (application site: 22% to 32%; nonapplication site: 2%)

1% to 10%:

Cardiovascular: Edema (3%)

Dermatologic: Contact dermatitis (2% to 9%), desquamation (application site: 7%), application site erythema (4%), pruritus (application site: 2% to 4%; nonapplication site: 2%); skin rash (3%), application site pain (2%), application site rash (2%), skin sclerosis (application site: 2%)

Gastrointestinal: Dyspepsia (8%), abdominal pain (6%), diarrhea (4%), flatulence (4%), nausea (2% to 4%), constipation (3%), halitosis (1%)

Genitourinary: Urinary tract infection (3%)

Hematologic & oncologic: Bruise (2%)

Infection: Infection (3%)

Respiratory: Paranasal sinus congestion (2%), sinusitis (1%)

Postmarketing and/or case reports: Accidental injury, aphthous stomatitis, asthenia, asthma, back pain, blurred vision, body odor, burning sensation of skin, cardiac disorder, cataract, chest pain, crusted skin, decreased appetite, depression, dizziness, drowsiness, dysgeusia, dyspnea, eczema, eye pain, facial edema, gastroenteritis, headache, hypersensitivity reaction, hypertension, increased blood pressure, increased serum creatinine, laryngismus, laryngitis, lethargy, lip edema, lower limb cramp, myalgia, neck stiffness, ophthalmic signs and symptoms, oral mucosa ulcer, otalgia, palpitations, pharyngeal edema, pharyngitis, rectal hemorrhage, skin discoloration, tongue edema, urticaria, visual disturbance, xerostomia

Transdermal patch:

1% to 10%:

Central nervous system: Dizziness (≤1%), hypoesthesia (≤1%)

Dermatologic: Hyperhidrosis (≤4%), localized erythema (≤4%), localized vesiculation (≤4%), skin discoloration (≤4%), xeroderma (local: ≤4%), dermatitis (2%)

Gastrointestinal: Nausea (3%), constipation (≤3%), diarrhea (≤3%), gastritis (≤3%), upper abdominal pain (≤3%), vomiting (≤3%), xerostomia (≤3%), dysgeusia (2%)

Local: Application site atrophy (≤4%), local irritation (≤4%), localized edema, local pruritus

Neuromuscular & skeletal: Hyperkinetic muscle activity (≤1%)

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cerebrovascular accident, thrombosis

Dermatologic: Allergic skin reaction

Gastrointestinal: Gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer, GI adverse effects

Postmarketing and/or case reports: Anaphylaxis, esophageal perforation, exfoliative dermatitis, hypertension, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure, anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy (excluding 3% gel).
• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in patients with heart failure (ACCF/AHA [Yancy, 2013]). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.
• Gastrointestinal events: [US Boxed Warning]: NSAIDs cause an increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).
• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).
• Hepatic effects: Transaminase elevations have been observed with oral chronic use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if signs or symptoms of hepatic disease develop or if systemic manifestations occur.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE inhibitors). Monitor potassium closely.
• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow, which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Long-term NSAID use may result in renal papillary necrosis and other renal injury/toxicity.
• Skin reactions: May cause potentially fatal serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity). Do not apply topical products to open skin wounds, infected areas, inflammations, or exfoliative dermatitis.

Disease-related concerns:

• Asthma: Contraindicated in patients with aspirin-sensitive asthma (excluding 3% gel); severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.
• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.
• Hepatic impairment: Use with caution in patients with hepatic impairment; patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs.
• Renal impairment: Avoid use in advanced renal disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients are at greater risk for serious GI, cardiovascular and/or renal adverse events; use with caution.

Dosage form specific issues:

• Appropriate use: Avoid contact with eyes and mucous membranes.
• Benzoyl alcohol and derivatives: Some dosage forms may contain benzoyl alcohol; large amounts of benzoyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzoyl alcohol with caution in neonates. See manufacturer's labeling.
• Gel: Avoid occlusive dressings and/or heat application to treated area.
• Patch: Contains conducting metal (eg, aluminum); remove patch prior to MRI.
• Gel, patch, solution: Combination use with oral NSAIDs is not recommended due to increased risk of adverse reactions (eg, rectal hemorrhage; more frequent abnormal creatinine, urea, hemoglobin); do not use concomitantly unless benefit outweighs risks, and monitor patient with periodic laboratory evaluations.

Monitoring Parameters

CBC, liver enzymes (periodically during chronic therapy starting 4 to 8 weeks after initiation), BUN/serum creatinine; potassium; monitor urine output; occult blood loss; blood pressure (baseline and during treatment)

Pregnancy

Pregnancy Considerations

Diclofenac crosses the placenta following systemic administration. The amount of diclofenac available systemically following topical application is less in comparison to oral doses. Reversible constriction of the ductus arteriosus in utero has been observed following topical application of diclofenac (Torloni 2006). Because NSAIDs may cause premature closure of the ductus arteriosus, product labeling for diclofenac specifically states use should be avoided starting at 30 weeks' gestation.

The chronic use of NSAIDs in females of reproductive potential may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in females having difficulty conceiving or those undergoing investigation of fertility.

Patient Education

What is this drug used for?

• It is used to treat a precancerous skin problem called actinic keratosis.
• It is used to ease pain.
• It is used to treat arthritis.

Frequently reported side effects of this drug

• Skin irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Abdominal ulcers like severe abdominal or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or abnormal swelling.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Burning or numbness feeling
• Chest pain
• Shortness of breath
• Fast heartbeat
• Severe abdominal pain
• Severe back pain
• Excessive weight gain
• Swelling of arms or legs
• Severe dizziness
• Passing out
• Severe headache
• Vision changes
• Flu-like symptoms
• Severe loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.