DICLOFENAC SODIUM

E. FOUGERA & CO. A division of Fougera Pharmaceuticals Inc.

DICLOFENAC SODIUM GEL, 3%

FULL PRESCRIBING INFORMATION: CONTENTS*

• DICLOFENAC SODIUM DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics
• DICLOFENAC SODIUM INDICATIONS AND USAGE
• CLINICAL STUDIES
• DICLOFENAC SODIUM CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General
  • Information for Patients
  • Drug Interactions
  • Oral Nonsteroidal Anti-Inflammatory Drugs
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy:
  • Labor and Delivery
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• DICLOFENAC SODIUM ADVERSE REACTIONS
• OVERDOSAGE
• DICLOFENAC SODIUM DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 100G CONTAINER
• PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 100 G CARTON

FULL PRESCRIBING INFORMATION

Rx Only

FOR DERMATOLOGIC USE ONLY. NOT FOR OPHTHALMIC USE.

DESCRIPTION

Diclofenac Sodium Gel, 3%, 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 Gel also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water.

1 g of Diclofenac Sodium Gel contains 30 mg of the active substance, diclofenac sodium.

CLINICAL PHARMACOLOGY

The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown. The contribution to efficacy of individual components of the vehicle has not been established.

Pharmacokinetics

When Diclofenac Sodium Gel is applied topically, diclofenac is absorbed into the epidermis. In a study in patients with compromised skin (mainly atopic dermatitis and other dermatitic conditions) of the hands, arms or face, approximately 10% of the applied dose (2 grams of 3% gel over 100 cm²) of diclofenac was absorbed systemically in both normal and compromised epidermis after seven days, with four times daily applications.

After topical application of 2 g Diclofenac Sodium Gel three times daily for six days to the calf of the leg in healthy subjects, diclofenac could be detected in plasma. Mean bioavailability parameters were AUC_0-t 9±19 ng/hr/mL (mean±SD) with a C_max of 4±5 ng/mL and a T_max of 4.5±8 hours.
In comparison, a single oral 75 mg dose of diclofenac (Voltaren^®)† produced an AUC of 1600 ng/hr/mL. Therefore, the systemic bioavailability after topical application of Diclofenac Sodium Gel is lower than after oral dosing.

Comparative bioavailability studies have not been conducted between available diclofenac topical products (gels containing 1 - 3% diclofenac) which have different dosing regimens. A cross-study evaluation of the data indicates that diclofenac is more bioavailable when applied to diseased skin and less bioavailable when applied to intact skin.

Blood drawn at the end of treatment from 60 patients with AK lesions treated with Diclofenac Sodium Gel in three adequate and well-controlled clinical trials was assayed for diclofenac levels. Each patient was administered 0.5 g of Diclofenac Sodium 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. These data indicate that systemic absorption of diclofenac in patients treated topically with Diclofenac Sodium Gel is much lower than that occurring after oral daily dosing of diclofenac sodium.

No information is available on the absorption of diclofenac when Diclofenac Sodium Gel is used under occlusion.

Diclofenac binds tightly to serum albumin. The volume of distribution of diclofenac following oral administration is approximately 550 mL/kg.

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.

Diclofenac and its metabolites are excreted mainly in the urine after oral dosing. Systemic clearance of diclofenac from plasma is 263±56 mL/min (mean±SD). The terminal plasma half-life is 1-2 hours. Four of the metabolites also have short terminal half-lives of 1-3 hours.

INDICATIONS AND USAGE

Diclofenac Sodium Gel is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.

CLINICAL STUDIES

Clinical trials were conducted involving a total of 427 patients (213 treated with Diclofenac Sodium 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 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 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.

CONTRAINDICATIONS

Diclofenac Sodium Gel is contraindicated in patients with a known hypersensitivity to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350 and/or hyaluronate sodium.

WARNINGS

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac. Diclofenac sodium should be given with caution to patients with the aspirin triad. The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.

PRECAUTIONS

General

Diclofenac Sodium Gel should be used with caution in patients with active gastrointestinal ulceration or bleeding and severe renal or hepatic impairments. Diclofenac Sodium Gel should not be applied to open skin wounds, infections, or exfoliative dermatitis. It should not be allowed to come in contact with the eyes.

The safety of the concomitant use of sunscreens, cosmetics or other topical medications and Diclofenac Sodium Gel is unknown.

Information for Patients

In clinical studies, localized dermal side effects such as contact dermatitis, exfoliation, dry skin and rash were found in patients treated with Diclofenac Sodium Gel at a higher incidence than in those with placebo.

Patients should understand the importance of monitoring and follow-up evaluation, the signs and symptoms of dermal adverse reactions, and the possibility of irritant or allergic contact dermatitis. If severe dermal reactions occur, treatment with Diclofenac Sodium Gel may be interrupted until the condition subsides. Exposure to sunlight and the use of sunlamps should be avoided.

Safety and efficacy of the use of Diclofenac Sodium Gel together with other dermal products, including cosmetics, sunscreens, and other topical medications on the area being treated, have not been studied.

Drug Interactions

Specific interaction studies between Diclofenac Sodium Gel and other topical or oral agents were not performed.

Oral Nonsteroidal Anti-Inflammatory Drugs

Although low, there is systemic exposure to diclofenac following labeled use of Diclofenac Sodium Gel. Therefore, concomitant administration of Diclofenac Sodium Gel with oral NSAIDS or aspirin may result in increased NSAID adverse effects.

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. (Note: Diclofenac Sodium Gel contains 3% diclofenac sodium.) 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 estimated systemic human exposure*), 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 estimated systemic human exposure).

A photococarcinogenicity study with up to 0.035% diclofenac in the Diclofenac Sodium vehicle Gel was conducted in hairless mice at topical doses up to 2.8 mg/kg/day. Median tumor onset was earlier in the 0.035% group (Diclofenac Sodium Gel contains 3% diclofenac sodium).

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 Gel. Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the estimated systemic human exposure) in male or female rats.

* Based on body surface area and assuming 10% bioavailability following topical application of 2 g Diclofenac Sodium Gel per day (1 mg/kg diclofenac sodium).

Pregnancy:

The safety of Diclofenac Sodium Gel has not been established during pregnancy. However, reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the estimated systemic human exposure*) in mice, 10 mg/kg/day (15 times the estimated systemic human exposure) in rats, and 10 mg/kg/day (30 times the estimated systemic human exposure) in rabbits have revealed no evidence of teratogenicity 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.

* Based on body surface area and assuming 10% bioavailability following topical application of 2 g Diclofenac Sodium Gel per day (1 mg/kg diclofenac sodium).

Diclofenac has been shown to cross the placental barrier in mice and rats. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the benefits to the mother justify the potential risk to the fetus. Because of the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should be avoided in late pregnancy.

Labor and Delivery

The effects of diclofenac on labor and delivery in pregnant women are unknown. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use of diclofenac during late pregnancy should be avoided and, as with other nonsteroidal anti-inflammatory drugs, it is possible that diclofenac may inhibit uterine contractions and delay parturition.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from diclofenac sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Actinic keratoses is not a condition seen within the pediatric population. Diclofenac Sodium Gel should not be used by children.

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.

ADVERSE REACTIONS

Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were treated with Diclofenac Sodium Gel drug product and 212 were treated with a vehicle gel. Eighty-seven percent (87%) of the Diclofenac Sodium Gel treated patients (183 patients) and 84% of the vehicle-treated patients (178 patients) experienced one or more adverse events (AEs) during the studies. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy.

Of the 211 patients treated with Diclofenac Sodium Gel, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated patients. Application site reactions (ASRs) were the most frequent AEs in both Diclofenac Sodium 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 Gel group than in the vehicle-treated patients.

Eighteen percent of Diclofenac Sodium Gel treated patients and 4% of vehicle-treated patients 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 patients treated with either Diclofenac Sodium Gel or vehicle (60- and 90-day treatment groups) during the phase 3 studies.

Skin and Appendages Adverse Events Reported for Diclofenac Sodium 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.

OVERDOSAGE

Due to the low systemic absorption of topically-applied Diclofenac Sodium Gel, overdosage is unlikely. There have been no reports of ingestion of Diclofenac Sodium Gel. In the event of oral ingestion, resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is excreted in the urine. The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation and respiratory depression.

DOSAGE AND ADMINISTRATION

Diclofenac Sodium Gel is applied to lesion areas twice daily. It is to be smoothed onto the affected skin gently. The amount needed depends upon the size of the lesion site. Assure that enough Diclofenac Sodium Gel is applied to adequately cover each lesion. Normally 0.5 g of gel is used 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 carefully re-evaluated and management reconsidered.

HOW SUPPLIED

Available in tubes of 100 g (NDC 0168-0803-01). Each gram of 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.

†Voltaren^® is a registered trademark of Novartis.

Manufactured by:

Almirall Hermal GmbH
D-21465 Reinbek, Germany
Made in Germany

Manufactured for:

E. Fougera & Co.
A division of Fougera Pharmaceuticals Inc.
Melville, NY 11747 USA

400134
R09/12

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 100G CONTAINER

NDC 0168-0803-01
Fougera^®
DICLOFENAC SODIUM
GEL 3%
FOR EXTERNAL USE ONLY.
NOT FOR OPHTHALMIC USE.
Rx Only
NET WT 100 grams

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 100 G CARTON

NDC 0168-0803-01
Rx Only
Fougera^®
DICLOFENAC SODIUM
GEL 3%
FOR EXTERNAL USE ONLY. NOT FOR OPHTHALMIC USE.
NET WT 100 grams