Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction 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 surgery.
NSAIDs cause an increased risk of serious 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.
Note: Safety: Use the lowest effective dose for the shortest duration of time; however, adverse effects associated with systemic diclofenac (eg, GI bleeding, cardiovascular thrombotic events, kidney toxicity) are less likely with topical formulations due to minimal systemic absorption. Concurrent use with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) is generally not recommended as topical treatment is unlikely to provide added pain relief.
Actinic keratosis (alternative agent):
Topical: Gel 3%: Apply to lesion area twice daily for 60 to 90 days. Normally, 0.5 g is used on each 5 cm × 5 cm lesion.
Osteoarthritis:
Lower extremity (eg, knee):
Topical: Gel 1% (OTC or Rx): Apply 4 g to each affected area up to 4 times daily; maximum dose per joint: 16 g/day; maximum total body dose (all combined joints): 32 g/day.
Topical: Solution 1.5%: Apply 40 drops to each affected knee up to 4 times daily. Note: Apply 10 drops at a time, rub in evenly, then apply 10 more drops until a total of 40 drops has been applied.
Topical: Solution 2%: Apply 40 mg (2 pump actuations) to each affected knee up to twice daily.
Upper extremity (eg, hand):
Topical: Gel 1% (OTC or Rx): Apply 2 g to each affected area up to 4 times daily; maximum dose per joint: 8 g/day; maximum total body dose (all combined joints): 32 g/day.
Pain, acute (eg, musculoskeletal):
Topical: Patch 1.3%: Apply 1 patch once (Licart) or twice (Flector) daily to most painful area.
Topical: Gel 1% (OTC or Rx) (off-label use): Apply up to 4 g to each affected area up to 4 times daily; maximum dose per area: 16 g/day; maximum total body dose (all combined areas): 32 g/day. Note: Dosing is based on general recommendations from manufacturer labeling.
Topical: Gel 1.16% (Canadian OTC product): Apply up to 4 g to affected area up to 4 times daily; amount needed depends on size of the painful area; 2 to 4 g is sufficient to treat an area of ~400 to 800 cm2.
Topical: Gel 2.32% (Canadian OTC product): Apply 2 g to affected area up to twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; avoid use in patients with advanced renal disease.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Diclofenac (topical): Pediatric drug information")
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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; avoid use in patients with advanced renal disease.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Start at lower end of dosing range. Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Cream, External, as sodium:
EnovaRX-Diclofenac Sodium: 2.5% (120 g) [contains cetyl alcohol]
Rexaphenac: 1% (120 g [DSC]) [contains isopropyl alcohol, propylene glycol]
Gel, External, as sodium:
Aspercreme Arthritis Pain: 1% (50 g, 100 g, 150 g) [contains isopropyl alcohol, propylene glycol]
Motrin Arthritis Pain: 1% (50 g, 100 g) [fragrance free; contains isopropyl alcohol, propylene glycol]
Voltaren: 1% (50 g, 100 g, 150 g, 350 g) [contains isopropyl alcohol, propylene glycol]
Generic: 1% (50 g, 100 g, 150 g [DSC]); 3% (100 g)
Kit, External, as sodium:
Diclo Gel: 1% [DSC] [contains isopropyl alcohol, propylene glycol]
Dicloprep-100: 1% [DSC] [contains isopropyl alcohol, propylene glycol]
DST Plus Pak: 1% [DSC] [contains isopropyl alcohol, propylene glycol]
ValcoPrep-100: 1% [DSC] [contains isopropyl alcohol, propylene glycol]
VennGel One: 1% [contains isopropyl alcohol, propylene glycol]
Patch, External, as epolamine:
Flector: 1.3% (5 ea [DSC], 30 ea) [contains edetate (edta) disodium, methylparaben, polysorbate 80, propylene glycol, propylparaben]
Generic: 1.3% (5 ea, 30 ea)
Patch 24 Hour, External, as epolamine:
Licart: 1.3% (2 ea, 5 ea) [contains edetate (edta) disodium, heparin sodium, methylparaben, polysorbate 80, propylene glycol, propylparaben]
Solution, External, 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); 2% (112 g)
Therapy Pack, External, as sodium:
Diclo Gel with Xrylix Sheets: 1% (1 ea [DSC]) [contains isopropyl alcohol, propylene glycol]
Diclozor: 1% (1 ea [DSC]) [contains isopropyl alcohol, propylene glycol]
Lexixryl: 1.5% (1 ea [DSC]) [contains propylene glycol]
Profinac: 1.5% (1 ea) [contains propylene glycol]
Xrylix: 1.5% (1 ea) [contains propylene glycol]
Xrylix II: 1.5% (1 ea) [contains alcohol, usp, propylene glycol]
May be product dependent
Diclozor therapy pack contains diclofenac gel (2 x 100 g) and occlusive dressings (10s).
DSG Pak contains Voltaren gel (100 g) and occlusive dressings (20s).
DST Plus Pak kit contains diclofenac gel.
EnovaRX-Diclofenac Sodium is a compounding kit for the preparation of diclofenac cream. Refer to manufacturer's labeling for compounding instructions.
Lexixryl therapy pack contains diclofenac solution (150 mL) and Xrylix kinesiology/cross tape (30s).
Rexaphenac is a compounding kit for the preparation of diclofenac cream. Refer to manufacturer's labeling for compounding instructions.
Xrylix therapy pack contains diclofenac solution (150 mL) and Xrylix kinesiology/cross tape (30s).
Vopac MDS kit contains diclofenac solution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, External, as sodium:
Pennsaid: 1.5% (15 mL, 30 mL, 60 mL) [contains propylene glycol]
Generic: 1.5% (15 mL, 30 mL, 60 mL, 120 mL, 150 mL)
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Flector: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021234s019lbl.pdf#page=24
Licart: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206976s007lbl.pdf#page=21
NSAID: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206976s000lbl.pdf#page=22
Pennsaid: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204623s011lbl.pdf#page=20
Solaraze: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021005s024lbl.pdf#page=22
Voltaren: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022122s011lbl.pdf#page=22
Gel: Apply to clean, dry, intact skin; 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 ≥1 hour following application. Wash hands immediately after application (unless hands are treated joint, then wait ≥1 hour to wash hands). Avoid sunlight to exposure areas. Avoid wearing clothes or gloves for ≥10 minutes after application.
1% formulation (Rx and OTC): 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 ≥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.
Topical:
Patch: Flector: Remove transparent liner prior to applying to skin. Apply to intact, nondamaged 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 (must allow air to flow through and not be occlusive). Should not be worn while bathing or showering. Fold used patches so the adhesive side sticks to itself and dispose of out of reach of children and pets.
Gel: Voltaren Emulgel 1.16% gel formulation [Canadian products]: For topical use only; do not apply to open wounds, eyes, or mucous membranes. Do not cover with occlusive dressings. Wash hands immediately after application unless hands are site being treated.
Gel 1%:
Rx: Relief of osteoarthritis pain in joints amenable to topical therapy (eg, ankle, elbow, foot, hand, knee, wrist).
OTC: Temporary relief of arthritis pain in the hand, wrist, elbow, foot, ankle, or knee.
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.
Diclofenac may be confused with Diflucan.
Voltaren may be confused with traMADol, Ultram, Verelan.
Transdermal patch (Flector) contains conducting metal (eg, aluminum); remove patch prior to MRI.
Diclofenac may be confused with Duphalac brand name for lactulose [multiple international markets].
Flexin: Brand name for diclofenac [Argentina], but also the brand name for cyclobenzaprine [Chile] and orphenadrine [Israel].
Flexin [Argentina] may be confused with Floxin brand name for flunarizine [Thailand], norfloxacin [South Africa], ofloxacin [US, Canada], and pefloxacin [Philippines].
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Topical gel:
>10%: Local: Application-site reaction (≤84%; including acne vulgaris [1%], alopecia [2%], application-site dermatitis [4%], application-site edema [3% to 4%], application-site irritation [<1%], application-site pain [15% to 26%], application-site pruritus [31% to 52%), application-site rash [35% to 46%], application-site scaling [6% to 24%], application-site vesicles [<1%], contact dermatitis [19% to 33%; nonapplication-site: 2%], hyperesthesia [3%], hypertonia [<1%], maculopapular rash [<1%], papule of skin [<1%], paresthesia [8%; nonapplication-site: 1%], purpuric rash [<1%], skin carcinoma [<1%], skin photosensitivity [3%], vasodilation [<1%], vesiculobullous dermatitis [4%], xeroderma [25% to 27%; nonapplication-site: 3%])
1% to 10%:
Cardiovascular: Chest pain (1% to 2%), hypertension (1% to 2%)
Dermatologic: Dermal ulcer (1% to 2%), pruritus (4%), skin rash (4%)
Endocrine & metabolic: Hypercholesterolemia (1%), hyperglycemia (1%)
Gastrointestinal: Abdominal pain (1% to 2%), diarrhea (2%), dyspepsia (2%)
Genitourinary: Hematuria (2%)
Hepatic: Increased serum alanine aminotransferase (2%), increased serum aspartate aminotransferase (3%)
Nervous system: Asthenia (2%), headache (7%), migraine (1%)
Neuromuscular and skeletal: Arthralgia (2%), arthropathy (2%), back pain (4%), hypokinesia (2%), increased creatine phosphokinase in blood specimen (4%), myalgia (2% to 3%), neck pain (2%)
Ophthalmic: Eye pain (2%)
Respiratory: Asthma (2%), dyspnea (2%), sinusitis (2%)
<1%:
Dermatologic: Seborrhea, skin hypertrophy, urticaria
Ophthalmic: Disease of the lacrimal apparatus (application site)
Topical solution:
>10%: Local: Application-site reaction (including application-site erythema [4%], application-site induration [2%], application-site pain [2%], application-site pruritus [2% to 4%; nonapplication-site: 2%], application-site rash (2%; nonapplication-site: 3%], application-site vesicles [2%], contact dermatitis [9%], crusted skin [scabbing: <1%], local skin exfoliation [7%]), xeroderma [22% to 32%; nonapplication-site: 2%)])
1% to 10%:
Cardiovascular: Edema (3%)
Dermatologic: Ecchymoses (2%)
Gastrointestinal: Abdominal pain (6%), constipation (3%), diarrhea (4%), dyspepsia (8%), flatulence (4%), halitosis (1%), nausea (2% to 4%)
Genitourinary: Urinary tract infection (3%)
Hematologic & oncologic: Bruise (2%)
Infection: Infection (3%)
Nervous system: Paresthesia (2%, including application site)
Respiratory: Paranasal sinus congestion (2%), sinusitis (1%)
Transdermal patch:
1% to 10%:
Gastrointestinal: Constipation (≤3%), diarrhea (≤3%), dysgeusia (2%), gastritis (≤3%), nausea (3%), upper abdominal pain (≤3%), vomiting (≤3%), xerostomia (≤3%)
Local: Application-site reaction (including application-site atrophy [≤4%]), application-site dermatitis [2%], application-site erythema [≤4%], application-site irritation [≤4%]), application-site vesicles [≤4%], hyperhidrosis [≤4%], local skin discoloration [≤4%], xeroderma [≤4%])
Nervous system: Dizziness (≤1%), hypoesthesia (≤1%)
Neuromuscular & skeletal: Hyperkinetic muscle activity (≤1%)
Frequency not defined (any formulation):
Cardiovascular: Acute myocardial infarction, coronary thrombosis, hypertension
Dermatologic: Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Gastrointestinal: Gastrointestinal hemorrhage, gastrointestinal inflammation, gastrointestinal perforation, gastrointestinal ulcer
Hypersensitivity: Anaphylaxis
Nervous system: Cerebrovascular accident
Postmarketing (any formulation):
Cardiovascular: Palpitations
Dermatologic: Body odor, burning sensation of skin, eczema, skin discoloration, urticaria
Gastrointestinal: Aphthous stomatitis, decreased appetite, gastroenteritis, oral mucosa ulcer
Hematologic & oncologic: Rectal hemorrhage
Hepatic: Increased serum transaminases (Daniels 2018)
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms, facial edema, hypersensitivity reaction, lip edema, tongue edema
Nervous system: Abnormal gait, depression, drowsiness, lethargy
Neuromuscular & skeletal: Lower limb cramp, muscle rigidity, neck stiffness
Ophthalmic: Blurred vision, cataract, visual disturbance
Otic: Otalgia
Renal: Increased serum creatinine
Respiratory: Laryngismus, laryngitis, pharyngeal edema, pharyngitis
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 nonsteroidal anti-inflammatory drugs; use in the setting of coronary artery bypass graft surgery; use on nonintact or damaged skin, including exudative dermatitis, eczema, infected lesions, burns, or wounds.
OTC labeling: When used for self-medication, do not use if previous allergic reaction to any other pain reliever/fever reducer or for strains, sprains, bruises, or sport injuries; prior to or following cardiac surgery; >2 body areas at the same time; in the eyes, nose, or mouth.
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; severe uncontrolled heart failure; active peptic ulcer; history of recurrent GI ulceration; active GI inflammatory disease; severe hepatic impairment or active hepatic disease; severely impaired or deteriorating renal function (CrCl <30 mL/minute); known hyperkalemia; pediatric patients <18 years of age; pregnancy; breastfeeding; prolonged treatment (>3 months).
Voltaren Emulgel: Concomitant use with other diclofenac-containing products or oral NSAIDS; pregnancy (last trimester).
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 (FDA 2015). 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.
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• 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.
Special populations:
• Older adult: 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.
Other warnings/precautions:
• Self-medication (OTC use): Prior to self-medication, patients should contact health care provider if they have had recurring stomach pain; ulcers; bleeding problems; high blood pressure; asthma; heart, liver, or kidney disease; other serious medical problems; are currently taking a diuretic, aspirin, or anticoagulant; or are ≥60 years of age. Discontinue use and contact health care provider if pain gets worse or lasts >21 days; redness or swelling occurs in affected area; fever or skin irritation occurs; signs of GI bleeding, heart disease, or stroke occur. Onset of pain relief may take up to 7 days after starting therapy; discontinue use if no pain relief after 7 days.
Children and adolescents may experience a higher frequency of certain adverse effects than adults, particularly headache (9% vs 1%) and dyspepsia (3% to 1%).
Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Specifically, the risk of GI bleeding may be increased with this combination. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: Nonsteroidal Anti-Inflammatory Agents (Topical) may diminish the therapeutic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Nonsteroidal Anti-Inflammatory Agents (Topical) may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anticoagulants: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents (Topical) may diminish the therapeutic effect of Beta-Blockers. Risk C: Monitor therapy
Corticosteroids (Systemic): Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the adverse/toxic effect of Corticosteroids (Systemic). Specifically, the risk of gastrointestinal bleeding, ulceration, and perforation may be increased. Risk C: Monitor therapy
CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the adverse/toxic effect of CycloSPORINE (Systemic). Specifically, the nephrotoxicity of cyclosporine (systemic) may be increased. Risk C: Monitor therapy
Deferasirox: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Digoxin: Nonsteroidal Anti-Inflammatory Agents (Topical) may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: Monitor therapy
Lithium: Nonsteroidal Anti-Inflammatory Agents (Topical) may increase the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents (Topical) may diminish the therapeutic effect of Loop Diuretics. Risk C: Monitor therapy
Methotrexate: Nonsteroidal Anti-Inflammatory Agents (Topical) may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: (Topical) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification
Salicylates: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the adverse/toxic effect of Salicylates. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of salicylates and topical NSAIDs is not recommended. If salicylates and topical NSAIDs are coadministered, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: Monitor therapy
Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents (Topical) may enhance the nephrotoxic effect of Tenofovir Products. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: Nonsteroidal Anti-Inflammatory Agents (Topical) may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Diclofenac (Topical). Risk C: Monitor therapy
Nonsteroidal anti-inflammatory drugs (NSAIDs) may delay or prevent rupture of ovarian follicles. This may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in patients having difficulty conceiving or those undergoing investigation of fertility.
Based on available information, NSAIDs can be continued in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Diclofenac crosses the placenta following systemic administration.
The amount of diclofenac available systemically following topical application is less in comparison to oral doses.
Birth defects have been observed following in utero nonsteroidal anti-inflammatory drug (NSAID) exposure in some studies; however, data are conflicting (Bloor 2013). Nonteratogenic effects, including prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage, have been observed in the fetus/neonate following in utero NSAID exposure (Bermas 2014; Bloor 2013). Maternal NSAID use may cause fetal renal dysfunction leading to oligohydramnios. Although rare, this may occur as early as 20 weeks' gestation and is more likely to occur with prolonged maternal use. Oligohydramnios may be reversible following discontinuation of the NSAID (Dathe 2019). In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013).
Maternal use of NSAIDs should be avoided beginning at 20 weeks' gestation. If NSAID use is necessary between 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible; consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found. 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.
Based on available information, NSAIDs can be continued during the first 2 trimesters of pregnancy in patients with rheumatic and musculoskeletal diseases; use in the third trimester is not recommended (ACR [Sammaritano 2020]).
Diclofenac is present in breast milk following oral administration. It is not known if diclofenac can be detected in breast milk following topical application.
The amount of diclofenac available systemically following topical application is less in comparison to oral doses. Nonsteroidal anti-inflammatory drugs are considered compatible for use in patients with rheumatic and musculoskeletal diseases who are breastfeeding; agents with a short half-life and established safety data in infants may be preferred (ACR [Sammaritano 2020]). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
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)
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%.
Protein binding: >99%, primarily to albumin.
Metabolism: Hepatic; undergoes first-pass metabolism; forms several metabolites (1 with weak activity).
Half-life elimination: Patch: ~12 hours; Solution 1.5%: 36.7 ± 20.8 hours (single application).
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.
Excretion: Urine (~65%); feces (~35%).
Gel (Diclofenac Sodium External)
1% (per gram): $0.04 - $0.58
3% (per gram): $1.12 - $11.79
Gel (Motrin Arthritis Pain External)
1% (per gram): $0.18
Gel (Voltaren External)
1% (per gram): $0.16
Kit (VennGel One External)
1% (per each): $3,400.00
Patch (Diclofenac Epolamine External)
1.3% (per each): $13.43 - $14.17
Patch (Flector External)
1.3% (per each): $12.44
Patch, 24-hour (Licart External)
1.3% (per each): $29.84
Solution (Diclofenac Sodium External)
1.5% (per mL): $1.74 - $10.90
2% (per gram): $17.32 - $23.99
Solution (Pennsaid External)
2% (per gram): $26.65
Therapy Pack (Profinac External)
1.5% (per each): $4,589.92
Therapy Pack (Xrylix External)
1.5% (per each): $4,961.96
Therapy Pack (Xrylix II External)
1.5% (per each): $4,961.96
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