Brand name: Solaraze
Drug class: Nonsteroidal Anti-inflammatory Agents
VA class: DE900
Chemical name: 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid monosodium salt
Molecular formula: C14H10Cl2NNaO2
CAS number: 15307-79-6
- Cardiovascular Risk
NSAIAs increase risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke). Risk may occur early in treatment and may increase with duration of use. (See Cardiovascular Thrombotic Effects under Cautions.)
Contraindicated in the setting of CABG surgery.
Prototypical NSAIA; phenylacetic acid derivative.
Uses for Diclofenac (Topical)
Treatment of actinic keratoses.
Has been used topically or orally for the symptomatic treatment of infusion-related superficial thrombophlebitis† [off-label].
Diclofenac (Topical) Dosage and Administration
Complete healing of the lesions or optimal therapeutic response may not occur until 30 days after cessation of therapy.
Apply to actinic keratosis lesions as a 3% gel.
Apply a sufficient amount (usually 0.5 g for each 5 cm × 5 cm lesion) and rub gently onto the lesions twice daily for 60–90 days.
Carefully re-evaluate any lesions that do not respond and reconsider management.
Cautions for Diclofenac (Topical)
Known hypersensitivity to diclofenac or any ingredient in the formulation.
In the setting of CABG surgery.
Cardiovascular Thrombotic Effects
NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.
Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.
Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.
Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.
In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.
In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.
Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.
Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs. FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.
Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.
Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia. Contraindicated in the setting of CABG surgery.
No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.
Other Warnings and Precautions
Heart Failure and Edema
Fluid retention and edema reported in patients receiving NSAIAs.
NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.
NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.
Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.
Some experts recommend avoiding use of NSAIAs, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.
Sensitivity reactions, including anaphylaxis, possible in patients without prior exposure to diclofenac. Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps).
Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs. Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Symptoms may resemble those of acute viral infection. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash. If signs or symptoms of DRESS develop, discontinue diclofenac and immediately evaluate the patient.
Use with caution in patients with active GI ulceration or bleeding.
For external use only; avoid contact with eyes. Do not apply to open skin wounds, infected lesions, or exfoliative dermatitis.
Safety and efficacy of concomitant use with other topical products (e.g., sunscreens, cosmetics, other topical medications) unknown.
Safety of diclofenac sodium 3% gel not established during pregnancy.
Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.
Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.
Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice. (See Advice to Patients.)
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs. Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios. Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis). Deaths associated with neonatal renal failure also reported. Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.
Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.
No evidence of teratogenicity observed with diclofenac in animals studies; maternally toxic doses associated with dystocia, prolonged gestation, reduced fetal weight and growth, and reduced fetal survival in rats.
Effects of diclofenac on labor and delivery not known.
Discontinue nursing or the drug because of potential risk to nursing infants.
Safety and efficacy not established in children. Actinic keratoses generally are not seen in the pediatric population; diclofenac sodium 3% gel should not be used by children.
Actinic keratoses occur frequently in an older patient population. No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.
Use with caution in patients with severe hepatic impairment.
Use with caution in patients with severe renal impairment.
Common Adverse Effects
Contact dermatitis, rash, dry skin, exfoliation (scaling).
Interactions for Diclofenac (Topical)
Specific drug interaction studies not performed.
Possible increased adverse effects if used with oral NSAIAs, including aspirin. Concurrent use of NSAIAs and aspirin increases risk of serious adverse GI events.
Diclofenac (Topical) Pharmacokinetics
Absorbed into epidermis after topical application to the skin.
Minimal systemic absorption following topical application to up to 3 actinic keratosis lesion areas (5 cm × 5 cm); serum diclofenac concentrations averaged 20 ng/mL following topical application twice daily for up to 105 days versus 1417 ng/mL following a single 50-mg oral dose of diclofenac sodium.
Effect of occlusive dressings on absorption not established.
Plasma Protein Binding
Bound to albumin.
Metabolized in the liver via hydroxylation and conjugation following oral administration; metabolism following topical administration is expected to be similar to that following oral administration.
Mainly excreted in urine following oral administration.
1–2 hours following oral administration.
20–25°C (may be exposed to 15–30°C). Protect from heat; do not freeze.
While the mechanism(s) of the topical effects has not been established, diclofenac has inhibited angiogenesis and induced neovascular regression in inflammatory tissue in animal models.
NSAIAs, including diclofenac, may inhibit angiogenesis through inhibition of substance P or by blocking the angiogenic effects of prostaglandin E2 (PGE2).
For topical use in the treatment of actinic keratoses, diclofenac sodium is commercially available as a 3% gel with benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water. The contribution of individual vehicle components to the efficacy of diclofenac sodium gel remains to be established.
Advice to Patients
Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.
Risk of adverse dermal effects, including irritant or allergic contact dermatitis, exfoliation, dry skin, and rash. Importance of reporting signs and symptoms of adverse dermal reactions. Necessity of interrupting therapy if severe dermal reactions occur.
Avoid exposure to sunlight and use of sunlamps.
Importance of monitoring and follow-up evaluation.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription, OTC, or herbal products, as well as any concomitant illness. Safety and efficacy of use with other topical products (e.g., sunscreens, cosmetics, other topical medications) are unknown.
Risk of serious skin reactions, including DRESS. Advise patients to discontinue use immediately if they develop any type of rash or fever and to promptly contact their clinician.
Risk of serious cardiovascular toxicity (e.g., MI, stroke) with NSAIAs. Importance of seeking immediate medical attention if signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) occur.
Risk of heart failure or edema with NSAIAs; importance of reporting dyspnea, unexplained weight gain, or edema.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of avoiding use of NSAIAs, including diclofenac sodium 3% gel, beginning at 20 weeks’ gestation unless otherwise advised by a clinician and of avoiding use beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; advise pregnant women that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours’ duration between about 20 and 30 weeks of gestation.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Diclofenac Sodium Gel
AHFS DI Essentials™. © Copyright 2023, Selected Revisions December 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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