Diclofenac sodium by Pharmaceutica North America, Inc DICLOFENAC SODIUM gel

Diclofenac sodium by

Drug Labeling and Warnings

Diclofenac sodium by is a Prescription medication manufactured, distributed, or labeled by Pharmaceutica North America, Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Distribution

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

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. Systemic clearance of diclofenac from plasma is 263±56 mL/min (mean±SD). The terminal plasma half-life is 1 to 2 hours. Four of the metabolites also have short terminal half-lives of 1 to 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 × 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.

    Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations)
    Diclofenac Sodium GelVehiclep-value
    Study 190 days treatment27/58 (47%)11/59 (19%)<0.001
    Study 290 days treatment18/53 (34%)10/55 (18%)0.061
    Study 360 days treatment15/48 (31%)5/49 (10%)0.021
    30 days treatment7/49 (14%)2/49 (4%)0.221
    Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location)
    ScalpForeheadFaceArm/ForearmBack of Hand
    Study 1 90 days treatment
    Diclofenac Sodium Gel1/4 (25%)17/30 (57%)9/17 (53%)4/12 (33%)6/16 (38%)
    Vehicle3/9 (33%)8/24 (33%)5/17 (29%)4/12 (33%)0/14 (0)
    p-value0.76460.09080.16821.0000.0650
    Study 2 90 days treatment
    Diclofenac Sodium Gel2/6 (33%)9/19 (47%)4/5 (80%)5/8 (63%)1/17 (6%)
    Vehicle0/4 (0)6/22 (27%)2/8 (25%)0/5 (0)3/16 (19%)
    p-value0.42350.18700.07270.08880.2818
    Study 3 60 days treatment
    Diclofenac Sodium Gel3/7 (43%)13/31 (42%)10/19 (53%)0/1 (0)2/8 (25%)
    Vehicle0/6 (0)5/36 (14%)2/13 (15%)0/2 (0)1/9 (11%)
    p-value0.22710.01530.0433--0.4637
    30 days treatment
    Diclofenac Sodium Gel2/5 (40%)4/29 (14%)3/14 (21%)0/0 (0)0/9 (0)
    Vehicle0/5 (0)2/29 (7%)2/18 (11%)0/1 (0)1/9 (11%)
    p-value0.22990.37480.4322--0.6521
    All data combined
    Diclofenac Sodium Gel8/22 (36%)43/109 (39%)26/55 (47%)9/21 (43%)9/50 (18%)
    Vehicle3/24 (13%)21/111 (19%)11/56 (20%)4/20 (20%)5/48 (10%)
    p-value0.09030.00130.00160.20430.3662
  • 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 exposure2), 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.


  • 2 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

    Teratogenic Effects

    Pregnancy Category B

    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 exposure3) 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.

    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.


  • 3 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).
  • 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.

    Table 1. Adverse Events Reported (>1% in Any Treatment Group) During Diclofenac Sodium Gel Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments
    60-day Treatment90-day Treatment
    Diclofenac Sodium
    (%) Gel
    Vehicle
    (%)
    Diclofenac Sodium
    (%) Gel
    Vehicle
    (%)
    N=48N=49N=114N=114
    BODY AS A WHOLE21202018
    Abdominal Pain2010
    Accidental Injury0042
    Allergic Reaction0013
    Asthenia0020
    Back Pain4022
    Chest Pain2010
    Chills0200
    Flu Syndrome10614
    Headache0676
    Infection4645
    Neck Pain0020
    Pain2022
    CARDIOVASCULAR SYSTEM2431
    Hypertension2010
    Migraine0210
    Phlebitis0200
    DIGESTIVE SYSTEM4068
    Constipation0002
    Diarrhea2023
    Dyspepsia2034
    METABOLIC AND NUTRITIONAL DISORDERS2872
    Creatine Phosphokinase Increased0041
    Creatinine Increased2201
    Edema0200
    Hypercholesteremia0210
    Hyperglycemia0210
    SGOT Increased0030
    SGPT Increased0020
    MUSCULOSKELETAL SYSTEM4034
    Arthralgia2002
    Arthrosis2000
    Myalgia2031
    NERVOUS SYSTEM2225
    Anxiety0201
    Dizziness0004
    Hypokinesia2000
    RESPIRATORY SYSTEM8876
    Asthma2000
    Dyspnea2020
    Pharyngitis2824
    Pneumonia2001
    Rhinitis2222
    Sinusitis0020
    SKIN AND APPENDAGES75868671
      Acne0201
      Application Site Reaction75718470
        Acne0410
        Alopecia2011
        Contact Dermatitis194334
        Dry Skin27122517
        Edema4030
        Exfoliation642413
        Hyperesthesia0031
        Pain15222630
        Paresthesia842020
        Photosensitivity Reaction0230
        Pruritus31595245
        Rash35204617
        Vesiculobullous Rash0041
    Contact Dermatitis2000
    Dry Skin0430
    Herpes Simplex0200
    Maculopapular Rash0200
    Pain2210
    Pruritus4641
    Rash21040
    Skin Carcinoma0622
    Skin Nodule0200
    Skin Ulcer2010
    SPECIAL SENSES2042
    Conjunctivitis2041
    Eye Pain0220
    UROGENITAL SYSTEM0045
    Hematuria0021
    OTHER0003
    Procedure0003

    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):

    Body as a Whole: abdominal pain or cramps4, headache4, fluid retention4, abdominal distention4, 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: diarrhea4, indigestion4, nausea4, constipation4, flatulence4, liver test abnormalities4, PUB4, 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: dizziness4, 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: rash4, pruritus4, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.

    Special Senses: tinnitus4, 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 Incidence greater than 1% marked with asterisk.
  • 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 × 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

    Diclofenac Sodium Gel, 3% is available in 100 g (NDC: 45861-063-01) tubes. Each gram of gel contains 30 mg of diclofenac sodium.

    Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from heat. Avoid freezing.

  • SPL UNCLASSIFIED SECTION

    Manufactured for: Pharmaceutica North America, Inc., Glendale, CA 91204
    Made in Canada

    Revised: December, 2015

    PK-8049-0
    113
    1215-0

  • PRINCIPAL DISPLAY PANEL - 100 g Tube Carton

    NDC: 45861-063-01

    100 g

    Diclofenac Sodium
    Gel 3%

    FOR EXTERNAL USE ONLY.
    NOT FOR OPHTHALMIC USE.

    Keep this and all medications out of the reach of children.

    Rx only

    PRINCIPAL DISPLAY PANEL - 100 g Tube Carton
  • INGREDIENTS AND APPEARANCE
    DICLOFENAC SODIUM 
    diclofenac sodium gel
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 45861-063
    Route of AdministrationTOPICAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    diclofenac sodium (UNII: QTG126297Q) (diclofenac - UNII:144O8QL0L1) diclofenac sodium30 mg  in 1 g
    Inactive Ingredients
    Ingredient NameStrength
    benzyl alcohol (UNII: LKG8494WBH)  
    hyaluronate sodium (UNII: YSE9PPT4TH)  
    water (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 45861-063-011 in 1 CARTON04/28/2016
    1100 g in 1 TUBE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20629804/28/2016
    Labeler - Pharmaceutica North America, Inc (962739699)

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