Diclofenac Sodium

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 vehicletreated 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 Treatment 90-day Treatment Diclofenac Sodium Gel (%) N=48 Gel Vehicle (%) N=49 Diclofenac Sodium Gel (%) N=114 Gel Vehicle (%) 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 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

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. Diclofenac Sodium Gel is contraindicated in the following patients: In the setting of coronary artery bypass graft (CABG) surgery.

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, 3% 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. Description

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 reevaluated and management reconsidered.

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

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.

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 Absorption 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 AUC0-t 9±19 ng/hr/mL (mean±SD) with a Cmax of 4±5 ng/mL and a Tmax of 4.5±8 hours. In comparison, a single oral 75 mg dose of diclofenac (Voltaren®)1 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 to 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 × 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. 1 Voltaren® is a registered trademark of its respective owner. 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.

20230110

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Diclofenac Sodium Diclofenac Sodium DICLOFENAC SODIUM DICLOFENAC

ANDA206298

Diclofenac Sodium

Diclofenac Sodium

80425-0235

HUMAN PRESCRIPTION DRUG

TOPICAL

Principal Display Panel label 1

SPL Unclassified Rx Only FOR DERMATOLOGIC USE ONLY. NOT FOR OPHTHALMIC USE.

Medguide Medication Guide Diclofenac (dye-KLOE-fen-ak) Sodium Gel, 3% What is the most important information I should know about Diclofenac Sodium Gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? Diclofenac Sodium Gel is an NSAID medicine that is used on the skin only (topical). Do not use Diclofenac Sodium Gel in or on the eyes. 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 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 Gel? Diclofenac Sodium Gel is an NSAID that is used on the skin (topical) to treat a skin condition called actinic keratosis. Diclofenac Sodium Gel is not for use in children. Who should not use Diclofenac Sodium Gel? Do not use Diclofenac Sodium Gel: if you have had an allergic reaction to any of the ingredients in Diclofenac Sodium Gel. See the end of this Medication Guide for a complete list of ingredients in Diclofenac Sodium Gel. right before or after heart bypass surgery. Before using Diclofenac Sodium 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 Gel or breastfeed. You should not do both. 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 Gel? Use Diclofenac Sodium Gel exactly as your healthcare provider tells you to use it. Apply Diclofenac Sodium Gel 2 times a day. Apply enough Diclofenac Sodium Gel to cover each skin lesion and gently rub in. Diclofenac Sodium 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. Wash your hands after applying Diclofenac Sodium Gel. What should I avoid while using Diclofenac Sodium Gel? Avoid spending time in sunlight or artificial light, such as tanning beds or sunlamps. Diclofenac Sodium Gel can make your skin sensitive to sunlight and the light from tanning beds and sunlamps. You should avoid applying Diclofenac Sodium Gel to open skin wounds, skin infections, or peeling skin. What are the possible side effects of Diclofenac Sodium Gel? Diclofenac Sodium Gel and other NSAIDs can cause serious side effects, including: See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT DICLOFENAC SODIUM GEL AND MEDICINES CALLED NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)?" new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life threatening allergic reactions 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 Gel and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms, legs, hands and feet Application site skin reactions are common with Diclofenac Sodium Gel and include: skin redness, itching, rash, dry skin, scaling, and peeling. If Diclofenac Sodium Gel is accidentally taken by mouth, call your healthcare provider or get medical help right away. These are not all 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 for more than 10 days. How should I store Diclofenac Sodium Gel? Store Diclofenac Sodium Gel at room temperature 68°F to 77°F (20°C to 25°C). Keep Diclofenac Sodium Gel away from heat. Avoid freezing Diclofenac Sodium Gel. Keep Diclofenac Sodium Gel and all medicines out of the reach of children. General information about the safe and effective use of Diclofenac Sodium Gel Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Diclofenac Sodium Gel for a condition for which it was not prescribed. Do not give Diclofenac Sodium 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 Gel, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Diclofenac Sodium Gel that is written for health professionals. What are the ingredients in Diclofenac Sodium Gel? Active ingredient: diclofenac sodium Inactive ingredient: benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water. Manufactured by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1 Distributed by: Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532 For more information, call 1-866-923-4914. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: September 2021

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 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 Gel 1/4 (25%) 17/30 (57%) 9/17 (53%) 4/12 (33%) 6/16 (38%) Vehicle 3/9 (33%) 8/24 (33%) 5/17 (29%) 4/12 (33%) 0/14 (0) p-value 0.7646 0.0908 0.1682 1.000 0.0650 Study 2 90 days treatment Diclofenac Sodium Gel 2/6 (33%) 9/19 (47%) 4/5 (80%) 5/8 (63%) 1/17 (6%) Vehicle 0/4 (0) 6/22 (27%) 2/8 (25%) 0/5 (0) 3/16 (19%) p-value 0.4235 0.1870 0.0727 0.0888 0.2818 Study 3 60 days treatment Diclofenac Sodium Gel 3/7 (43%) 13/31 (42%) 10/19 (53%) 0/1 (0) 2/8 (25%) Vehicle 0/6 (0) 5/36 (14%) 2/13 (15%) 0/2 (0) 1/9 (11%) p-value 0.2271 0.0153 0.0433 - 0.4637 30 days treatment Diclofenac Sodium Gel 2/5 (40%) 4/29 (14%) 3/14 (21%) 0/0 (0) 0/9 (0) Vehicle 0/5 (0) 2/29 (7%) 2/18 (11%) 0/1 (0) 1/9 (11%) p-value 0.2299 0.3748 0.4322 - 0.6521 All data combined Diclofenac Sodium Gel 8/22 (36%) 43/109 (39%) 26/55 (47%) 9/21 (43%) 9/50 (18%) Vehicle 3/24 (13%) 21/111 (19%) 11/56 (20%) 4/20 (20%) 5/48 (10%) p-value 0.0903 0.0013 0.0016 0.2043 0.3662

How Supplied/Storage and Handling Diclofenac Sodium Gel, 3% is available in 100 g (NDC 80425-0235-01) 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.

Boxed Warning WARNING: RISK OF SERIOUS CARDIOVASCULAR 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. Diclofenac Sodium Gel is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.