Diclofenac (Systemic)

AHFS Class: Other Nonsteroidal Anti-inflammatory Agents (28:08.04.92)

View the associated AHFS monograph.

Brands: Arthrotec^® , Cataflam^® , Voltaren^®; also available generically.

Introduction

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

Uses

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

Inflammatory Diseases

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}

Used 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

Management of juvenile rheumatoid arthritis†.^{3 128 210}

Symptomatic relief of acute gouty arthritis†.^{121 130 131 132}

Symptomatic treatment of infusion-related superficial thrombophlebitis†.^{310 311}

Pain

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

Dysmenorrhea

Symptomatic management of primary dysmenorrhea.³⁰³

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}

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}

Dosage

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

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} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{1 302 303}

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}

Inflammatory Diseases.

> Osteoarthritis. Oral—

^a 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 a

> Rheumatoid Arthritis. Oral—

^b 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 b

> 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

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

Special Populations

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

Dosage reductions may be necessary.^{1 302 303}

Cautions

Contraindications

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

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

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

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

Warnings/Precautions

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}

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} (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} Use with caution in patients with hypertension; monitor BP.^{1 302 303} Impaired response to certain diuretics may occur.^{1 302 303} (See Specific Drugs under Interactions.)

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

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}

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}

Potential for overt renal decompensation.^{1 171 302 303} 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} (See Renal Impairment under Cautions.)

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

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

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

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

Do not use multiple diclofenac-containing preparations concomitantly.^{1 302 303}

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

Hepatic Effects. Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^{1 302 303}

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

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{1 302 303} Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.^{1 302 303}

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

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

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

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

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

Pregnancy.

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

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}

Pediatric Use. Safety and efficacy not established in children;^{1 302 303} however, used with good results in a limited number of children for the management of juvenile rheumatoid arthritis† in children 3–16 years of age.^{3 128 210}

Geriatric Use. Caution advised.^{1 302 303} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{1 302 303}

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

Common Adverse Effects

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}

Interactions

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

Pharmacokinetics

Absorption

Well absorbed following oral administration.^{1 3 51 52 53 57 68 189 302 303} Undergoes first-pass metabolism; only 50–60% of a dose reaches systemic circulation as unchanged drug.^{1 52 53 73 284 302 303}

Peak plasma concentration usually attained within about 1 hour (diclofenac potassium conventional tablets), 2 hours (diclofenac sodium delayed-release tablets), or 5.25 hours (diclofenac sodium extended-release tablets).^{1 3 51 52 302 303 307}

Single 50- or 100-mg doses of diclofenac potassium provide pain relief within 30 minutes.³⁰⁷

Pain relief lasts up to 8 hours following administration of single 50- or 100-mg doses of diclofenac potassium.³⁰⁷

Food delays time to reach peak plasma concentration but does not affect extent of absorption following administration as conventional, delayed-release, or extended-release tablets.^{1 302 303}

Distribution

Widely distributed in animals.^{3 51 52}

Concentrations in synovial fluid may exceed those in plasma.^{1 3 62 63 64 65 66 67 68 69 302 303}

>99%.^{1 3 51 52 58 59 66 302 303}

Elimination

Metabolized in the liver via hydroxylation and conjugation.^{1 3 51 52 68 70 302 303} Some metabolites may exhibit anti-inflammatory activity.^{1 3 22 302 303}

Excreted in urine (65%) and in feces via biliary elimination (35%) as metabolites.^{1 3 51 55 56 70 71 302 303}

1–2 hours.^{2 53 57 60 302 303}

In geriatric patients, pharmacokinetic profile similar to that in younger adults.³⁰⁷

In patients with renal impairment, plasma clearance not substantially altered,^{1 3 208 302 303} although clearance of metabolites may be decreased.^{3 72}

Stability

Storage

Tablets. Tight containers at ≤30°C.^{1 302 303}

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{285 286 287 288 289 290}

• Pharmacologic actions similar to those of other prototypical NSAIAs;^{1 3 20 21 22 23 24 25 26 189 302 303} exhibits anti-inflammatory, analgesic, and antipyretic activity.^{1 3 21 22 23 189 302 303}

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.^{1 302 303}

• Risk of serious cardiovascular events with long-term use.^{1 302 303}

• Risk of GI bleeding and ulceration.^{1 167 181 302 303}

• Risk of serious skin reactions.^{1 302 303} Risk of anaphylactoid and other sensitivity reactions.^{1 302 303}

• Risk of hepatotoxicity.^{1 302 303}

• Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{1 302 303}

• Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.^{1 302 303}

• Importance of discontinuing diclofenac and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.^{1 302 303} Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{1 302 303}

• Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^{1 302 303}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 302 303} Importance of avoiding diclofenac in late pregnancy (third trimester).^{1 302 303}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 302 303}

• Importance of informing patients of other important precautionary information.^{1 302 303} (See Cautions.)

Preparations

Diclofenac Potassium

Routes	Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	50 mg*	Cataflam® (with povidone)	Novartis
			Diclofenac Potassium Tablets	Apotex, Mylan, Sandoz, Teva

* available by nonproprietary name

Diclofenac Sodium

Routes	Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, delayed-release (enteric-coated)	25 mg*	Diclofenac Sodium Delayed-release Tablets	Sandoz
		50 mg*	Diclofenac Sodium Delayed-release Tablets	Actavis, Pliva, Roxane, Sandoz, Watson
		75 mg*	Diclofenac Sodium Delayed-release Tablets	Actavis, Pliva, Roxane, Sandoz, Watson
			Voltaren® (with povidone and propylene glycol)	Novartis
	Tablets, extended-release	100 mg*	Diclofenac Sodium Extended Release Tablets	Actavis, Dexcel, Mylan, Sandoz, Teva, Watson
			Voltaren®-XR (with povidone)	Novartis

* available by nonproprietary name

Diclofenac Sodium Combinations

Routes	Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, delayed-release (enteric-coated core), film-coated	50 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer	Arthrotec® (with povidone)	Searle
		75 mg diclofenac sodium enteric-coated core, with 200 mcg of misoprostol outer layer	Arthrotec® (with povidone)	Searle

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit www.drugstore.com.

Cataflam 50MG Tablets (NOVARTIS): 100/$328.51 or 300/$966.18

Diclofenac Potassium 50MG Tablets (SANDOZ): 60/$39.99 or 180/$99.97

Diclofenac Sodium 0.1% Solution (BAUSCH & LOMB): 2/$25.99 or 7/$65.97

Diclofenac Sodium 0.1% Solution (BAUSCH & LOMB): 5/$35.99 or 15/$95.97

Diclofenac Sodium 25MG Enteric-coated Tablets (SANDOZ): 60/$42.38 or 180/$112.36

Diclofenac Sodium 50MG Enteric-coated Tablets (WATSON LABS): 90/$17 or 180/$20

Diclofenac Sodium 75MG Enteric-coated Tablets (WATSON LABS): 60/$26.99 or 180/$68.99

Diclofenac Sodium CR 100MG 24-hour Tablets (MYLAN): 30/$74.92 or 90/$208.78

Voltaren 0.1% Solution (NOVARTIS): 5/$76.99 or 15/$212.97

Voltaren 0.1% Solution (NOVARTIS): 2/$49.11 or 7/$137.86

Voltaren 25MG Enteric-coated Tablets (NOVARTIS): 60/$58.09 or 180/$167.96

Voltaren 75MG Enteric-coated Tablets (NOVARTIS): 60/$174.97 or 180/$494.95

Voltaren-XR 100MG 24-hour Tablets (NOVARTIS): 30/$175.43 or 90/$500.4

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Selected Revisions July 2007, © Copyright, May 2004, American Society of Health-System Pharmacists, Inc. 7272 Wisconsin Avenue, Bethesda, MD 20814.

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