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Diclofenac (Topical)

Pronunciation

Pronunciation

(dye KLOE fen ak)

Index Terms

  • Diclofenac Diethylamine [CAN]
  • Diclofenac Epolamine
  • Diclofenac Sodium

Dosage Forms

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

Cream, Transdermal, as sodium:

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

Gel, Transdermal, as sodium:

Solaraze: 3% (100 g) [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:

Vopac MDS: 1.5% [contains propylene glycol]

Patch, Transdermal, as epolamine:

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

Solution, Transdermal, as sodium:

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

Pennsaid: 1.5% (150 mL [DSC]); 2% (112 g) [contains propylene glycol]

Generic: 1.5% (150 mL)

Therapy Pack, External, as sodium:

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

Therapy Pack, Transdermal, as sodium:

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

DSG Pak: 1% (1 ea [DSC]) [contains isopropyl alcohol, propylene glycol]

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

Brand Names: U.S.

  • Diclo Gel with Xrylix Sheets
  • Diclozor
  • DSG Pak [DSC]
  • Flector
  • Klofensaid II
  • Pennsaid
  • Rexaphenac
  • Solaraze
  • Voltaren
  • Vopac MDS
  • Xrylix

Pharmacologic Category

  • Nonsteroidal Anti-inflammatory Drug (NSAID)
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Topical

Pharmacology

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.

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)

Canadian labeling (not in US labeling): Relief of pain associated with acute, localized joint/muscle injuries (eg, sports injuries, strains) in patients ≥16 years of age

Gel 3%: Treatment of actinic keratosis (AK) in conjunction with sun avoidance

Patch: Treatment of acute pain due to minor strains, sprains, and contusions

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 (excluding 3% gel); 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 (patch only).

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; breast-feeding

Voltaren Emulgel: Concomitant use with other diclofenac-containing products or other NSAIDS

Dosing: Adult

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

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:

US labeling:

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

Canadian labeling: Apply 40 drops 4 times daily or 50 drops 3 times daily to each affected knee for up to 3 months

Dosing: Geriatric

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

Dosing: Pediatric

Acute pain (strains, sprains, contusions): Topical: Gel (Voltaren Emulgel [Canadian product]): Adolescents ≥16 years: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; avoid use in patients with advanced renal disease.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

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 with gel and smooth into skin gently.

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

ACE 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 ACE Inhibitors. Monitor therapy

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: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. 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

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

Anticoagulants: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Apixaban: NSAID (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

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. 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 NSAID (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. Specifically, elevated diclofenac concentrations have been reported. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (e.g., hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: NSAID (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. 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

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: NSAID (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

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. 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: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. 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

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

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

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

NSAID (COX-2 Inhibitor): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of NSAID (COX-2 Inhibitor). 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

PEMEtrexed: NSAID (Nonselective) may increase the serum concentration of PEMEtrexed. Management: Patients with mild-to-moderate renal insufficiency (estimated creatinine clearance 45-79 mL/min) should avoid NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Consider therapy modification

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

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

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

Rivaroxaban: NSAID (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: NSAID (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (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: May enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

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

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. 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): NSAID (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Voriconazole: May increase the serum concentration of Diclofenac (Topical). 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: Headache (7%), hyperesthesia (3%), paresthesia (2%), pain (1% to 2%), migraine (1%)

Dermatologic: Application site paresthesia (≤8%), vesiculobullous dermatitis (application site 4%), skin rash (4%), alopecia (application site 2%), skin photosensitivity (application site 3%), 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 ALT (2% to 4%), increased serum AST (2% to 4%), increased liver enzymes

Neuromuscular and skeletal: Back pain (4%), increased creatine phosphokinase (4%), myalgia (2% to 3%), arthralgia (2%), arthropathy (2%), hypokinesia (2%), neck pain (2%), weakness (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% (Limited to important or life-threatening): Application site irritation, application site papules, application site reaction (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation), application site vesicles, edema, hepatic failure, hepatitis (fulfillment; with and without jaundice), seborrhea, 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 induration (2%), application site pain (2%), application site rash (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: Sinus congestion (2%), sinusitis (1%)

Postmarketing and/or case reports (Limited to important or life-threatening): Accidental injury, aphthous stomatitis, asthma, body odor, burning sensation of skin, cardiovascular disease, cataract, chest pain, depression, eczema, eye disease, gastroenteritis, hypersensitivity reaction, hypertension, increased serum creatinine, laryngismus, oral mucosa ulcer, palpitations, rectal hemorrhage, skin discoloration, visual disturbance

Transdermal patch:

1% to 10%:

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

Dermatologic: Hyperhidrosis (<4%), local dryness (<4%), localized erythema (<4%), localized vesiculation (<4%), skin discoloration (<4%), dermatitis (2%), hypersensitivity reaction (dermal)

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

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

Neuromuscular & skeletal: Hyperkinesia (<1%)

Postmarketing and/or case reports (Limited to important or life-threatening): Cerebrovascular accident, edema, myocardial infarction, Stevens-Johnson syndrome

ALERT: U.S. Boxed Warning

Serious cardiovascular thrombotic events (Flector, Klofensaid II, Pennsaid, Solaraze, and Voltaren):

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

Diclofenac is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Serious gastrointestinal bleeding, ulceration and perforation (Flector, Klofensaid II, Pennsaid, and Voltaren):

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse reactions, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These reactions can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk of serious GI events.

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 Risk Factor

B (gel 3%)

C (gel 1%, solution, patch)

D (≥30 weeks gestation [gel 1%, patch, solution])

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. When administered orally, diclofenac crosses the placenta. 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. Additional adverse fetal and maternal effects have been observed following oral use of diclofenac. Because they may cause premature closure of the ductus arteriosus, US product labeling notes that the use of NSAIDs late in pregnancy should be avoided; the product labeling for most products specifically states use should be avoided starting at 30 weeks gestation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience skin irritation. Have patient report immediately to prescriber signs of signs of abdominal ulcers (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), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (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, angina, shortness of breath, tachycardia, severe abdominal pain, severe back pain, excessive weight gain, swelling of arm or leg, severe dizziness, passing out, severe headache, vision changes, flu-like symptoms, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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