Diclofenac sodium

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Boxed Warning section

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

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

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

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 × 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.

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

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 50 g and 100 g tubes.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

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) ].

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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) ]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

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

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

DESCRIPTION SECTION

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, 3% 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.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

Clinical trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium topical gel and 214 with a gel vehicle). Each subject had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm × 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. Subjects were instructed to apply a small amount of diclofenac sodium topical gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all 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 Topical Gel Vehicle p-value Study 1 90 days treatment 27/58 (47%) 11/59 (19%)

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Diclofenac Sodium Topical Gel, 3% is available in 100 g (NDC 68788-8236-1) tubes. Each gram of topical gel contains 30 mg of diclofenac sodium. NDC 68788-8236-1 100g tube.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

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.

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

Manufactured by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1 Distributed by: Taro Pharmaceuticals U.S.A., Inc. , Hawthorne, NY 10532 Revised: February 2023 Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides

SPL MEDGUIDE SECTION

SPL MEDGUIDE SECTION

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: February 2023 Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides Medication Guide Diclofenac (dye-KLOE-fen-ak) Sodium Topical Gel, 3% What is the most important information I should know about diclofenac sodium topical gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o 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: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: • past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs • taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" • increasing doses of NSAIDs • longer use of NSAIDs • smoking • drinking alcohol • older age • poor health • advanced liver disease • bleeding problems NSAIDs should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What is diclofenac sodium topical gel? Diclofenac sodium topical gel is an NSAID that is used on the skin (topical) to treat a skin condition called actinic keratosis. Diclofenac sodium topical gel is not for use in children. Do not use diclofenac sodium topical gel: • if you have had an allergic reaction to any of the ingredients in diclofenac sodium topical gel. See the end of this Medication Guide for a complete list of ingredients in diclofenac sodium topical gel. • if you have a history of asthma, hives, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe allergic reactions that can sometimes lead to death, have happened in people with a history of these types of allergic reactions to NSAIDs. • on skin that is inflamed, or has eczema, infected sores (lesions), burns or wounds. • right before or after heart bypass surgery. Before using diclofenac sodium topical gel, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will use diclofenac sodium topical gel or breastfeed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. How should I use diclofenac sodium topical gel? • Use diclofenac sodium topical gel exactly as your healthcare provider tells you to use it. • Apply diclofenac sodium topical gel 2 times a day. • Apply enough diclofenac sodium topical gel to cover each skin lesion (usually a pea-sized amount) and gently rub in. • Diclofenac sodium topical gel may be used for 60 to 90 days. You may not see improvement of skin lesions for up to 30 days after stopping treatment. See your healthcare provider if lesions do not respond to treatment. • Avoid getting diclofenac sodium topical gel in your eyes, nose and mouth. If diclofenac sodium topical gel gets into your eyes, nose or mouth wash out your eyes, nose or mouth with water or saline right away. Call your healthcare provider if irritation continues for more than 1 hour. • Wash your hands well after applying diclofenac sodium topical gel. What should I avoid while using diclofenac sodium topical gel? • Avoid spending time in sunlight or artificial light, such as tanning beds or sunlamps. Diclofenac sodium topical gel can make your skin sensitive to sunlight and the light from tanning beds and sunlamps. Talk to your healthcare provider about sun protection measures and wear loose-fitting clothes that cover your skin while out in sunlight. Stop using diclofenac sodium topical gel if you notice that you are beginning to get sunburn. • Do not apply diclofenac sodium topical gel to open skin wounds, skin infections, or peeling skin. What are the possible side effects of diclofenac sodium topical gel? Diclofenac sodium topical gel and other NSAIDs can cause serious side effects, including: See " Error! Hyperlink reference not valid." • life threatening allergic reactions • worsening of asthma in people who are aspirin-sensitive • life-threatening skin reactions • liver problems including liver failure • new or worse high blood pressure • heart failure • kidney problems including kidney failure • low red blood cells (anemia) Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop using diclofenac sodium topical gel and call your healthcare provider right away if you get any of the following symptoms: • nausea • 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 topical gel including: skin redness, itching, rash, dry skin, scaling, and peeling. If you take too much NSAID, call your healthcare provider or get medical help right away. Diclofenac sodium topical gel may cause fertility problems in females, which may affect your ability to have a child. Talk to your healthcare provider if this a concern for you. These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs. How should I store diclofenac sodium topical gel? • Store diclofenac sodium topical gel at room temperature 68°F to 77°F (20°C to 25°C). • Keep diclofenac sodium topical gel away from heat. Avoid freezing diclofenac sodium topical gel. Keep diclofenac sodium topical gel and all medicines out of the reach of children. General information about the safe and effective use of diclofenac sodium topical gel. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do...

PRINCIPAL DISPLAY PANEL - 100 g Tube Carton

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 68788-8236-1 PHARMACIST: Dispense the enclosed Medication Guide to each patient. 100 g Diclofenac Sodium Topical Gel 3% FOR EXTERNAL USE ONLY. NOT FOR OPHTHALMIC USE. Rx only Keep this and all medications out of the reach of children. TARO Relabeled By: Preferred pharmaceuticals Inc.