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Diclofenac (Systemic)

Pronunciation

Pronunciation

(dye KLOE fen ak)

Index Terms

  • Cataflam
  • Diclofenac Potassium
  • Diclofenac Sodium
  • Voltaren
  • Zorvolex

Dosage Forms

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

Capsule, Oral, as base:

Zorvolex: 18 mg, 35 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #2 (indigotine)]

Capsule, Oral, as potassium:

Zipsor: 25 mg [contains gelatin (bovine)]

Packet, Oral, as potassium:

Cambia: 50 mg (1 ea, 9 ea) [contains aspartame, saccharin sodium; anise-mint flavor]

Solution, Intravenous, as sodium:

Dyloject: 37.5 mg/mL (1 mL)

Tablet, Oral, as potassium:

Cataflam: 50 mg [DSC]

Generic: 50 mg

Tablet Delayed Release, Oral, as sodium:

Generic: 25 mg, 50 mg, 75 mg

Tablet Extended Release 24 Hour, Oral, as sodium:

Voltaren-XR: 100 mg [DSC]

Generic: 100 mg

Brand Names: U.S.

  • Cambia
  • Cataflam [DSC]
  • Dyloject
  • Voltaren-XR [DSC]
  • Zipsor
  • Zorvolex

Pharmacologic Category

  • Analgesic, Nonopioid
  • Nonsteroidal Anti-inflammatory Drug (NSAID)
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Oral

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.

Distribution

~1.4 L/kg

Metabolism

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

Excretion

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

Onset of Action

Cataflam (potassium salt) is more rapid than the sodium salt because it dissolves in the stomach instead of the duodenum

Suppository [Canadian product]: more rapid onset, but slower rate of absorption when compared to enteric coated tablet

Time to Peak

Serum: Note: Fasted values reported for oral products; may be delayed with food.

Cambia: ~0.25 hours

Cataflam, Zorvolex: ~1 hour

Voltaren XR ~5 hours

Zipsor: ~0.5 hour

Injection: ~5 minutes

Suppository [Canadian product]: ≤1 hour; Note: Suppository: Cmax: Approximately two-thirds of that observed with enteric coated tablet (equivalent 50 mg dose)

Tablet, delayed release (diclofenac sodium): ~2 hours

Half-Life Elimination

Oral: ~2 hours; Injection: ~1 to 2 hours

Protein Binding

>99%, primarily to albumin

Use: Labeled Indications

Analgesia

Capsules/immediate-release tablets only: Relief of mild to moderate acute pain

Injection only: Management of mild to moderate acute pain and moderate to severe acute pain (alone or in combination with opioid analgesics) in adults

Ankylosing spondylitis (delayed-release tablets only): Acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis

Dysmenorrhea (immediate-release tablets only): Treatment of primary dysmenorrhea

Migraine (powder for oral solution only): Acute treatment of migraine attacks with or without aura in adults

Osteoarthritis (immediate-release, extended-release, and delayed-release tablets; capsules [Zorvolex]; and suppositories [Canadian product] only): Relief of signs and symptoms of osteoarthritis.

Rheumatoid arthritis (immediate-release, extended-release, and delayed-release tablets; and suppositories [Canadian product] only): Relief of signs and symptoms of rheumatoid arthritis.

Use: Unlabeled

Juvenile idiopathic arthritis (JIA)

Contraindications

Hypersensitivity to diclofenac (eg, anaphylactoid reactions, serious skin reactions) or bovine protein (Zipsor only) or any component of the formulation; patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; treatment of perioperative pain in the setting of CABG surgery; patients with moderate to severe renal impairment in the perioperative period and who are at risk for volume depletion (injection only)

Canadian labeling: Additional contraindications (not in U.S. labeling): Severe uncontrolled heart failure, active gastric/duodenal/peptic ulcer; active GI bleed or perforation; regional ulcer, gastritis, or ulcerative colitis; cerebrovascular bleeding or other bleeding disorders; inflammatory bowel disease; severe hepatic impairment; active hepatic disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease; known hyperkalemia; patients <16 years of age; breast-feeding; pregnancy (third trimester); use of diclofenac suppository if recent history of bleeding or inflammatory lesions of rectum/anus

Dosing: Adult

Analgesia:

Oral:

Immediate-release tablet: 50 mg 3 times daily; may administer 100 mg loading dose, followed by 50 mg every 8 hours

Canadian labeling: 50 mg every 6 to 8 hours for up to 7 days (maximum: 100 mg daily)

Immediate-release capsule:

Zipsor (diclofenac potassium): 25 mg 4 times daily

Zorvolex (diclofenac acid): 18 mg or 35 mg 3 times daily

IV: 37.5 mg every 6 hours as needed (maximum: 150 mg daily).

Primary dysmenorrhea: Oral: Immediate-release tablet: 50 mg 3 times daily; may administer 100 mg loading dose, followed by 50 mg every 8 hours

Canadian labeling: Immediate release tablet: Day 1: Initial: 100 mg then 50 mg every 6 to 8 hours (maximum: 200 mg daily); Day 2 and beyond (up to 7 days): 50 mg every 6 to 8 hours (maximum: 100 mg daily)

Rheumatoid arthritis:

Oral: Immediate-release tablet: 150 to 200 mg daily in 3 to 4 divided doses; Delayed-release tablet: 150 to 200 mg daily in 2 to 4 divided doses; Extended-release tablet: 100 mg daily (may increase dose to 200 mg daily in 2 divided doses)

Canadian labeling: Enteric-coated tablet: 50 mg every 8 hours (maximum: 100 mg daily); Slow-release tablet: 75 to 100 mg daily (maximum: 100 mg daily)

Rectal suppository [Canadian product]: Insert 50 mg or 100 mg rectally as single dose to substitute for final oral daily dose (maximum combined dose [rectal and oral]: 100 mg daily

Osteoarthritis:

Oral:

Immediate-release tablet: 150 to 200 mg daily in 3 to 4 divided doses; Delayed-release tablet: 150 to 200 mg daily in 2 to 4 divided doses; Extended-release tablet: 100 mg daily; may increase dose to 200 mg daily in 2 divided doses

Canadian labeling: Enteric-coated tablet: 50 mg every 8 hours (maximum: 100 mg daily); Slow-release tablet: 75 to 100 mg daily (maximum: 100 mg daily)

Immediate-release capsule: Zorvolex (diclofenac acid): 35 mg 3 times daily.

Rectal suppository [Canadian product]: Insert 50 mg or 100 mg rectally as single dose to substitute for final oral daily dose (maximum combined dose [rectal and oral]: 100 mg daily)

Ankylosing spondylitis: Oral: Delayed-release tablet: 100 to 125 mg daily in 4 to 5 divided doses

Migraine: Oral: Oral solution: 50 mg (one packet) as a single dose at the time of migraine onset; safety and efficacy of a second dose have not been established.

Dosing: Geriatric

Refer to adult dosing. Use lowest recommended dose and frequency in elderly to initiate therapy for indications listed in adult dosing.

Dosing: Pediatric

Juvenile idiopathic arthritis (off-label use): Children ≥3 years and Adolescents: Oral: Delayed-release tablet (diclofenac sodium): 2 to 3 mg/kg/day in divided doses (Haapasaari, 1983; Hashkes, 2005)

Dosing: Renal Impairment

U.S. labeling: There are no dosage adjustments provided in the manufacturer's labeling; not recommended in patients with advanced renal disease or significant renal impairment; use of injection is contraindicated in patients with moderate to severe renal impairment in the perioperative period and who are at risk for volume depletion.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; however, the manufacturer recommends that reduced dosages should be considered. Use in severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease is contraindicated.

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

U.S. labeling: May require dosage adjustment due to extensive hepatic metabolism. Additional product-specific recommendations:

Cambia: Use in patients with hepatic impairment only if benefits outweigh risks

Zorvolex: Initial: Initiate treatment at the lowest dose; if efficacy is not achieved with the lowest dose, discontinue use.

Injection:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Use is not recommended (has not been studied).

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; however, the manufacturer recommends that reduced dosages should be considered. Use is contraindicated in severe liver impairment or active liver disease.

Hepatic impairment during treatment: Persistent or worsening abnormal liver function tests, clinical signs/symptoms consistent with liver disease, or systemic manifestations of liver disease (eg, eosinophilia, rash, abdominal pain, diarrhea, dark urine): Discontinue immediately.

Reconstitution

Oral solution: Empty contents of packet into 1-2 ounces (30-60 mL) of water (do not use other liquids); mix well and administer immediately.

Administration

Injection: Administer as an IV bolus over 15 seconds.

Oral: Do not crush delayed- or extended-release tablets. Administer with food or milk to avoid gastric distress.

Cambia, Zorvolex: Taking with food may cause a reduction in effectiveness.

Rectal suppository [Canadian product]: Remove entire plastic wrapping prior to inserting rectally.

Dietary Considerations

Oral formulations may be taken with food to decrease GI distress. However, food may reduce effectiveness of oral solution and Zorvolex capsules. Some products may contain phenylalanine.

Storage

Capsule, powder for oral solution: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Injection: Store at 20°C to 25°C (68°F to 77°F). Do not freeze. Protect from light.

Suppository [Canadian product]: Store at 15°C to 30°C (59°F to 86°F); protect from heat.

Tablet: Store immediate-release and ER tablets below 30°C (86°F); store delayed-release tablets at 20°C to 25°C (68°F to 77°F). Protect from moisture.

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

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

CYP2C9 Inducers (Strong): May decrease the serum concentration of Diclofenac (Systemic). Monitor therapy

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. 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

Deferiprone: UGT1A6 Inhibitors may increase the serum concentration of Deferiprone. 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

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

Nalmefene: Diclofenac (Systemic) may increase the serum concentration of Nalmefene. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: 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

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

Resveratrol: May increase the serum concentration of Diclofenac (Systemic). 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: Diclofenac (Systemic) may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination 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 (Systemic). Management: Consider using a lower dose of diclofenac when used with voriconazole. Arthrotec (diclofenac and misoprostol) labeling recommends limiting the total daily dose to a maximum of 50 mg twice daily. Consider therapy modification

Adverse Reactions

Injection: Frequency not always defined.

Cardiovascular: Edema (≤ 10%), cerebrovascular accident, hypertension, myocardial infarction, significant cardiovascular event

Central Nervous System: Headache (≤10%), dizziness (8%)

Dermatologic: Pruritus (≤10%), skin rash (≤10%), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & Metabolic: Fluid retention

Gastrointestinal: Constipation (13%), abdominal pain (≤10%), diarrhea (≤10%), dyspepsia (≤10%), esophageal perforation (≤10%), flatulence (≤10%), gastrointestinal ulcer (≤10%; including gastric/duodenal), heartburn (≤10%), intestinal perforation (≤10%), nausea (≤10%), vomiting (≤10%)

Hematologic & Oncologic: Anemia (≤10%), hemorrhage (≤10%), prolonged bleeding time (≤10%)

Hepatic: Increased liver enzymes (≤10%), increased serum transaminases (15%), increased serum ALT (≤4%; >8X ULN: ≤1%), increased serum AST (2% to ≤4%; >8X ULN: ≤1%)

Hypersensitivity: Anaphylactoid reaction

Local: Infusion site reaction (10%), extravasation (3%)

Otic: Tinnitus (≤10%)

Renal: Renal insufficiency (≤10%)

Miscellaneous: Wound healing impairment (8%), gastrointestinal inflammation

<1% (Limited to important or life-threatening): Abnormal Dreams, agranulocytosis, alopecia, anaphylaxis, angioedema, anxiety, aplastic anemia, asthma, auditory impairment, blurred vision, cardiac arrhythmia, change in appetite, colitis, coma, confusion, congestive heart failure, conjunctivitis, convulsions, cystitis, depression, diaphoresis, drowsiness, dyspnea, dysuria, ecchymoses, eosinophilia, eructation, erythema multiforme, esophagitis, exfoliative dermatitis, fever, fulminant hepatitis, gastritis, gastrointestinal hemorrhage, glossitis, hallucination, hematemesis, hematuria, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity, hyperglycemia, hypertension, hypotension, infection, insomnia, interstitial nephritis, jaundice, leukopenia, lymphadenopathy, malaise, melena, meningitis, nervousness, oliguria, palpitations, pancreatitis, pancytopenia, paresthesia, pneumonia, polyuria, proteinuria, purpura, rectal hemorrhage, renal failure, respiratory depression, sepsis, skin photosensitivity, stomatitis, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, weakness, weight changes

Oral: Frequency not always defined.

>10%:

Cardiovascular: Edema (33%)

Hepatic: Increased serum transaminases (≤3 x ULN; 15%)

1% to 10%:

Cardiovascular: Hypertension (2% to 3%)

Central nervous system: Headache (4% to 8%), procedural pain (3%), dizziness (2%), falling (2%)

Dermatologic: Pruritus (7%), skin rash

Gastrointestinal: Constipation (5% to 8%), nausea (6% to 7%), diarrhea (6%), GI adverse effects (gastric ulcer, hemorrhage, and perforation; ≤4%, risk increases with therapy duration), abdominal pain (2% to 3%), vomiting (3%), dyspepsia (2% to 3%), flatulence (2% to 3%), heartburn, abdominal discomfort (2%), duodenal ulcer

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Bruise (3%), anemia, prolonged bleeding time

Hepatic: Increased serum ALT (>3 x ULN: ≤4%; >8 x ULN: ≤1%), increased serum AST (>3 x ULN; ≤4%; >8 x ULN: ≤1%)

Infection: Influenza (3%)

Neuromuscular & skeletal: Osteoarthritis (5%), arthralgia (3%), back pain (3%), limb pain (3%)

Renal: Renal function abnormality

Otic: Tinnitus

Renal: Increased serum creatinine (2%), renal function abnormality

Respiratory: Upper respiratory tract infection (8%), nasopharyngitis (6%), sinusitis (3% to 5%), cough (4%), bronchitis (3%)

<1% (Limited to important or life-threatening): Agranulocytosis, alopecia, anaphylactoid reaction, aplastic anemia, aseptic meningitis, asthma, cardiac arrhythmia, cardiac failure, cerebrovascular accident, colitis, coma, conjunctivitis, cystitis, decreased hemoglobin, depression, diplopia, eosinophilia, erythema multiforme, esophageal ulcer, esophagitis, gastritis, hearing loss, hemolytic anemia, hepatic failure, hepatitis, hyperglycemia, hypotension, interstitial nephritis, intestinal perforation, lymphadenopathy, memory impairment, meningitis, myocardial infarction, pancreatitis, pancytopenia, peptic ulcer, pneumonia, psychotic reaction, purpura, rectal hemorrhage, renal failure, respiratory depression, seizure, sepsis, skin photosensitivity, Stevens-Johnson syndrome, tachycardia, toxic epidermal necrolysis, vasculitis

Rectal suppository [Canadian product]:

Also refer to adverse reactions associated with oral formulations.

<1% (Limited to important or life-threatening): Hemorrhoids (exacerbation), local hemorrhage, proctitis

ALERT: U.S. Boxed Warning

Cardiovascular risk:

Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors of cardiovascular disease may be at greater risk.

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

Gastrointestinal risk:

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse reactions, including bleeding, inflammation, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients 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. Do not use in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.

• Cardiovascular events: [U.S. Boxed Warning]: NSAIDs are associated with an increased risk of adverse cardiovascular thrombotic events, including MI and stroke. Risk may increase with dose and duration of use or preexisting cardiovascular risk factors or disease. Carefully evaluate individual cardiovascular risk profiles (eg, hypertension, ischemic heart disease, diabetes, smoking) prior to prescribing and consider alternative agents if appropriate. Use caution with fluid retention. Avoid use in heart failure (ACCF/AHA [Yancy, 2013]). Concurrent administration of ibuprofen, and potentially other nonselective NSAIDs, may interfere with aspirin’s cardioprotective effect. 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.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long term therapy.

• Gastrointestinal events: [U.S. Boxed Warning]: NSAIDs may increase risk of gastrointestinal irritation, inflammation, ulceration, bleeding, and perforation. These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, the 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). Canadian labeling contraindicates use in patients with active gastric/duodenal/peptic ulcer; active GI bleed or perforation; or regional ulcer, gastritis, or ulcerative colitis.

• Genitourinary effects: Persistent urinary symptoms (eg, dysuria, bladder pain), cystitis, or hematuria may occur any time after initiating NSAID therapy. Discontinue therapy with symptom onset and evaluate for origin.

• 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 use, generally within the first 2 months of therapy, but may occur at any time. Risk may be higher with diclofenac than other NSAIDS (Laine, 2009; Rostom, 2005). Significant elevations in transaminases (eg, >3 x ULN) occur before patients become symptomatic. Periodically monitor transaminases beginning 4 to 8 weeks after initiation of therapy. Severe hepatic reactions (eg, fulminant hepatitis, liver failure) have occurred with NSAID use. Use with caution in patients with hepatic porphyria (may trigger attack; Jose, 2008). Patients should be educated about symptoms of hepatotoxicity. Avoid concurrent hepatotoxins if possible and use the lowest effective dose for the shortest duration. Discontinue therapy if hepatic injury is suspected (persistent or worsening LFT abnormality, clinical signs/symptoms of liver disease, or systemic manifestations of hypersensitivity [eosinophilia, rash]).

• 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. Canadian labeling contraindicates use with known hyperkalemia.

• 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. Patients with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly are at greatest risk. Long-term NSAID use may result in renal papillary necrosis and other renal injury/toxicity.

• Skin reactions: NSAIDs may cause photosensitivity as well as serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal; discontinue use at first sign of skin rash or hypersensitivity.

Disease-related concerns:

• Aseptic meningitis: May increase the risk of aseptic meningitis (rarely), especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

• Asthma: Do not administer to patients with aspirin-sensitive asthma; severe bronchospasm may occur, which can be fatal. Use caution in patients with other forms of asthma.

• Coronary artery bypass graft surgery: [U.S. Boxed Warning]: Use is contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.

• Dehydration: Use caution when initiating therapy in patients with considerable dehydration; rehydrate patient before starting therapy and monitor renal function closely.

• Hepatic impairment: Use with caution in patients with decreased hepatic function. Canadian labeling contraindicates use in severe hepatic impairment or active hepatic disease.

• Hypertension: Use with caution; may cause new-onset hypertension or worsening of existing hypertension. Monitor blood pressure closely with therapy initiation and during therapy.

• Renal impairment: Not recommended for use in patients with advanced renal disease. Injection is not recommended in patients with moderate to severe renal impairment and is contraindicated in patients with moderate to severe renal impairment in the perioperative period and who are at risk for volume depletion.

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.

Dosage form specific issues:

• Injection: Not indicated for long-term use.

• Oral solution: Only indicated for acute treatment of migraine; not indicated for migraine prophylaxis or cluster headache. Contains phenylalanine.

• Zipsor: Contains gelatin; use is contraindicated in patients with history of hypersensitivity to bovine protein.

Other warnings/precautions:

• Bioequivalence: Different formulations of oral diclofenac are not bioequivalent, even if the milligram strength is the same; do not interchange products.

• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.

Monitoring Parameters

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

Canadian labeling also recommends periodic ophthalmic evaluation during extended therapy or with onset of vision changes.

Pregnancy Risk Factor

C (oral, injection)/D (≥30 weeks gestation [oral, injection])

Pregnancy Considerations

Adverse events were not observed in the initial animal reproduction studies; therefore, manufacturers classify most dosage forms of diclofenac as pregnancy category C (oral, injection: Category D ≥30 weeks gestation). Diclofenac crosses the placenta and can be detected in fetal tissue and amniotic fluid. NSAID exposure during the first trimester is not strongly associated with congenital malformations; however, cardiovascular anomalies and cleft palate have been observed following NSAID exposure in some studies. The use of a NSAID close to conception may be associated with an increased risk of miscarriage. Nonteratogenic effects have been observed following NSAID administration during the third trimester including: Myocardial degenerative changes, prenatal constriction of the ductus arteriosus, fetal tricuspid regurgitation, failure of the ductus arteriosus to close postnatally; renal dysfunction or failure, oligohydramnios; gastrointestinal bleeding or perforation, increased risk of necrotizing enterocolitis; intracranial bleeding (including intraventricular hemorrhage), platelet dysfunction with resultant bleeding; pulmonary hypertension. Because they may cause premature closure of the ductus arteriosus, use of NSAIDs in pregnancy (particularly late pregnancy) should be avoided. Product labeling for Cambia, Zipsor, and Zorvolex specifically notes that use at ≥30 weeks' gestation should be avoided. Use in the third trimester is contraindicated in the Canadian labeling. The chronic use of NSAIDs in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication. A registry is available for pregnant women exposed to autoimmune medications including diclofenac. For additional information contact the Organization of Teratology Information Specialists, OTIS Autoimmune Diseases Study, at 877-311-8972

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, nausea, constipation, heartburn, vomiting, diarrhea, flatulence, fatigue, injection site pain, or sweating a lot. Have patient report immediately to prescriber 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 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 high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any severe bleeding or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, weight gain), shortness of breath, severe dizziness, passing out, excessive weight gain, swelling of arm or leg, angina, tachycardia, severe headache, vision changes, severe loss of strength and energy, severe abdominal pain, signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), or 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) (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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