diclofenac topical (Rx, OTC)

>10%

Dry skin (25-27%)

Rash (20-35%)

Contact dermatitis (19-33%)

Pain (15-26%)

Paresthesia (≤ 20%)

Pruritus (≤ 52%)

Exfoliation (6-24%)

1-10%

Hypertension

Chest pain

Skin ulcer

Diarrhea

Dyspepsia

Alepesia

Photosensitivity

Edema

Conjunctivitis

Hematuria

Asthma

Pneumonia

<1%

Application site pruritus

Other application site reactions

Postmarketing Reports

Dermal allergic reactions

Photoallergic reactions

Contraindications

Hypersensitivity to diclofenac, aspirin other NSAIDs or any ingredient

CABG perioperative period

History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs

Flector patch: Use on non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infection lesions, burns or wounds

Cautions

Long-term administration of NSAIDs resulted in renal papillary necrosis and other renal injury; renal toxicity also seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion

Risks of: cardiovascular thrombotic events; GI bleeding & ulceration; hepatotoxicity (with Na-salt)

Anemia has occurred in NSAID-treated patients

Diclofenac associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma

May lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events; coadministration with angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs

Randomized controlled trials demonstrated an ~2-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients

Increases in serum potassium concentration reported with use of NSAIDs, even in some patients without renal impairment; patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state

Diclofenac may cause premature closure of the fetal ductus arteriosus; avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation (third trimester) (see Pregnancy)

Pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infections

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically

Even a used diclofenac contains a large amount of diclofenac epolamine (as much as 170 mg); potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used drug; store and keep out of the reach of children and pets

Avoid contact of diclofenac with eyes and mucosa

Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin

NSAIDs can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and may occur without warning

Drug reaction with eosinophilia and systemic symptoms (DRESS)

• Drug Reaction reported in patients taking NSAIDs; some of these events have been fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
• Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; sometimes symptoms of DRESS may resemble an acute viral infection
• Eosinophilia is often present; because this disorder is variable in its presentation, other organ systems not noted here may be involved
• Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, discontinue therapy and evaluate the patient immediately

Pregnancy

Use of NSAIDs can cause premature closure of fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment

Because of these risks, limit dose and duration of use between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy

Use of NSAIDs at about 30 weeks gestation or later in pregnancy increases risk of premature closure of fetal ductus arteriosus

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in first or second trimesters of pregnancy are inconclusive

In animal reproduction studies, drug administered orally to pregnant rats and rabbits during period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from maximum recommended human dose (MRHD)

In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose; drug administered orally to both male and female rats prior to mating and throughout mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD (

Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization

In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre-and post-implantation loss; prostaglandins also have been shown to have an important role in fetal kidney development

In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses

Reproductive potential

• Based on mechanism of action, the use of prostaglandin-mediated NSAIDs may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some
• Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation
• Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation; consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing investigation of infertility

Lactation

Data from published literature reports with oral preparations of diclofenac indicate presence of small amounts of diclofenac in human milk

There are no data on effects on breastfed infant, or effects on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from the drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Decreases formation of prostaglandin by inhibiting cyclooxygenase enzymes 1 and 2; may have anti-inflammatory effects by inhibiting chemotaxis, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels

Absorption

Absorption: 10% in epidermis (Solaraze gel); 6% systemic (Voltaren gel); 2-3% (topical solution)

Peak plasma time: 4.5 hr (Solaraze); 10-14 hr (Voltaren gel); 10-20 hr (Flector Patch); 6 hr (Licart)

Peak plasma concentration: 1.01 (Licart); 2.2-8.1 ng/mL (Flector Patch; while resting), and 2.7-7.2 ng/mL (Flector Patch; during exercise)

AUC: 18.58 ng·hr/mL (Licart)

Distribution

Protein bound: >99%

Metabolism

Metabolites: 4'- hydroxy- (very weak pharmacological activity), 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac

Primarily mediated by CPY2C9 Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion

Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8

CY3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac.

Excretion

Half-Life: 12 hr (patch)

Excretion: Urine (~65%); bile (~35%, conjugates of unchanged diclofenac)

Topical Administration

Wash your hands after applying, handling, or removing

Do not apply external heat and/or occlusive dressings to treated joints

Do not apply to open wounds

Avoid contact with eyes and mucous membranes

Avoid exposure of the treated joint(s) to natural or artificial sunlight

Avoid use on treated skin site with other topical products, including sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medications

Concomitant use with oral NSAIDs not evaluated, and may increase adverse NSAIDs effects

Gel

• Avoid showering/bathing for at least 1 hr after application; wash hands after use, unless hands are the treated joint
• If applied to hand(s) for treatment; inform patient not to wash the treated hand(s) for at least 1 hr after the application
• Avoid wearing of clothing or gloves for at least 10 minutes after applying gel

Topical system or transdermal patch

• If patch begins to peel-off, tape down edges of the topical system
• If problems with adhesion persist, overlay topical system with a mesh netting sleeve, where appropriate (eg, to secure topical systems applied to ankles, knees, or elbows)
• Do not apply to non-intact or damaged skin resulting from any etiology (eg, exudative dermatitis, eczema, infected lesion, burns, wounds)
• Do not wear when bathing or showering

Storage

Gel: Store at 20-25°C (68-77°F)

Transdermal patch: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

Topical system

• Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
• Once envelope is opened, stable up to 6 months, if stored at room temperature in the re-sealed envelope