Diclopak diclofenac sodium, capsaicin Diclofenac Sodium Diclofenac Sodium ALCOHOL DIMETHYL SULFOXIDE GLYCERIN PROPYLENE GLYCOL WATER DICLOFENAC SODIUM DICLOFENAC Rugby Capsaicin External Analgesic Capsaicin CARBOMER COPOLYMER TYPE A (ALLYL PENTAERYTHRITOL CROSSLINKED) CETYL ACETATE METHYLPARABEN PPG-20 METHYL GLUCOSE ETHER DISTEARATE PROPYLENE GLYCOL PROPYLPARABEN STEARETH-100 STEARIC ACID STEARYL ALCOHOL TROLAMINE WATER CAPSAICIN CAPSAICIN

Diclofenac Sodium Topical Solution, 1.5% w/w is a nonsteroidal anti-inflammatory drug, available as a clear, colorless to faintly pink orange solution for topical application. Diclofenac Sodium Topical Solution contains 1.5% w/w diclofenac sodium, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug (NSAID), designated chemically as 2-[(2,6- dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. It is a white to off-white crystalline powder, hygroscopic that is freely soluble in methanol, soluble in ethanol (96 %), sparingly soluble in water, practically insoluble in chloroform and in ether. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2 and it has the following structural formula: Each 1 mL of solution contains 16.05 mg of diclofenac sodium. The inactive ingredients in diclofenac sodium topical solution include: alcohol, dimethyl sulfoxide (DMSO, 45.5% w/w), glycerin, propylene glycol and purified water. diclofig

Diclofenac sodium topical solution is a nonsteroidal anti-inflammatory drug indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s). Diclofenac sodium topical solution is a nonsteroidal anti-inflammatory drug indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s). (1) Uses temporarily relieves minor aches and pains of muscles and joints due to: • simple backache • arthritis • strains • sprains

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. The recommended dose is 40 drops on each painful knee, 4 times a day. (2) Apply diclofenac sodium topical solution to clean, dry skin. (2.1) Dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread diclofenac sodium topical solution evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution. (2.1) Wash hands completely after administering the product. Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). (2.2) Do not get diclofenac sodium topical solution in your eyes, nose or mouth (2.2). 2.1 General Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNING AND PRECAUTIONS (5.2)] For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops per knee, 4 times a day. Apply diclofenac sodium topical solution to clean, dry skin. To avoid spillage, dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread diclofenac sodium topical solution evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution. To treat the other knee, if symptomatic, repeat the procedure. Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended. 2.2 Special Precautions Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee. Wash and dry hands after use. Do not apply diclofenac sodium topical solution to open wounds. Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes. Do not apply external heat and/or occlusive dressings to treated knees. Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry. Protect the treated knee(s) from natural or artificial sunlight Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Directions Adults and children 18 years of age and older: • apply a thin film of cream to affected area and gently rub in until fully absorbed • unless treating hands, wash hands thoroughly with soap and water immediately after application • for best results, apply 3 to 4 times daily. Children under 18 years: ask a doctor

Diclofenac sodium 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 allergic-type reactions after taking aspirin or other NSAIDs. (4) In the setting of CABG surgery (4)

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)] 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to diclofenac sodium of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasians, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application site reactions: In controlled trials, the most common treatment-related adverse events in patients receiving diclofenac sodium topical solution were application site skin reactions. Application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution and oral diclofenac. In the open label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Adverse Events Common to the NSAID Class: In controlled trials, subjects treated with diclofenac sodium experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 1). The combination of diclofenac sodium topical solution and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases. Table 1 lists all adverse reactions occurring in ≥1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Reactions occurring in ≥1% of patients treated with Diclofenac Sodium Topical Solution, 1.5% w/w in placebo and oral diclofenac-controlled trials table1 6.2 Postmarketing Experience In non-U.S. postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole Abdominal pain, accidental injury, allergic reaction, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, lack of drug effect, neck rigidity, pain Cardiovascular Palpitation, cardiovascular disorder Digestive Diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis Metabolic and Nutritional Creatinine increased Musculoskeletal Leg cramps, myalgia Nervous Depression, dizziness, drowsiness, lethargy, paresthesia, paresthesia at application site Respiratory Asthma, dyspnea, laryngismus, laryngitis, pharyngitis Skin and Appendages At the Application Site: Contact dermatitis, contact dermatitis with vesicles, dry skin, pruritus, rash; Other Skin and Appendages Adverse Reactions: Eczema, rash, pruritus, skin discoloration, urticaria Special Senses Abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion

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 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 PRECAUTIONS; Hematological Toxicity). 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; Gastrointestinal Bleeding, Ulceration, and Perforation). Intervention: Concomitant use of diclofenac and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see PRECAUTIONS: Hematological Toxicity). Diclofenac is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors , Angiotens in 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 and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac 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; Renal Toxicity and Hyperkalemia). 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 with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects ( see WARNINGS; Renal Toxicity and Hyperkalemia). 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 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 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 and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine: Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates: Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy ( see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed: Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac 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. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs ): Monitor patients for bleeding who are concomitantly using diclofenac sodium with drugs that interfere with hemostasis. Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended (7) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers : Concomitant use with diclofenac sodium may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) ACE Inhibitors and ARBs : Concomitant use with diclofenac sodium in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) Diuretics : NSAIDS can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) Digoxin : Concomitant use with diclofenac sodium can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7)

Purpose External analgesic

For external use only Read all warnings and directions before use. Test first on small area of skin. Do not use • on wounds or damaged skin • if you are allergic to capsicum or chili peppers

When using this product • you may experience a burning sensation. The intensity of this reaction varies among individuals and may be severe. With regular use, this sensation generally disappears after several days. • avoid contact with the eyes, lips, nose and mucous membranes • do not tightly wrap or bandage the treated area • do not apply heat to the treated area immediately before or after use

Stop use and ask a doctor if • condition worsens or does not improve after regular use • severe burning persists or blistering occurs

Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center immediately.

Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature]. Other information store at room temperature 15° - 30°C (59° - 86°F)