Diclofenac Sodium

1 INDICATIONS AND USAGE Diclofenac sodium topical gel is indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. • Diclofenac sodium topical gel has not been evaluated for use on the spine, hip, or shoulder. Diclofenac sodium topical gel is a non-steroidal anti-inflammatory drug indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. • Diclofenac sodium topical gel was not evaluated for use on joints of the spine, hip, or shoulder. (14.1)

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • Lower extremities: Apply the gel (4 g) to the affected area 4 times daily. Do not apply more than 16 g daily to any one affected joint of the lower extremities. (2.2) • Upper extremities: Apply the gel (2 g) to the affected area 4 times daily. Do not apply more than 8 g daily to any one affected joint of the upper extremities. (2.3) • Total dose should not exceed 32 g per day, over all affected joints. (2.3) Diclofenac sodium topical gel should be measured onto the enclosed dosing card to the appropriate 2 g or 4 g designation. (2) 2.1 Dosing Card [See the patient Instructions for Use] The dosing card can be found attached to the inside of the carton. The proper amount of diclofenac sodium topical gel should be measured using the dosing card supplied in the drug product carton. The dosing card is made of clear polypropylene. The dosing card should be used for each application of drug product. The gel should be applied within the rectangular area of the dosing card up to the 2 gram or 4 gram line (2 g for each elbow, wrist, or hand, and 4 g for each knee, ankle, or foot). The 2 g line is 2.25 inches long. The 4 g line is 4.5 inches long. The dosing card containing diclofenac sodium topical gel can be used to apply the gel. The hands should then be used to gently rub the gel into the skin. After using the dosing card, hold with fingertips, rinse, and dry. If treatment site is the hands, patients should wait at least one (1) hour to wash their hands. 2.2 Lower extremities, including the feet, ankles, or knees Apply the gel (4 g) to the affected foot, ankle, or knee 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected foot, or knee or ankle. The entire foot includes the sole, top of the foot and the toes. Do not apply more than 16 g daily to any single joint of the lower extremities. 2.3 Upper extremities including the hands, wrists, or elbows Apply the gel (2 g) to the affected hand, wrist, or elbow 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected hand, wrist, or elbow. The entire hand includes the palm, back of the hands, and the fingers. Do not apply more than 8 g daily to any single joint of the upper extremities. Total dose should not exceed 32 g per day, over all affected joints. 2.4 Special Precautions • Avoid showering/bathing for at least 1 hour after the application. Inform patient to wash his/her hands after use, unless the hands are the treated joint. If diclofenac sodium topical gel is applied to the hand(s) for treatment; inform patient not to wash the treated hand(s) for at least 1 hour after the application. • Do not apply diclofenac sodium topical gel to open wounds. • Avoid contact of diclofenac sodium topical gel with eyes and mucous membranes. • Do not apply external heat and/or occlusive dressings to treated joints. • Avoid exposure of the treated joint(s) to natural or artificial sunlight. • Avoid concomitant use of diclofenac sodium topical gel on the treated skin site with other topical products, including sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medications • Concomitant use of diclofenac sodium topical gel with oral non-steroidal anti-inflammatory drugs (NSAIDs) has not been evaluated, and may increase adverse NSAIDs effects. Do not use combination therapy with diclofenac sodium topical gel and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. • Avoid wearing of clothing or gloves for at least 10 minutes after applying diclofenac sodium topical gel

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7) • Heart Failure and Edema : Avoid use of diclofenac sodium topical gel in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) • Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of diclofenac sodium topical gel in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) • Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) • Exacerbation of Asthma Related to Aspirin Sensitivity : Diclofenac sodium topical gel is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions : Discontinue diclofenac sodium topical gel at first appearance of rash or other signs of hypersensitivity ( 5.9) • Premature Closure of Fetal Ductus Arteriosus : Avoid use in pregnant women starting at 30 weeks gestation. (5.10 , 8.1) • Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11 , 7) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions (5.2) ] . Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in…

4 CONTRAINDICATIONS Diclofenac sodium topical gel is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions ( 5.7 , 5.9 )] • 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 ( 5.7 , 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1 )] • Known hypersensitivity to diclofenac or any components of the drug product. (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4) • In the setting of CABG surgery. (4)

7 DRUG INTERACTIONS 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 (5.11) ] . Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. 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 (5.2) ] . 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 (5.11) ] . 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 (5.6) ] . • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 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 (5.6) ] . 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 clea…

8.1 Pregnancy Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation Risk Summary Use of NSAIDs, including diclofenac sodium topical gel, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including diclofenac sodium topical gel, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of diclofenac sodium topical gel in pregnant women. Human and animal studies indicate that diclofenac crosses the placenta. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 5, 5, and 10 times, respectively, the maximum recommended topical dose of diclofenac sodium topical gel, despite the presence of maternal and fetal toxicity at these doses [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Clinical Considerations 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 Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose (MRHD) of diclofenac sodium topical gel based on bioavailability and body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 5 and 10 times the MRHD based on bioavailability and BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (approximately 1 and 2 times the MRHD based on bioavailability and BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.

8.3 Females and Males of Reproductive Potential Infertility Females 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. 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [ see Warnings and Precautions (5.1) ] • GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions (5.2) ] • Hepatotoxicity [ see Warnings and Precautions (5.3) ] • Hypertension [ see Warnings and Precautions (5.4) ] • Heart Failure and Edema [ see Warnings and Precautions (5.5) ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5.6) ] • Anaphylactic Reactions [ see Warnings and Precautions (5.7) ] • Serious Skin Reactions [ see Warnings and Precautions (5.9) ] • Hematologic Toxicity [ see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence >2% of patients treated with diclofenac sodium topical gel and greater than placebo) are application site reactions, including dermatitis. ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 o r www.fda.gov/medwatch . 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical development, 913 patients were exposed to diclofenac sodium topical gel in randomized, double-blind, multicenter, vehicle-controlled, parallel-group studies in osteoarthritis of the superficial joints of the extremities. Of these, 513 patients received diclofenac sodium topical gel for osteoarthritis of the knee and 400 were treated for osteoarthritis of the hand. Additionally, 583 patients were exposed to diclofenac sodium topical gel in an uncontrolled, open-label, long-term safety trial in osteoarthritis of the knee. Of these, 355 patients were treated for osteoarthritis of 1 knee and 228 were treated for osteoarthritis of both knees. Duration of exposure ranged from 8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety trial. Short-Term Placebo-Controlled Trials: Adverse reactions observed in at least 1% of patients treated with diclofenac sodium topical gel: Non-serious adverse reactions that were reported during the short-term placebo-controlled studies comparing diclofenac sodium topical gel and placebo (vehicle gel) over study periods of 8 to 12 weeks (16 g per day), were application site reactions. These were the only adverse reactions that occurred in >1% of treated patients with a greater frequency in the diclofenac sodium topical gel group (7%) than the placebo group (2%). Table 1 lists the types of application site reactions reported. Application site dermatitis was the most frequent type of application site reaction and was reported by 4% of patients treated with diclofenac sodium topical gel, compared to 1% of placebo patients. Table 1. Non-serious Application Site Adverse Reactions (≥1% diclofenac sodium topical gel Patients) – Short-term Controlled Trials Adverse Reaction † Diclofenac sodium topical gel, 1% N=913 Placebo (vehicle) N=876 N (%) N (%) Any application site reaction 62 (7) 19 (2) Application site dermatitis 32 (4) 6 (<1) Application site pruritus 7 (<1) 1 (<1) Application site erythema 6 (<1) 3 (<1) Application site paresthesia 5 (<1) 3 (<1) Application site dryness 4 (<1) 3 (<1) Application site vesicles 3 (<1) 0 Application site irritation 2 (<1) 0 Application site papules 1 (<1) 0 † Preferred Term according to MedDRA 9.1. In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for patients treated with diclofenac sodium topical gel for patients in the placebo group. Application site reactions, including application site dermatitis, were the most frequent reason for treatment discontinuation. Long-Term Open-Label Safety Trial: In the open-label, long-term safety study, distribution of …