Diclofenac Sodium

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Anaphylactic Reactions [ see Warnings and Precautions ( 5.1 )] Exacerbation of Asthma Related to Aspirin Sensitivity [ see Warnings and Precautions ( 5.2 )] Serious Skin Reactions [ see Warnings and Precautions ( 5.3 )] Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.4 )] GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.5 )] Hepatotoxicity [ see Warnings and Precautions ( 5.6 )] Hypertension [ see Warnings and Precautions ( 5.7 )] Heart Failure and Edema [ see Warnings and Precautions ( 5.8 )] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.9 )] Hematologic Toxicity [ see Warnings and Precautions ( 5.12 )] Photosensitivity [ see Warnings and Precautions ( 5.15 )] Most common adverse reactions with diclofenac sodium topical gel are application site reactions, including dermatitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/med.watch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Of the 423 subjects evaluable for safety in adequate and well-controlled trials, 211 were treated with diclofenac sodium topical gel drug product and 212 were treated with a vehicle gel. Eighty-seven percent (87%) of the diclofenac sodium topical gel-treated subjects (183 subjects) and 84% of the vehicle-treated subjects (178 subjects) experienced one or more adverse events (AEs) during the trials. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy. Of the 211 subjects treated with diclofenac sodium topical gel, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated subjects. Application site reactions (ASRs) were the most frequent AEs in both diclofenac sodium topical gel- and vehicle-treated groups. Of note, four reactions, contact dermatitis, rash, dry skin and exfoliation (scaling) were significantly more prevalent in the diclofenac sodium topical gel group than in the vehicle-treated subjects. Eighteen percent of diclofenac sodium topical gel-treated subjects and 4% of vehicle-treated subjects discontinued from the clinical trials due to adverse events (whether considered related to treatment or not). These discontinuations were mainly due to skin irritation or related cutaneous adverse reactions. Table 1 below presents the AEs reported at an incidence of >1% for subjects treated with either diclofenac sodium topical gel or vehicle (60- and 90-day treatment groups) during the phase 3 trials. Table 1. Adverse Events Reported (>1% in Any Treatment Group) During Diclofenac sodium topical gel Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments 60-day Treatment 90-day Treatment Diclofenac sodium topical gel (%) Gel Vehicle (%) Diclofenac sodium topical gel (%) Gel Vehicle (%) N=48 N=49 N=114 N=114 BODY AS A WHOLE 21 20 20 18 Abdominal Pain 2 0 1 0 Accidental Injury 0 0 4 2 Allergic Reaction 0 0 1 3 Asthenia 0 0 2 0 Back Pain 4 0 2 2 Chest Pain 2 0 1 0 Chills 0 2 0 0 Flu Syndrome 10 6 1 4 Headache 0 6 7 6 Infection 4 6 4 5 Neck Pain 0 0 2 0 Pain 2 0 2 2 CARDIOVASCULAR SYSTEM 2 4 3 1 Hypertension 2 0 1 0 Migraine 0 2 1 0 Phlebitis 0 2 0 0 DIGESTIVE SYSTEM 4 0 6 8 Constipation 0 0 0 2 Diarrhea 2 0 2 3 Dyspepsia 2 0 3 4 METABOLIC AND NUTRITIONAL DISORDERS 2 8 7 2 Creatine Phosphokinase Increased 0 0 4 1 Creatinine Increased 2 2 0 1 Edema 0 2 0 0 Hypercholesteremia 0 2 1 0 Hyperglycemia 0 2 1 0 SGOT Increased 0 0 3 0 SGPT Increased 0 0 2 0 MUSCULOSKELETAL SYSTEM 4 0 3 4 Arthralgia 2 0 0 2 Arthrosis 2 0 0 0 Myalgia 2 0 3 1 NERVOUS SYSTEM 2 2 2 5 Anxiety 0 2 0 1 Dizziness 0 0 0 4 Hypokinesia 2 0 0 0 RESPIRATORY SYSTEM 8 8 7 6 Asthma 2 0 0 0 Dyspnea 2 0 2 0 Pharyngitis 2 8 2 4 Pneumonia 2 0 0 1 Rhinitis 2 2 2 2 Sinusitis 0 0 2 0 SKIN AND APPENDAGES 75 86 86 71 Acne 0 2 0 1 Application Site Reaction 75 71 84 70 Acne 0 4 1 0 Alopecia 2 0 1 1 Contact Dermatitis 19 4 33 4 Dry Skin 27 12 25 17 Edema 4 0 3 0 Exfoliation 6 4 24 13 Hyperesthesia 0 0 3 1 Pain 15 22 26 30 Paresthesia 8 4 20 20 Photosensitivity Reaction 0 2 3 0 Pruritus 31 59 52 45 Rash 35 20 46 17 Vesiculobullous Rash 0 0 4 1 Contact Dermatitis 2 0 0 0 Dry Skin 0 4 3 0 Herpes Simplex 0 2 0 0 Maculopapular Rash 0 2 0 0 Pain 2 2 1 0 Pruritus 4 6 4 1 Rash 2 10 4 0 Skin Carcinoma 0 6 2 2 Skin Nodule 0 2 0 0 Skin Ulcer 2 0 1 0 SPECIAL SENSES 2 0 4 2 Conjunctivitis 2 0 4 1 Eye Pain 0 2 2 0 UROGENITAL SYSTEM 0 0 4 5 Hematuria 0 0 2 1 OTHER 0 0 0 3 Procedure 0 0 0 3 Skin and Appendages Adverse Events Reported for diclofenac sodium topical gel at Less Than 1% Incidence in the Phase 3 Studies: skin hypertrophy, paresthesia, seborrhea, urticaria, application site reactions (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation). Adverse Reactions Reported for Oral Diclofenac Dosage Form (not topical diclofenac sodium gel): *Incidence Greater than 1% marked with asterisk. Body as a Whole: abdominal pain or cramps*, headache*, fluid retention*, abdominal distention*, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions, chest pain. Cardiovascular: hypertension, congestive heart failure, palpitations, flushing, tachycardia, premature ventricular contractions, myocardial infarction, hypotension. Digestive: diarrhea*, indigestion*, nausea*, constipation*, flatulence*, liver test abnormalities*, PUB*, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice, melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome, appetite change, pancreatitis with or without concomitant hepatitis, colitis, intestinal perforation. Hemic and Lymphatic: hemoglobin decrease, leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura, bruising. Metabolic and Nutritional Disorders: azotemia, hypoglycemia, weight loss. Nervous System: dizziness*, insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia, memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation, psychotic reaction. Respiratory: epistaxis, asthma, laryngeal edema, dyspnea, hyperventilation, edema of pharynx. Skin and Appendages: rash*, pruritus*, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis. Special Senses: tinnitus*, blurred vision, taste disorder, reversible and irreversible hearing loss, scotoma, vitreous floaters, night blindness, amblyopia. Urogenital: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency, nocturia, hematuria, impotence, vaginal bleeding.

4 CONTRAINDICATIONS Diclofenac sodium topical gel is contraindicated in the following patients: With known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions ( 5.1 , 5.3 ) and Description ( 11 )] With the history of asthma, urticaria, or other allergic type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions ( 5.1 , 5.2 )] Application on damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds [see Warnings and Precautions ( 5.3 )] In the setting of coronary bypass graft (CABG) surgery [see Warnings and Precautions ( 5.4 )] Known hypersensitivity to diclofenac or any components of the drug product. ( 4 , 11 ) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) Use on damaged skin. ( 4 ) In the setting of coronary artery bypass graft (CABG) surgery. ( 4 )

11 DESCRIPTION Diclofenac sodium topical gel, 3%, intended for dermatologic use, contains the active ingredient, diclofenac sodium, in a clear, transparent, colorless to slightly yellow or orange gel base. Diclofenac sodium is a white or slightly yellowish hygroscopic crystalline powder. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble in ether. The chemical name for diclofenac sodium is: Sodium [ o- (2,6-dichloranilino) phenyl] acetate Diclofenac sodium has a molecular weight of 318.13. The CAS number is CAS-15307-79-6. The structural formula is represented below: Diclofenac sodium topical gel, 3% also contains benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water. 1 g of diclofenac sodium topical gel, 3% contains 30 mg of the active substance, diclofenac sodium. Image

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Apply diclofenac sodium topical gel gently to lesion areas twice daily to adequately cover each lesion. Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. Avoid contact of diclofenac sodium topical gel with eyes and mucous membranes. Use the lowest effective dosage for shortest duration consistent with the individual patient treatment goals. ( 2 ) Apply to lesion areas twice daily to adequately cover each lesion. ( 2 ) Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. ( 2 ) The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. ( 2 ) Avoid contact in eyes, nose, or mouth. ( 2 )

1 INDICATIONS AND USAGE Diclofenac sodium topical gel is indicated for the topical treatment of actinic keratoses (AK). Diclofenac sodium topical gel is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the topical treatment of actinic keratoses (AK). ( 1 )

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma have been reported. [see Warnings and Precautions ( 5.4 , 5.5 , 5.7 , 5.9 )] . Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. In the event of oral ingestion, resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. For additional information about overdosage treatment, call a poison control center (1-800-222-1222).

7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.5 )] . Aspirin Clinical Impact: In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.5 )] . Intervention: Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.12 )] . Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.9 )] . When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.9 )] . Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac sodium topical gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions ( 5.5 )] . Intervention: The concomitant use of diclofenac sodium topical gel with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs) Monitor patients for bleeding who are using diclofenac sodium topical gel concomitantly with drugs that interfere with hemostasis. ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers Concomitant use with diclofenac sodium topical gel may diminish the antihypertensive effect of these drugs. ( 7 ) ACE Inhibitors and ARBs Concomitant use with diclofenac sodium topical gel in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. ( 7 ) Diuretics NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. ( 7 ) Digoxin Concomitant use with diclofenac sodium topical gel may increase serum concentration and prolong half-life of digoxin. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown. 12.2 PHARMACODYNAMICS The pharmacodynamics of diclofenac sodium topical gel in the treatment of actinic keratosis has not been assessed. 12.3 Pharmacokinetics Absorption Diclofenac levels were measured at the end of treatment from 60 patients with AK lesions treated with diclofenac sodium topical gel in three adequate and well-controlled clinical trials. Each patient was administered 0.5 g of diclofenac sodium topical gel twice a day for up to 105 days. There were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL. Distribution Diclofenac binds tightly to serum albumin. Metabolism Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise. Elimination Diclofenac and its metabolites are excreted mainly in the urine after oral dosing.

12.1 Mechanism of Action The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown.

12.2 PHARMACODYNAMICS The pharmacodynamics of diclofenac sodium topical gel in the treatment of actinic keratosis has not been assessed.

12.3 Pharmacokinetics Absorption Diclofenac levels were measured at the end of treatment from 60 patients with AK lesions treated with diclofenac sodium topical gel in three adequate and well-controlled clinical trials. Each patient was administered 0.5 g of diclofenac sodium topical gel twice a day for up to 105 days. There were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL. Distribution Diclofenac binds tightly to serum albumin. Metabolism Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise. Elimination Diclofenac and its metabolites are excreted mainly in the urine after oral dosing.

20230112

10

3 DOSAGE FORMS AND STRENGTHS Topical gel, 3%. Each gram of diclofenac sodium topical gel contains 30 mg of diclofenac sodium in a clear, transparent, colorless to slightly yellow or orange gel base. Diclofenac sodium topical gel, 3% is supplied in 100 g tubes. Topical gel, 3% ( 3 )

Diclofenac Sodium Diclofenac Sodium Topical DICLOFENAC SODIUM DICLOFENAC BENZYL ALCOHOL HYALURONATE SODIUM WATER PEG-7 METHYL ETHER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium topical gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodium in albino mice. When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the MRHD based on BSA comparison), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the MRHD based on BSA comparison). Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells. Fertility studies have not been conducted with diclofenac sodium topical gel. Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the MRHD based on BSA comparison) in male or female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium topical gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodium in albino mice. When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the MRHD based on BSA comparison), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the MRHD based on BSA comparison). Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells. Fertility studies have not been conducted with diclofenac sodium topical gel. Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the MRHD based on BSA comparison) in male or female rats.

ANDA212351

Diclofenac Sodium

Diclofenac Sodium Topical

62332-581

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 62332-581-31 Net Wt. 100 g Rx Only Diclofenac Sodium Topical Gel, 3% container label carton label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium topical gel and periodically during the course of ongoing therapy. Special Application Instructions ● Instruct patients not to apply diclofenac sodium topical gel to damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. ● Instruct patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using diclofenac sodium topical gel. If patients need to be outdoors while using diclofenac sodium topical gel, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with diclofenac sodium topical gel at the first evidence of sunburn. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Exacerbation of Asthma Related to Aspirin Sensitivity Inform patients with aspirin sensitive asthma not to use diclofenac sodium topical gel. Advise patients with preexisting asthma to report any changes in the signs and symptoms of asthma to their healthcare provider [see Contraindications ( 4 ) and Warnings and Precautions 5.2 ] . Serious Skin Reactions including DRESS Advise patients to stop using diclofenac sodium topical gel immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions ( 5.3 , 5.10 )] . Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions ( 5.4 )] . Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.5 )] . Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). Inform the patient that diclofenac sodium topical gel may increase the risk of elevated liver enzymes. Advise the patient that laboratory evaluation is needed prior to and periodically during treatment. Advise the patient that if signs or symptoms of liver injury occur, discontinue diclofenac sodium topical gel and seek medical advice promptly [see Warnings and Precautions ( 5.6 )] . Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions ( 5.8 )] . Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium topical gel, may be associated with reversible delay in ovulation [see Use in Specific Populations ( 8.3 )]. Fetal Toxicity Inform pregnant women to avoid use of diclofenac sodium topical gel and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac sodium topical gel is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.1 )] . Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of diclofenac sodium topical gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7 )] . Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium topical gel until they talk to their healthcare provider [see Drug Interactions ( 7 )] . Exposure to Eyes and Mucosal Membranes Instruct patients to avoid contact of diclofenac sodium topical gel with the eyes and mucosal membranes. Advise patients that if eye or mucosal membrane contact occurs, immediately wash out with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions ( 5.16 )] . Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA Manufactured by: Alembic Pharmaceuticals Limited (Derma Division), Karakhadi, Vadodara 391450, India. Mfg. License No.: G/25/2216

SPL MEDGUIDE MEDICATION GUIDE Diclofenac Sodium Topical Gel, 3% (dye kloe' fen ak soe' dee um) What is the most important information I should know about diclofenac sodium topical gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: ● Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: ○ with increasing doses of NSAIDs ○ with longer use of NSAIDs Do not take or use NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)". Avoid taking NSAIDs after a recent heart attack unless your healthcare provider tells you to. You may have an increased risk of another heart attack, if you take or use NSAIDs after a recent heart attack. ● Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: ○ anytime during use ○ without warning symptoms ○ that may cause death The risk of getting an ulcer or bleeding increases with: ○ past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs ○ taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" ○ increasing doses of NSAIDs ○ longer use of NSAIDs ○ smoking ○ drinking alcohol ○ older age ○ poor health ○ advanced liver disease ○ bleeding problems NSAIDs should only be used: ● exactly as prescribed ● at the lowest dose possible for your treatment ● for the shortest time needed What is diclofenac sodium topical gel ? Diclofenac sodium topical gel is an NSAID that is used on the skin (topical) to treat a skin condition called actinic keratosis (AK). Diclofenac sodium topical gel is not for use in children. Do not use diclofenac sodium topical gel : ● if you have had a allergic reaction to any of the ingredients in diclofenac sodium topical gel. See the end of this Medication Guide for a complete list of ingredients in diclofenac sodium topical gel. ● if you have a history of asthma, hives, or other allergic-type reactions after taking aspirin or other NSAIDs.Severe allergic reactions that can sometimes lead to death, have happened in people with a history of these types of allergic reactions to NSAIDs. ● on skin that is inflamed, or has eczema, infected sores (lesions), burns or wounds. ● right before or after heart bypass surgery. Before using diclofenac sodium topical gel, tell your healthcare provider about all of your medical conditions, including if you: ● have liver or kidney problems ● have high blood pressure ● have asthma ● are pregnant or plan to become pregnant. Taking NSAIDS at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. ● are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will use diclofenac sodium topical gel or breastfeed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. How should I use diclofenac sodium topical gel ? ● Use diclofenac sodium topical gel exactly as your healthcare provider tells you to use it. ● Apply diclofenac sodium topical gel 2 times a day. ● Apply enough diclofenac sodium topical gel to cover each skin lesion (usually a pea-sized amount) and gently rub in. ● Diclofenac sodium topical gel may be used for 60 to 90 days. You may not see improvement of skin lesions for up to 30 days after stopping treatment. See your healthcare provider if lesions do not respond to treatment. ● Avoid getting diclofenac sodium topical gel in your eyes, nose and mouth. If diclofenac sodium topical gel gets into your eyes, nose or mouth wash out your eyes, nose or mouth with water or saline right away. Call your healthcare provider if irritation continues for more than 1 hour. ● Wash your hands well after applying diclofenac sodium topical gel. What should I avoid while using diclofenac sodium topical gel ? ● Avoid spending time in sunlight or artificial light, such as tanning beds or sunlamps. Diclofenac sodium topical gel can make your skin sensitive to sunlight and the light from tanning beds and sunlamps. Talk to your healthcare provider about sun protection measures and wear loose-fitting clothes that cover your skin while out in sunlight. Stop using diclofenac sodium topical gel if you notice that you are beginning to get sunburn. ● Do not apply diclofenac sodium topical gel to open skin wounds, skin infections, or peeling skin. What are the possible side effects of diclofenac sodium topical gel ? Diclofenac sodium topical gel and other NSAIDs can cause serious side effects, including: See "What is the most important information I should know about diclofenac sodium topical gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? ● life threatening allergic reactions ● worsening of asthma in people who are aspirin-sensitive ● life-threatening skin reactions ● liver problems including liver failure ● new or worse high blood pressure ● heart failure ● kidney problems including kidney failure ● low red blood cells (anemia) Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: ● shortness of breath or trouble breathing ● chest pain ● weakness in one part or side of your body ● slurred speech ● swelling of the face or throat Stop using diclofenac sodium topical gel and call your healthcare provider right away if you get any of the following symptoms: ● nausea ● vomit blood ● more tired or weaker than usual ● there is blood in your bowel movement, or it is black and sticky like tar ●diarrhea ● unusual weight gain ● itching ● skin rash or blisters with fever ● your skin or eyes look yellow ● swelling of the arms, legs, hands and feet. ● Indigestion or stomach pain ● flu-like symptoms Application site skin reactions are common with diclofenac sodium topical gel including: skin redness, itching, rash, dry skin, scaling, and peeling. If you take too much NSAID, call your healthcare provider or get medical help right away. Diclofenac sodium topical gel may cause fertility problems in females, which may affect your ability to have a child. Talk to your healthcare provider if this a concern for you. These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs ● Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. ● Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs. How should I store diclofenac sodium topical gel ? ● Store diclofenac sodium topical gel at room temperature 68°F to 77°F (20°C to 25°C). ● Keep diclofenac sodium topical gel away from heat. Avoid freezing diclofenac sodium topical gel. Keep diclofenac sodium topical gel and all medicines out of the reach of children. General information about the safe and effective use of diclofenac sodium topical gel . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use diclofenac sodium topical gel for a condition for which it was not prescribed. Do not give diclofenac sodium topical gel to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about diclofenac sodium topical gel, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about diclofenac sodium topical gel that is written for health professionals. What are the ingredients in diclofenac sodium topical gel ? Active ingredient: diclofenac sodium Inactive ingredients: benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water. Manufactured for: Alembic Pharmaceuticals, Inc . Bedminster, NJ 07921, USA Manufactured by: Alembic Pharmaceuticals Limited (Derma Division) , Karakhadi, Vadodara 391450, India. Mfg. License No.: G/25/2216 For more information, go to www.alembicusa.com or call 1-866-210-9797. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 1/2023

14 CLINICAL STUDIES Clinical trials were conducted involving a total of 427 subjects (213 treated with diclofenac sodium topical gel and 214 with a gel vehicle). Each subject had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any subject. All subjects were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Subjects were excluded from participation for reasons of known or suspected hypersensitivity to any diclofenac sodium topical gel ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Subjects were instructed to apply a small amount of diclofenac sodium topical gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all subjects were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term subject follow-ups, after the 30-day assessments, were performed for the detection of recurrence. Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations) Diclofenac sodium topical gel Vehicle p-value Study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001 Study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061 Study 3 60 days treatment 15/48 (31%) 5/49 (10%) 0.021 30 days treatment 7/49 (14%) 2/49 (4%) 0.221 Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location) Scalp Forehead Face Arm/ Forearm Back of Hand Study 1 90 days treatment Diclofenac sodium topical gel Vehicle p-value 1/4 (25%) 3/9 (33%) 0.7646 17/30 (57%) 8/24 (33%) 0.0908 9/17 (53%) 5/17 (29%) 0.1682 4/12 (33%) 4/12 (33%) 1.000 6/16 (38%) 0/14 (0) 0.0650 Study 2 90 days treatment Diclofenac sodium topical gel Vehicle p-value 2/6 (33%) 0/4 (0) 0.4235 9/19 (47%) 6/22 (27%) 0.1870 4/5 (80%) 2/8 (25%) 0.0727 5/8 (63%) 0/5 (0) 0.0888 1/17 (6%) 3/16 (19%) 0.2818 Study 3 60 days treatment Diclofenac sodium topical gel Vehicle p-value 3/7 (43%) 0/6 (0) 0.2271 13/31 (42%) 5/36 (14%) 0.0153 10/19 (53%) 2/13 (15%) 0.0433 0/1 (0) 0/2 (0) - 2/8 (25%) 1/9 (11%) 0.4637 30 days treatment Diclofenac sodium topical gel Vehicle p-value 2/5 (40%) 0/5 (0) 0.2299 4/29 (14%) 2/29 (7%) 0.3748 3/14 (21%) 2/18 (11%) 0.4322 0/0 (0) 0/1 (0) - 0/9 (0) 1/9 (11%) 0.6521 All data combined Diclofenac sodium topical gel Vehicle p-value 8/22 (36%) 3/24 (13%) 0.0903 43/109 (39%) 21/111 (19%) 0.0013 26/55 (47%) 11/56 (20%) 0.0016 9/21 (43%) 4/20 (20%) 0.2043 9/50 (18%) 5/48 (10%) 0.3662

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.9 , 5.14 )]. Of the 211 subjects treated with diclofenac sodium topical gel in controlled clinical trials, 143 subjects were 65 years of age and over. Of those 143 subjects, 55 subjects were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use Actinic keratoses is not a condition seen within the pediatric population. Diclofenac sodium topical gel should not be used by children.

8.1 Pregnancy Risk Summary Use of NSAIDs, including diclofenac sodium topical gel, can cause premature closure of the 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 diclofenac sodium topical gel use between about 20 and 30 weeks of gestation and avoid diclofenac sodium topical gel use at about 30 weeks of gestation and later in pregnancy. Oligohydramnios/Neonatal Renal Impairment 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. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium topical gel, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses at least 15 times, the maximum recommended human dose (MRHD) of diclofenac sodium topical gel (see Data) . Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization, and administration of prostaglandin synthesis inhibitors such as diclofenac sodium, 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. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium topical gel, can cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment If after careful consideration of alternative treatment options for actinic keratoses, an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium topical gel treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical gel and follow up according to clinical practice. Labor or Delivery There are no studies on the effects of diclofenac sodium topical gel during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The multiples provided in this labeling are based on an MRHD that assumes 10% bioavailability following topical application of 2 g diclofenac sodium topical gel per day (1 mg/kg diclofenac sodium). Reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the MRHD based on body surface area (BSA) comparisons) in mice, 10 mg/kg/day (15 times the MRHD based on BSA comparisons) in rats, and 10 mg/kg/day (30 times the MRHD based on BSA comparisons) in rabbits have revealed no evidence of malformations despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

8 USE IN SPECIFIC POPULATIONS Infertility NSAIDS are associated with reversible infertility. Consider withdrawal of diclofenac sodium topical gel in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including diclofenac sodium topical gel, can cause premature closure of the 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 diclofenac sodium topical gel use between about 20 and 30 weeks of gestation and avoid diclofenac sodium topical gel use at about 30 weeks of gestation and later in pregnancy. Oligohydramnios/Neonatal Renal Impairment 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. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium topical gel, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses at least 15 times, the maximum recommended human dose (MRHD) of diclofenac sodium topical gel (see Data) . Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization, and administration of prostaglandin synthesis inhibitors such as diclofenac sodium, 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. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium topical gel, can cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment If after careful consideration of alternative treatment options for actinic keratoses, an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium topical gel treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical gel and follow up according to clinical practice. Labor or Delivery There are no studies on the effects of diclofenac sodium topical gel during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The multiples provided in this labeling are based on an MRHD that assumes 10% bioavailability following topical application of 2 g diclofenac sodium topical gel per day (1 mg/kg diclofenac sodium). Reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the MRHD based on body surface area (BSA) comparisons) in mice, 10 mg/kg/day (15 times the MRHD based on BSA comparisons) in rats, and 10 mg/kg/day (30 times the MRHD based on BSA comparisons) in rabbits have revealed no evidence of malformations despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. 8.2 Lactation Risk Summary Data from published literature cases with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diclofenac sodium topical gel and any potential adverse effects on the breastfed infant from the diclofenac sodium topical gel or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The systemic bioavailability after topical application of diclofenac sodium topical gel is lower than after oral dosing [see Clinical Pharmacology ( 12.3 )] . 8.3 Females and Males of Reproductive Potential Female Infertility Based on the mechanism of action, the use of prostaglandin mediated NSAIDs, including diclofenac sodium topical gel, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology ( 12.1 )]. 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, including diclofenac sodium topical gel, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Actinic keratoses is not a condition seen within the pediatric population. Diclofenac sodium topical gel should not be used by children. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.9 , 5.14 )]. Of the 211 subjects treated with diclofenac sodium topical gel in controlled clinical trials, 143 subjects were 65 years of age and over. Of those 143 subjects, 55 subjects were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING Available in tubes of 100 g (NDC 62332-581-31). Each gram of topical gel contains 30 mg of diclofenac sodium. Storage: Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Protect from heat. Avoid freezing.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions (5.4 ) ]. Diclofenac sodium topical gel is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.4 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at a greater risk for serious GI events [ see Warnings and Precautions ( 5.5 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR EVENTS AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. ( 5.4 ) Diclofenac sodium topical gel is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. ( 4 , 5.4 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.5 )