PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

1 INDICATIONS AND USAGE

Diclofenac sodium topical gel is indicated for the topical treatment of actinic keratoses (AK).

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, 5.10) 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) ]

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) ]
• DRESS [see Warnings and Precautions ( 5.10)]
• Hematologic Toxicity [ see Warnings and Precautions ( 5.12) ]
• Photosensitivity [ see Warnings and Precautions ( 5.15) ]

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

**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 forOralDiclofenac 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of diclofenac sodium topical gel and other topical diclofenac products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions from diclofenac sodium topical gel: burning sensation, hypersensitivity.

Adverse reactions from other topical diclofenac products: hypoesthesia, gait disturbance, musculoskeletal stiffness.

7 DRUG INTERACTIONS

See Table 2 for clinically significant drug interactions with diclofenac.

Table 2: Clinically Significant Drug Interactions with Diclofenac

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 gel base. Diclofenac sodium topical gel is supplied in 100 g tubes.

Medication Guide

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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.

8 USE IN SPECIFIC POPULATIONS

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

Of the 211 subjects treated with diclofenac sodium gel in controlled clinical studies, 143 subjects were 65 and over. Of those 143 subjects, 55 subjects were 75 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

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).

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 gel base. Diclofenac sodium is a white to slightly yellow 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 also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water.

1 g of diclofenac sodium topical gel contains 30 mg of the active substance, diclofenac sodium.

16 HOW SUPPLIED/STORAGE AND HANDLING

Available in tubes of 100 g (NDC 45802-111-01). Each gram of topical gel contains 30 mg of diclofenac sodium.

**Storage:**Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F). Protect from heat. Avoid freezing.

14 CLINICAL STUDIES

Clinical trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium topical gel and 214 with a gel vehicle). Each patient 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 patient. All patients 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. Patients 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. Patients 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 patients 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 patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.

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 By Padagis
Yeruham, Israel

Distributed By
Padagis
Allegan, MI 49010

www.padagis.com

7B400 RC J5
Rev 11-22

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.

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 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 vitropoint mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivoassays 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