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Special Alerts
Transdermal Patches: Risk of Burns During MRI - March 2009
The U.S. Food and Drug Administration (FDA) has issued a public health advisory regarding the risk of burns associated with the use of transdermal medication patches containing aluminum or other metals during MRI screening. The package labeling for certain metal-containing patches includes a warning related to the risk of burns if the patches are not removed prior to MRI procedures. However, not all transdermal medication patches with metallic backings have this warning in the labeling. Although metal materials are present in certain patches, it may not be visible. The FDA is currently reviewing the components of all transdermal medication systems to ensure that proper warnings are present in the labeling of those patches that do contain metal materials. In the interim, the FDA recommends that healthcare professionals who refer patients to have an MRI procedure should identify patients who are wearing a transdermal medication patch prior to the scan. Those patients who are wearing a transdermal medication patch should be advised on the proper removal of the patch prior to the procedure as well as reapplication following the scan.
Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Diclofenac may be confused with Diflucan®, Duphalac®
Cataflam® may be confused with Catapres®
Voltaren® may be confused with traMADol, Ultram®, Verelan®
Transdermal patch (Flector®) contains conducting metal (eg, aluminum); remove patch prior to MRI.
Pronunciation
(dye KLOE fen ak)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes gel, patch
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Capsule: Relief of mild-to-moderate acute pain
Immediate-release tablet: Ankylosing spondylitis; primary dysmenorrhea; acute and chronic treatment of rheumatoid arthritis, osteoarthritis
Delayed-release tablet: Acute and chronic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis
Extended-release tablet: Chronic treatment of osteoarthritis, rheumatoid arthritis
Ophthalmic solution: Postoperative inflammation following cataract extraction; temporary relief of pain and photophobia in patients undergoing corneal refractive surgery
Suppository (CAN; not available in U.S.): Symptomatic treatment of rheumatoid arthritis and osteoarthritis (including degenerative joint disease of hip)
Topical gel 1%: Relief of osteoarthritis pain in joints amenable to topical therapy (eg, ankle, elbow, foot, hand, knee, wrist)
Canadian labeling (not in U.S. labeling): Relief of pain associated with acute, localized joint/muscle injuries (eg, sports injuries, strains) in patients ?16 years of age
Topical gel 3%: Actinic keratosis (AK) in conjunction with sun avoidance
Topical patch: Acute pain due to minor strains, sprains, and contusions
Use: Dental
Immediate-release tablets: Acute treatment of mild-to-moderate pain
Use: Unlabeled/Investigational
Juvenile rheumatoid arthritis
Pregnancy Risk Factor
B (topical gel 3%); C (ophthalmic, oral, topical gel 1%, topical patch); D (?30 weeks gestation [oral])
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: 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 late in pregnancy should be avoided (use after 31 or 32 weeks gestation is not recommended by some clinicians). Product labeling for Zipsor™ specifically notes that use at ?30 weeks gestation should be avoided and, therefore, classifies diclofenac as pregnancy category D at this time. 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
Lactation
Excreted in breast milk/not recommended
Breast-Feeding Considerations
Low concentrations of diclofenac can be found in breast milk. Breast-feeding is not recommended by the manufacturer. Use while breast-feeding is contraindicated in Canadian labeling.
Contraindications
Hypersensitivity to diclofenac or any component of the formulation; hypersensitivity to bovine protein (capsule formulation only); patients who exhibited asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; perioperative pain in the setting of coronary artery bypass graft (CABG) surgery
Topical patch: Do not apply to nonintact or damaged skin (eg, exudative dermatitis, eczema, infected lesions, burns or wounds)
Additional contraindications in Canadian labeling (not in U.S. labeling): 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 (Clcr <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 rectal/anal bleeding or inflammatory lesions
Warnings/Precautions
Boxed warnings:
• Cardiovascular events: See “Concerns related to adverse effects” below.
• Coronary artery bypass graft surgery: See “Disease-related concerns” below.
• Gastrointestinal events: See “Concerns related to adverse effects” below.
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 be increased with duration of use or pre-existing cardiovascular risk factors or disease. Carefully evaluate individual cardiovascular risk profiles prior to prescribing. Use caution with fluid retention. Avoid use in heart failure. 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 ?325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt, 2008).
• Genitourinary effects: Long-term NSAID use may result in renal papillary necrosis while persistent urinary symptoms (eg, dysuria, bladder pain), cystitis, or hematuria may occur anytime 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 chronic use, generally within in the first 2 months of therapy, but may occur at any time (manufacturer labeling). A recent clinical trial concluded that transaminase elevations occur 4-6 months after initiation of therapy (Laine, 2009). Significant elevations in transaminases (eg, >3 x ULN) occur before patients become symptomatic. Periodic transaminase monitoring should occur in patients on chronic therapy beginning 4-8 weeks after initiation. Rarely, severe hepatic reactions (eg, fulminant hepatitis, liver failure) have occurred with NSAID use. Use with caution in patients with hepatic porphyria (may trigger attack). 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.
• 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); discontinue use at first sign of skin rash or hypersensitivity.
Disease-related concerns:
• Aseptic meningitis: May increase the risk of aseptic meningitis, 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. Use caution in patients with other forms of asthma.
• Coronary artery bypass graft surgery (CABG): [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.
• Hepatic impairment: Use with caution in patients with decreased hepatic function.
• 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: 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 ACEI, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Not recommended for use in patients with advanced renal disease.
Special populations:
• Elderly: The elderly are at increased risk for adverse effects (especially peptic ulceration, CNS effects, and renal toxicity) from NSAIDs even at low doses.
Dosage form specific issues:
• Capsule: Contains gelatin; use is contraindicated in patients with history of hypersensitivity to bovine protein.
• Ophthalmic drops: Monitor patients for 1 year following application of ophthalmic drops for corneal refractive procedures. Patients using ophthalmic drops should not wear soft contact lenses. Ophthalmic drops may slow/delay healing or prolong bleeding time following surgery.
• Topical gel: Do not apply topical gel to the eyes, mucous membranes, open wounds, infected areas, or to exfoliative dermatitis. Avoid use of occlusive dressings. Should not be used concomitantly with sunscreens, cosmetics, lotions, moisturizers, insect repellents, or other topical medication on the same skin sites. Avoid sunlight exposure to treated areas.
• Transdermal patch: Contains conducting metal (eg, aluminum); remove patch prior to MRI. Do not apply topical patch to the eyes, mucous membranes, open wounds, infected areas, or to exudative dermatitis. Patch should not be worn during bathing or showering.
Other warnings/precautions:
• Surgical/dental procedures: Withhold for at least 4-6 half-lives prior to surgical or dental procedures.
Adverse Reactions
Ophthalmic solution (drops):
>10%: Ocular: Lacrimation (30%), keratitis (28%), intraocular pressure increased (15%), transient burning/stinging (15%)
1% to 10%:
Cardiovascular: Facial edema (?3%)
Central nervous system: ?3%: Dizziness, fever, headache, insomnia, pain
Gastrointestinal: ?3%: Abdominal pain, nausea, vomiting
Neuromuscular & skeletal: ?3%: Pain, weakness
Ocular: 5%: Abnormal vision, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal lesions, corneal opacity, discharge, eyelid swelling, injection, iritis, irritation, itching, lacrimation disorder, ocular allergy
Respiratory: Rhinitis (?3%)
Miscellaneous: Viral infection (?3%)
<1%, postmarketing, and/or case reports: Corneal erosion, corneal infiltrates, corneal perforation, corneal thinning, corneal ulceration, epithelial breakdown, superficial punctuate keratitis
Oral:
1% to 10%:
Cardiovascular: Edema
Central nervous system: Dizziness, headache, somnolence
Dermatologic: Pruritus, rash
Endocrine & metabolic: Fluid retention
Gastrointestinal: Abdominal distension, abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI perforation, heartburn, nausea, peptic ulcer/GI bleed, vomiting
Hematologic: Anemia, bleeding time increased
Hepatic: Liver enzyme abnormalities (>3 x ULN; ?4%)
Otic: Tinnitus
Renal: Renal function abnormal
Miscellaneous: Diaphoresis increased
<1%, postmarketing, and/or case reports: Agranulocytosis, alopecia, anaphylactoid reactions, anaphylaxis, angioedema, aplastic anemia, anxiety, appetite changes, arrhythmia, aseptic meningitis, asthma, azotemia, blurred vision, chest pain, CHF, colitis, coma, confusion, conjunctivitis, cystitis, depression, diplopia, disorientation, dreams abnormal, drowsiness, dyspnea, dysuria, ecchymosis, eosinophilia, eructation, erythema multiforme, esophageal lesions, esophagitis, exfoliative dermatitis, fever, fulminant hepatitis, gastritis, glossitis,hallucination, hearing impairment, hearing loss, hematemesis, hematuria, hemoglobin decreased, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity, hyper-/hypotension, hyper-/hypoglycemia, infection, insomnia, interstitial nephritis, intestinal perforation, jaundice, laryngeal edema, leukopenia, lymphadenopathy, malaise, melena, memory disturbance, meningitis, MI, nephrotic syndrome, nervousness, oliguria, palpitation, pancreatitis, pancytopenia, paresthesia, pharynx edema, photosensitivity, pneumonia, polyuria, proteinuria, psychotic reactions, purpura, rectal bleeding, renal failure, renal papillary necrosis, respiratory depression, seizure, sepsis, somnolence, Stevens-Johnson syndrome, stomatitis, stroke, swelling of lips and tongue, syncope, tachycardia, taste disorder, thrombocytopenia, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, weight change, weakness, xerostomia
Rectal suppository (CAN; not available in U.S.):
Also refer to adverse reactions associated with oral formulations.
1%, postmarketing, and/or case reports: Local: Bleeding, hemorrhoid exacerbation, irritation, proctitis
Topical gel:
>10%: Local: Application site reactions (incidence increased with 3% gel): Pruritus (?52%), rash (35% to 46%), contact dermatitis (4% to 33%), dry skin (?27%), pain (15% to 26%), exfoliation (3% gel; 6% to 24%), paresthesia (?20%)
1% to 10% (reported for 3% gel):
Cardiovascular: Chest pain, hypertension
Central nervous system: Headache, pain
Dermatologic: Pruritus, rash, skin ulcer
Endocrine & metabolic: Hypercholesterolemia, hyperglycemia
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia
Genitourinary: Hematuria
Hepatic: Liver enzymes increased
Local: Alopecia, edema, photosensitivity
Neuromuscular and skeletal: Arthralgia, arthrosis, back pain, CPK increased, hypokinesia, myalgia, neck pain, weakness
Ocular: Conjunctivitis
Respiratory: Asthma, dyspnea, pneumonia, sinusitis
Miscellaneous: Flu-like syndrome
Topical patch:
1% to 10%:
Central nervous system: Dizziness, hypaesthesia
Dermatologic: Dermatitis (2%), dermal allergic reaction
Gastrointestinal: Nausea (3%), dysgeusia (2%), abdominal pain, constipation, diarrhea, gastritis, vomiting, xerostomia
Local: Application site dryness, irritation, erythema, atrophy, discoloration, hyperhidrosis, and vesicles, edema, itching
Neuromuscular & skeletal: Hyperkinesia
Metabolism/Transport Effects
Substrate (minor) of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4; Inhibits CYP1A2 (moderate), 2C9 (weak), 2E1 (weak), 3A4 (weak)
Drug Interactions
ACE Inhibitors: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: 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. Risk C: Monitor therapy
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anticoagulants: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Antiplatelet Agents: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Risk D: 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. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of NSAID (Nonselective). Risk C: Monitor therapy
CycloSPORINE: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Drotrecogin Alfa: Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: 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. Risk C: Monitor therapy
Glucosamine: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur. Risk D: 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. Risk D: Consider therapy modification
HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Risk C: Monitor therapy
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ketorolac: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Latanoprost: NSAID (Ophthalmic) may diminish the therapeutic effect of Latanoprost. Risk C: Monitor therapy
Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Risk D: Consider therapy modification
Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Methotrexate: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Methotrexate. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of other Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pemetrexed: NSAID (Nonselective) may increase the serum concentration of Pemetrexed. Management: Patients with mild-to-moderate renal insufficiency (CrCl 45-79 mL/minute) may use ibuprofen with caution, but should avoid other NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Risk D: Consider therapy modification
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Quinolone Antibiotics: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolone Antibiotics. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy
Thiazide Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Thrombolytic Agents: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
Treprostinil: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Risk C: Monitor therapy
Vancomycin: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Vancomycin. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): NSAID (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification
Voriconazole: May increase the serum concentration of Diclofenac. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).
Herb/Nutraceutical: Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose, fenugreek, feverfew, garlic, ginger, ginkgo biloba, grapeseed, green tea, ginseng (Siberian), guggul, horse chestnut, horseradish, licorice, prickly ash, red clover, reishi, SAMe (s-adenosylmethionine), sweet clover, turmeric, white willow (all have additional antiplatelet activity).
Storage
Capsule: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.
Ophthalmic solution: Store at 15°C to 25°C (59°F to 77°F).
Suppository (CAN; not available in U.S.): Store at 15°C to 30°C (59°F to 86°F); protect from heat.
Tablet: Store below 30°C (86°F). Protect from moisture; store in tight container.
Topical gel: Store at controlled room temperature of 20°C to 25°C (68°F to 77°F); do not freeze.
Voltaren® Emulgel™ [CAN]: Store at 15°C to 30°C (59°F to 86°F)
Transdermal patch: Store at controlled room temperature 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep envelope sealed when not being used.
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Onset of action:
Cataflam® is more rapid than sodium salt (Voltaren®) because it dissolves in the stomach instead of the duodenum
Suppository: More rapid onset, but slower rate of absorption when compared to enteric coated tablet
Absorption: Topical gel: 6% to 10%
Distribution: ~1.4 L/kg
Protein binding: 99%, primarily to albumin
Metabolism: Hepatic; undergoes first-pass metabolism; forms several metabolites (1 with weak activity)
Bioavailability: Voltaren®, Cataflam®: 55%
Half-life elimination: Voltaren®, Cataflam®: ~2 hours; Patch: ~12 hours
Time to peak, serum: Cataflam®: ~1 hour; Flector®: 10-20 hours; Solaraze® Gel: ~5 hours; Voltaren®: ~2 hours; Voltaren® Gel: 10-14 hours; Voltaren® XR ~5 hours; Zipsor™: ~0.5 hour; Suppository: ?1 hour. Note: Suppository: Cmax: Approximately two-thirds of that observed with enteric coated tablet (equivalent 50 mg dose).
Excretion: Urine (65%); feces (35%)
Dosage
Adults:
Oral:
Analgesia:
Immediate release tablet: Starting dose: 50 mg 3 times/day (maximum dose: 150 mg/day); may administer 100 mg loading dose, followed by 50 mg every 8 hours (maximum dose day 1: 200 mg/day; maximum dose day 2 and thereafter: 150 mg/day)
Immediate release capsule: 25 mg 4 times/day
Primary dysmenorrhea: Immediate release tablet: Starting dose: 50 mg 3 times/day (maximum dose: 150 mg/day); may administer 100 mg loading dose, followed by 50 mg every 8 hours (maximum dose day 1: 200 mg/day; maximum dose day 2 and thereafter: 150 mg/day)
Rheumatoid arthritis: Immediate or delayed release tablet: 150-200 mg/day in 2-4 divided doses; Extended release tablet: 100-200 mg/day
Canadian labeling: 150 mg/day in 3 divided doses (75-150 mg/day of slow release tablet)
Osteoarthritis: Immediate or delayed release tablet: 100-150 mg/day in 2-3 divided doses; Extended release tablet: 100 mg/day
Canadian labeling: 150 mg/day in 3 divided doses (75-150 mg/day of slow release tablet)
Ankylosing spondylitis: Delayed release tablet: 100-125 mg/day in 4-5 divided doses
Ophthalmic:
Cataract surgery: Instill 1 drop into affected eye 4 times/day beginning 24 hours after cataract surgery and continuing for 2 weeks
Corneal refractive surgery: Instill 1-2 drops into affected eye within the hour prior to surgery, within 15 minutes following surgery, and then continue for 4 times/day, up to 3 days
Rectal suppository (not available in U.S.):
Osteoarthritis: Canadian labeling: Insert 50 mg or 100 mg suppository rectally as single dose to substitute for final (third) oral daily dose; maximum combined dose (rectal and oral): 150 mg/day
Rheumatoid arthritis: Canadian labeling: Insert 50 mg or 100 mg suppository rectally as single dose to substitute for final (third) oral daily dose (maximum combined dose [rectal and oral]: 150 mg/day
Topical gel:
Actinic keratoses (Solaraze® Gel): Apply 3% gel to lesion area twice daily for 60-90 days
Acute pain (strains, sprains, contusions) (Voltaren® Emulgel™ [CAN; not available in U.S.]): Apply to affected area(s) of skin 3 or 4 times daily for up to 7 days
Osteoarthritis (Voltaren® Gel): Note: Maximum total body dose of 1% gel should not exceed 32 g per day
Lower extremities: Apply 4 g of 1% gel to affected area 4 times daily (maximum: 16 g per joint per day)
Upper extremities: Apply 2 g of 1% gel to affected area 4 times daily (maximum: 8 g per joint per day)
Transdermal patch: Acute pain (strains, sprains, contusions): Apply 1 patch twice daily to most painful area of skin
Dosage adjustment in renal impairment: Not recommended in patients with advanced renal disease or significant renal impairment
Dosage adjustment in hepatic impairment: May require dosage adjustment.
Elderly: No specific dosing recommendations; elderly may demonstrate adverse effects at lower doses than younger adults, and >60% may develop asymptomatic peptic ulceration with or without hemorrhage; monitor renal function
Dental Usual Dosing
Pain: Adults: Oral: Starting dose: 50 mg 3 times/day; maximum dose: 150 mg/day
Administration: Oral
Do not crush tablets. Administer with food or milk to avoid gastric distress. Take with full glass of water to enhance absorption.
Administration: Topical
Topical gel:
1% formulation: Apply gel to affected area or joint and rub into skin gently, making sure to apply to entire affected area or joint. Do not cover with occlusive dressings or apply sunscreens, cosmetics, or other medications to affected area. Do not wash area for one hour following application. Wash hands immediately after application (unless hands are treated joint).
3% formulation: Apply to lesion with gel and smooth into skin gently. Do not cover lesion with occlusive dressings or apply sunscreens, cosmetics, or other medications to affected area.
Transdermal patch: Apply to intact, nondamaged skin. Remove transparent liner prior to applying to skin. Wash hands after applying as well as after removal of patch. May tape down edges of patch, if peeling occurs. 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.
Administration: Other
Ophthalmic: Wait at least 5 minutes before administering other types of eye drops.
Rectal suppository: Remove entire plastic wrapping prior to inserting rectally.
Monitoring Parameters
Monitor electrolytes, CBC, liver enzymes (periodically during chronic therapy starting 4-8 weeks after initiation), BUN/serum creatinine; monitor urine output; occult blood loss; vision examinations (with prolonged use); blood pressure
Dietary Considerations
Oral formulations may be taken with food to decrease GI distress.
Diclofenac potassium = Cataflam®; potassium content: 5.8 mg (0.15 mEq) per 50 mg tablet
Patient Education
Oral: Take this medication exactly as directed; do not increase dose without consulting prescriber. Do not crush or chew tablets. Take with 8 oz of water, along with food or milk products to reduce GI distress. Maintain adequate hydration unless instructed to restrict fluid intake. Avoid alcohol, aspirin and aspirin-containing medication, or any other anti-inflammatory medications unless consulting prescriber. You may experience dizziness, nervousness, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, dry mouth, or heartburn (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or constipation (increased exercise, fluids, fruit, or fiber may help). GI bleeding, ulceration, or perforation can occur with or without pain; discontinue medication and contact prescriber if persistent abdominal pain or cramping, or blood in stool occurs. Report chest pain or palpitations; breathlessness or respiratory difficulty; unusual bruising/bleeding or blood in urine, stool, mouth, or vomitus; unusual fatigue; skin rash or itching; jaundice, unusual weight gain, or swelling of extremities; change in urinary pattern; change in vision or hearing (ringing in ears). Pregnancy/breast-feeding precautions: Consult prescriber if you are pregnant. This drug should not be used in the 3rd trimester of pregnancy. Consult prescriber if you are breast-feeding.
Ophthalmic: For ophthalmic use only. Apply prescribed amount as often as directed. Wash hands before using. Tilt head back and look upward. Gently pull down lower lid and put drop(s) in inner corner of eye. Do not let tip of applicator touch eye; do not contaminate tip of applicator (may cause eye infection, eye damage, or vision loss). Close eye and roll eyeball in all directions. Do not blink for 1/2minute. Apply gentle pressure to inner corner of eye for 30 seconds. Wipe away excess from skin around eye. Do not use any other eye preparation for at least 10 minutes. Do not share medication with anyone else. May cause sensitivity to bright light (dark glasses may help); temporary stinging or blurred vision may occur. Inform prescriber if you experience eye pain, redness, burning, watering, dryness, double vision, puffiness around eye, vision changes, other adverse eye response, worsening of condition, or lack of improvement.
Gel: This preparation is for topical use only. Do not use more often than recommended; use at regular intervals. Wash hands before and after use. Follow directions on prescription label. Gently apply enough of the gel to cover the lesion. Advise prescriber if you are using any other skin preparations. Avoid direct sunlight and sunlamps while using this medication. You may experience dry skin, itching, peeling, swelling, or tingling at site of application. If severe skin reaction develops, stop applications and notify your prescriber at once.
Geriatric Considerations
Elderly are a high-risk population for adverse effects from nonsteroidal anti-inflammatory agents. As much as 60% of the elderly can develop peptic ulceration and/or hemorrhage asymptomatically. The concomitant use of H2 blockers and sucralfate is not effective as prophylaxis with the exception of NSAID-induced duodenal ulcers which may be prevented by the use of ranitidine. Misoprostol and proton pump inhibitors are the only agents proven to help prevent the development of NSAID-induced ulcers. Also, concomitant disease and drug use contribute to the risk for GI adverse effects. Use lowest effective dose for shortest period possible. Consider renal function decline with age. Use of NSAIDs can compromise existing renal function especially when Clcr is ?30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high dose situations, but elderly may demonstrate these adverse effects at lower doses than younger adults.
Anesthesia and Critical Care Concerns/Other Considerations
The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.
In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema; may precipitate renal failure in dehydrated patients.
Cardiovascular Considerations
Blood Pressure: In short-term use, NSAIDs vary considerably in their effect on blood pressure. A meta-analysis (Pope, 1993) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short.
Heart Failure: The use of NSAIDs in the treatment of patients with heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with heart failure, particularly in the elderly population. The ACC/AHA 2009 heart failure guidelines suggest that NSAIDs be avoided or withdrawn whenever possible in patients with current or prior symptoms of heart failure and reduced LVEF.
Risk of Cardiovascular Events: Patients at increased risk of cardiovascular adverse events include patients immediately postoperative (10-14 days) from CABG surgery, and those with existing CAD, CVD, or history of TIA. Prescribers are encouraged to use the lowest effective dose for the shortest duration of time based on individual patient treatment goals. Available evidence reviewed by the FDA does not suggest an increased risk of serious CV events when NSAIDs are given short term and in the lower doses used OTC.
Dental Health: Effects on Dental Treatment
The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®). See Effects on Bleeding.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause nervousness or dizziness; may rarely cause depression
Mental Health: Effects on Psychiatric Treatment
May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease the clearance of lithium resulting in elevated serum levels and potential toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Evaluate cardiac risk and potential for GI bleeding prior to prescribing this medication. Assess other medications patient may be taking for effectiveness and interactions. Monitor blood pressure at the beginning of therapy and periodically during use. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions (systemic or ophthalmic) at beginning of therapy and periodically throughout therapy. Schedule ophthalmic evaluations for patients who develop eye complaints during long-term NSAID therapy. Assess knowledge/teach patient appropriate use (oral, ophthalmic, gel), interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product; [CAN] = Canadian product [not available in U.S]
Capsule, liquid filled, as potassium:
Zipsor™: 25 mg [contains gelatin]
Gel, as diethylamine:
Voltaren® Emulgel™ [CAN]: 1.16% (20 g, 50 g, 100 g)
Gel, as sodium:
Solaraze®: 3% (50 g, 100 g)
Voltaren® Gel: 1% (100 g)
Solution, ophthalmic, as sodium [drops]: 0.1% (2.5 mL, 5 mL)
Voltaren Ophthalmic®: 0.1% (2.5 mL, 5 mL)
Suppository, as sodium [CAN]:
Voltaren®: 50 mg, 100 mg
Tablet, as potassium: 50 mg
Cataflam®: 50 mg
Tablet, delayed release, enteric coated, as sodium: 50 mg, 75 mg
Voltaren®: 25 mg [DSC], 50 mg [DSC], 75 mg
Tablet, extended release, as sodium: 100 mg
Voltaren®-XR: 100 mg
Transdermal system, topical, as epolamine:
Flector®: 1.3% (30s) [180 mg]
Pricing: U.S. (www.drugstore.com)
Gel (Solaraze)
3% (50): $140.21
3% (100): $452.67
Patch (Flector)
1.3% (30): $170.03
Solution (Diclofenac Sodium)
0.1% (2.5): $15.99
0.1% (5): $25.99
Solution (Voltaren)
0.1% (2.5): $50.99
0.1% (5): $76.99
Tablet, 24-hour (Diclofenac Sodium CR)
100 mg (30): $74.92
Tablet, 24-hour (Voltaren-XR)
100 mg (30): $192.79
Tablet, EC (Diclofenac Sodium)
25 mg (60): $61.99
50 mg (90): $35.99
75 mg (60): $41.82
Tablet, EC (Voltaren)
25 mg (60): $58.09
75 mg (60): $192.30
Tablets (Cataflam)
50 mg (100): $361.04
Tablets (Diclofenac Potassium)
50 mg (60): $39.99
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International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
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