Diclofenac Potassium

Class: Other Nonsteroidal Anti-inflammatory Agents
Note: This monograph also contains information on diclofenac epolamine, Diclofenac Sodium
Chemical Name: 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt
Molecular Formula: C₁₄H₁₁C₁₂NO₂•KC₁₄H₁₁C₁₂NO₂^.NaC₂₀H₂₄Cl₂N₂O₃
CAS Number: 15307-81-0
Brands: Arthrotec, Cataflam, Flector, Voltaren

• Cardiovascular Risk


• 
  

  Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).^{1 302 303 317 318} Risk may increase with duration of use.^{1 302 303 317 318} Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.^{1 302 303 317 318} (See Cardiovascular Effects under Cautions.)

  
  


• 
  

  Contraindicated for the treatment of pain in the setting of CABG surgery.^{1 302 303 317 318}

  
  

• GI Risk


• 
  

  Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).^{1 302 303 317 318} Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.^{1 302 303 317 318} Geriatric individuals are at greater risk for serious GI events.^{1 302 303 317 318} (See GI Effects under Cautions.)

  
  

REMS:

FDA approved a REMS for diclofenac to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Prototypical NSAIA;^{1 2 3 4 5 6 7 8 9 189 302 303 317 318} phenylacetic acid derivative;^{1 2 3 4 5 6 7 8 9 189 262} structurally related to meclofenamate sodium and mefenamic acid.²⁰³

Uses for Diclofenac Potassium

Inflammatory Diseases

Orally for symptomatic treatment of osteoarthritis,^{1 81 82 83 84 85 86 89 90 107 108 109 110 111 112 113 114 121 125 126 133 274 302 303} rheumatoid arthritis,^{1 74 75 76 77 78 79 80 87 88 107 115 116 117 118 119 121 125 126 129 254 302 303} and ankylosing spondylitis.^{1 91 120 121 125 127 274}

Orally in fixed combination with misoprostol for the symptomatic treatment of osteoarthritis and rheumatoid arthritis in patients at high risk for developing NSAIA-induced gastric or duodenal ulcers and in patients at high risk for developing complications from these ulcers.²⁸⁴

Topically (as gel) for the symptomatic treatment of osteoarthritis-related joint pain.^{318 321} Used for joints amenable to topical therapy (e.g., hands, knees); has not been evaluated on joints of the spine, hip, or shoulder.³¹⁸

Orally for management of juvenile rheumatoid arthritis†.^{3 128 210}

Orally for symptomatic relief of acute gouty arthritis†.^{121 130 131 132}

Orally or topically for symptomatic treatment of infusion-related superficial thrombophlebitis†.^{310 311}

Pain

Orally for relief of pain, including postoperative (e.g., orthopedic, gynecologic, oral) pain, in adults.^{276 277 278 279 303}

Transdermally for relief of acute pain due to minor strains, sprains, and contusions.^{317 319}

Dysmenorrhea

Orally for symptomatic management of primary dysmenorrhea.³⁰³

Diclofenac Potassium Dosage and Administration

General

• 
  

  Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.^{1 302 303 317}

  
  

Administration

Oral Administration

Diclofenac sodium delayed-release (enteric-coated) and extended-release tablets are not recommended for relief of acute pain^{3 248} or primary dysmenorrhea¹ because of slow onset of action.^{53 54 56 57 60 61}

Topical Administration

Diclofenac Sodium 1% Gel

Apply gel 4 times daily to the affected joint.³¹⁸ Use the dosing card from the manufacturer to measure the appropriate dose.³¹⁸ Apply the gel within the oblong area of the dosing card up to the appropriate (2- or 4-g of gel) line; then use the dosing card to apply the gel.³¹⁸ Gently massage the gel into the skin; ensure gel is applied to the entire affected joint (e.g., foot [including sole, top of foot, and toes], knee, ankle, hand [including palm, back of hand, and fingers], elbow, wrist).³¹⁸

Allow application site to dry for 10 minutes before covering treated area with clothing; wait at least 60 minutes before bathing or showering.³¹⁸ Wash hands after application unless the treated joint is in the hand.³¹⁸

Do not apply to open wounds, infected or inflamed areas of skin, or areas affected with exfoliative dermatitis; avoid contact with eyes and mucous membranes.³¹⁸

Do not expose treated joint to external heat or to natural or artificial sunlight; do not use occlusive dressings.³¹⁸

Avoid application of sunscreens, cosmetics, lotions, moisturizers, insect repellents, or other topical agents to the same site; concomitant use with other topical agents not studied.³¹⁸

Diclofenac Epolamine Transdermal System

Apply transdermal system to the most painful area twice daily.³¹⁷ Apply to intact skin; do not apply to damaged skin (e.g., wounds, burns, infected areas of skin, areas affected with eczema or exudative dermatitis).³¹⁷

Wash hands after handling the system.³¹⁷

Avoid contact with eyes and mucous membranes.³¹⁷

Do not wear the transdermal system while bathing or showering.³¹⁷

If a system should begin to peel off during the period of use, the edges of the system may be taped to the skin.³¹⁷

Dosage

Available as diclofenac potassium, diclofenac sodium, or diclofenac epolamine; dosage expressed in terms of the salt.^{1 302 303 317 318}

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{1 302 303 317} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{1 302 303 317}

Commercially available diclofenac sodium enteric-coated tablets (Voltaren), diclofenac sodium extended-release tablets (Voltaren-XR), and diclofenac potassium immediate-release tablets (Cataflam) are not necessarily bioequivalent on a mg-per-mg basis.^{1 302 303}

Adults

Inflammatory Diseases

Osteoarthritis

Oral

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.²⁸⁴

Preparation	Dosage
Diclofenac potassium conventional tablets	100–150 mg daily, given as 50 mg 2 or 3 times daily303
Diclofenac sodium delayed-release tablets	100–150 mg daily, given as 50 mg 2 or 3 times daily or 75 mg twice daily1
Diclofenac sodium extended-release tablets	100 mg once daily302
Diclofenac sodium (in fixed combination with misoprostol)	50 mg 3 times daily284

Topical (gel)

For lower extremity (i.e., knees, ankles, feet) joint pain, massage 4 g of diclofenac sodium 1% gel into the affected joint 4 times daily.³¹⁸

For upper extremity (i.e., elbows, wrists, hands) joint pain, massage 2 g of diclofenac sodium 1% gel into the affected joint 4 times daily.³¹⁸

If multiple joints are treated, total daily dose applied to all joints should be ≤32 g of gel daily.³¹⁸

Rheumatoid Arthritis

Oral

May change dosage to 50 or 75 mg twice daily in patients who do not tolerate usual dosage; however, these dosages may be less effective in preventing NSAIA-induced ulcers.²⁸⁴

Preparation	Dosage
Diclofenac potassium conventional tablets	150–200 mg daily, given as 50 mg 3 or 4 times daily303
Diclofenac sodium delayed-release tablets	150–200 mg daily, given as 50 mg 3 or 4 times daily or 75 mg twice daily1
Diclofenac sodium extended-release tablets	100 mg once daily; may increase to 100 mg twice daily 302
Diclofenac sodium (in fixed combination with misoprostol)	50 mg 3 or 4 times daily284

Ankylosing Spondylitis

Oral

100–125 mg daily (as diclofenac sodium delayed-release tablets); administer as 25 mg 4 times daily, with 5th dose at bedtime as needed.^{1 91 125}

Pain

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets).³⁰³ Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).³⁰³

Topical (transdermal system)

Apply 1 transdermal system (diclofenac epolamine 1.3%) twice daily.³¹⁷

Dysmenorrhea

Oral

50 mg 3 times daily (as diclofenac potassium conventional tablets).³⁰³ Some patients may benefit from initial dose of 100 mg (followed by 50-mg doses).³⁰³

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis

Topical (gel)

Maximum total daily dose applied to all affected joints: 32 g of diclofenac sodium 1% gel.³¹⁸ Maximum 16 g of gel applied daily to any single lower extremity joint and 8 g applied daily to any single upper extremity joint.³¹⁸

Special Populations

Renal Impairment

Dosage adjustment not required.^{1 3 72 247 248 302 303}

Hepatic Impairment

Reduction of oral dosage may be necessary.^{1 302 303}

Cautions for Diclofenac Potassium

Contraindications

• 
  

  Known hypersensitivity to diclofenac or any ingredient in the formulation.^{1 302 303 317 318}

  
  


• 
  

  History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{1 141 144 145 146 147 168 225 302 303 317 318}

  
  


• 
  

  Treatment of perioperative pain in the setting of CABG surgery.^{1 302 303 317 318}

  
  


• 
  

  Diclofenac sodium in fixed combination with misoprostol is contraindicated in pregnant women.²⁸⁴

  
  

Warnings/Precautions

Warnings

Consider potential benefits and risks of diclofenac therapy as well as alternative therapies before initiating therapy with the drug.^{1 302 303 317} Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{1 302 303 317 318}

Cardiovascular Effects

Selective COX-2 inhibitors have been associated with increased risk of cardiovascular events (e.g., MI, stroke) in certain situations.³⁰⁵ Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.^{312 313 314} Current evidence suggests that use of diclofenac is associated with increased cardiovascular risk.^{312 313 314 316}

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dosage for the shortest duration necessary.^{1 302 303 317 318}

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).³⁰⁵

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{1 302 303 317 318} (See Specific Drugs under Interactions.)

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{1 302 303 317 318} Use with caution in patients with hypertension; monitor BP.^{1 302 303 317 318} Impaired response to certain diuretics may occur.^{1 302 303 317 318} (See Specific Drugs under Interactions.)

Fluid retention and edema reported.^{1 302 303 317 318} Caution in patients with fluid retention or heart failure.^{1 302 303 317 318}

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.^{1 167 181 187 256 259 260 267 268 282 292 300 302 303 317 318}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{249 254 284 292 293} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{249 254 292} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).²⁴⁹

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{1 302 303 317 318}

Potential for overt renal decompensation.^{1 171 302 303 317 318} Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{1 160 174 185 191 284 302 303 306 315 317 318} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions (e.g., anaphylaxis, angioedema) reported.^{1 302 303 317 318}

Immediate medical intervention and discontinuance for anaphylaxis.^{1 302 303 317 318}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^{1 302 303 317 318}

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{1 302 303 317 318} Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^{1 302 303 317 318}

General Precautions

Do not use multiple diclofenac-containing preparations concomitantly.^{1 302 303} Concomitant use of diclofenac sodium 1% gel and oral NSAIAs may increase risk of adverse effects.³¹⁸

Observe the usual cautions, precautions, and contraindications associated with misoprostol therapy when diclofenac is used in fixed combination with misoprostol.²⁸⁴

Hepatic Effects

Severe, sometimes fatal, reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure reported rarely with diclofenac.^{1 302 303 317 318 323}

Elevations of serum ALT or AST reported.^{1 302 303 317 318 323}

Monitor for symptoms and/or signs suggesting liver dysfunction.^{1 302 303 317 318 323} Obtain serum transaminase values 4–8 weeks after initiating therapy; monitor periodically during long-term therapy.^{317 318 323} ALT (SGPT) is the recommended hepatic function marker for monitoring liver injury.^{317 318 323}

Discontinue if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).^{1 164 255 302 303 317 318 323}

Hematologic Effects

Anemia reported rarely.^{1 302 303 317 318} Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.^{1 248 302 303 317 318}

May inhibit platelet aggregation and prolong bleeding time.^{3 40 41 42 43 165 166}

Precautions Specific to Diclofenac Sodium 1% Gel

Minimize or avoid exposure of treated areas to natural or artificial sunlight.³¹⁸ Topical application of diclofenac gel formulations has resulted in early onset of ultraviolet (UV) light-related skin tumors in animal studies.^{318 321} The potential effects of topical diclofenac gel on skin response to UV damage in humans are not known.³¹⁸

Application to nonintact skin may alter absorption and tolerability; apply only to intact skin.³¹⁸

Avoid contact with the eyes and mucous membranes.³¹⁸ If contact with the eyes occurs, thoroughly rinse the eyes with water or saline.³¹⁸ If ocular irritation persists for >1 hour, consult a clinician.³¹⁸

Precautions Specific to Diclofenac Epolamine Transdermal System

Avoid contact with eyes and mucous membranes.³¹⁷ If contact with the eyes occurs, thoroughly rinse the eyes with water or saline.³¹⁷ If ocular irritation persists for >1 hour, consult a clinician.³¹⁷

Do not apply to nonintact or damaged skin.³¹⁷

Patient should bathe or shower after removing one transdermal system and before applying a new system; the transdermal system should not be worn during bathing or showering.³¹⁷

Store and discard transdermal systems in a manner that avoids accidental exposure or ingestion by children or pets.³¹⁷

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.^{1 248 302 303 317 318}

May mask certain signs of infection.^{1 302 303 317 318}

Obtain CBC and chemistry profile periodically during long-term use.^{1 302 303 317 318}

Specific Populations

Pregnancy

Category C.^{1 302 303 317 318} Avoid use in third trimester because of possible premature closure of the ductus arteriosus.^{1 302 303 317 318}

Category X (in fixed combination with misoprostol).²⁸⁴ Misoprostol exhibits abortifacient activity and can cause serious fetal harm.²⁸⁴

Lactation

Distributed into milk; ³ discontinue nursing or the drug.^{1 302 303 317 318}

Pediatric Use

Safety and efficacy not established in children.^{1 302 303 317 318}

Good results with oral diclofenac obtained in a limited number of children 3–16 years of age for the management of juvenile rheumatoid arthritis†.^{3 128 210}

Geriatric Use

Oral diclofenac: Caution advised.^{1 302 303} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{1 302 303 317 318}

Diclofenac sodium 1% gel: No substantial difference in safety and efficacy in individuals ≥65 years of age compared with younger individuals; possibility of greater sensitivity to the drug in some geriatric individuals.³¹⁸

Diclofenac epolamine transdermal system: Insufficient experience in individuals ≥65 years of age to determine whether geriatric patients respond differently than younger individuals.³¹⁷

Use diclofenac with caution because of age-related decreases in renal function.^{317 318} May be useful to monitor renal function.^{317 318}

Hepatic Impairment

Reduction of oral dosage may be necessary.^{1 302 303}

Renal Impairment

Metabolites eliminated principally via the kidney.^{1 302 303}

Use with caution in patients with renal disease.^{1 302 303 317 318} Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.^{1 248 302 303 304 317 318}

Common Adverse Effects

Oral diclofenac: Abdominal pain or cramps,^{1 75 86 93 107 113 136 302 303} constipation,^{1 75 113 132 134 136 302 303} diarrhea,^{1 84 86 87 93 95 125 134 302 303} flatulence,^{1 302 303} GI bleeding,^{1 302 303} GI perforation, ^{1 302 303} peptic ulcer,^{1 302 303} vomiting, ^{1 302 303} dyspepsia,^{1 302 303} nausea,^{1 76 78 84 85 93 95 96 97 98 99 109 111 113 126 129 134 165 302 303} dizziness,^{1 102 107 113 125 129 165 302 303} headache,^{1 89 90 91 93 95 107 110 113 118 125 127 129 132 165 302 303} liver function test abnormalities,^{1 116 125 165 189 209 223 255 302 303} renal function abnormalities,^{1 302 303} anemia,^{1 302 303} prolonged bleeding time,^{1 302 303} pruritus,^{1 302 303} rash,^{1 302 303} tinnitus,^{1 302 303} edema.^{1 109 125 132 159 165 302 303}

Diclofenac sodium 1% gel: Application site reactions (e.g., dermatitis).³¹⁸

Diclofenac epolamine transdermal system: Application site reactions (e.g., pruritus, dermatitis), nausea, altered taste.³¹⁷

Interactions for Diclofenac Potassium

Protein-bound Drugs

Only minimally displaces other highly protein-bound drugs from binding sites; however, may be displaced from binding sites by other highly protein-bound drugs.^{51 52 59 61}

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Reduced BP response to ACE inhibitor1 248 302 303 317 318 Possible deterioration of renal function in individuals with renal impairment315	Monitor BP1 248 302 303 317 318
Angiotensin II receptor antagonists	Reduced BP response to angiotensin II receptor antagonist315 Possible deterioration of renal function in individuals with renal impairment315
Antacids (magnesium- or aluminum-containing)	Delayed diclofenac absorption3 189 238
Anticoagulants (warfarin)	Possible bleeding complications1 302 303 317 318	Caution advised1 302 303
Aspirin	Decreased peak plasma concentration and AUC of diclofenac;22 61 184 202 302 303 limited data indicate that diclofenac does not inhibit antiplatelet effect of aspirin262 Increased risk of GI ulceration and other complications1 302 303 317 318 No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs305 317 318	Manufacturer states that concomitant use not recommended1 302 303 317 318
Cyclosporine	Possible increase in nephrotoxic effects of cyclosporine1 302 303 318	Caution advised1 302 303 318
Diuretics (furosemide, thiazides)	Reduced natriuretic effects1 22 179 302 303 317 318	Monitor for diuretic efficacy and renal failure1 302 303 317 318
Lithium	Increased plasma lithium concentrations1 176 188 265 302 303 317 318	Monitor for lithium toxicity1 302 303 317 318
Methotrexate	Severe, sometimes fatal toxicity associated with increased plasma methotrexate concentrations175 307	Caution advised1 302 303 317 318
Quinolones (ciprofloxacin)	Possible increased risk of seizures183 197 198

Diclofenac Potassium Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.^{1 3 51 52}