DICLOFENAC POTASSIUM

1 INDICATIONS AND USAGE Diclofenac potassium for oral solution is indicated for the acute treatment of migraine attacks with or without aura in adults (18 years of age or older). Limitations of Use: Diclofenac potassium for oral solution is not indicated for the prophylactic therapy of migraine. The safety and effectiveness of diclofenac potassium for oral solution have not been established for cluster headache, which is present in an older, predominantly male population. Diclofenac potassium for oral solution is a non-steroidal anti-inflammatory drug (NSAID) indicated for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older ( 1 ) Limitations of Use ( 1 ): Diclofenac potassium for oral solution is not indicated for the prophylactic therapy of migraine Safety and effectiveness of diclofenac potassium for oral solution not established for cluster headache, which is present in an older, predominantly male population

2 DOSAGE AND ADMINISTRATION Single 50 mg dose; mix single packet contents with 1 to 2 ounces (30 to 60 mL) of water prior to administration Use the lowest effective dose for shortest duration consistent with individual patient treatment goals ( 2.1 ) 2.1 Acute Treatment of Migraine Administer one packet (50 mg) of diclofenac potassium for oral solution for the acute treatment of migraine. Empty the contents of one packet into a cup containing 1 to 2 ounces (30 to 60 mL) of water, mix well and drink immediately. Do not use liquids other than water. Taking diclofenac potassium for oral solution with food may cause a reduction in effectiveness compared to taking diclofenac potassium for oral solution on an empty stomach [ see Clinical Pharmacology ( 12.3 ) ]. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. The safety and effectiveness of a second dose have not been established. 2.2 Non-Interchangeability with Other Formulations of Diclofenac Different formulations of oral diclofenac (e.g., diclofenac potassium for oral solution, diclofenac sodium enteric-coated tablets, diclofenac sodium extended-release tablets, or diclofenac potassium immediate-release tablets) may not be bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulation of diclofenac to diclofenac potassium for oral solution.

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 , 8.6 , 12.3 ) 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 potassium for oral solution 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 potassium for oral solution 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 potassium for oral solution is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue diclofenac potassium for oral solution at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ) Medication Overuse Headache : Detoxification may be necessary. ( 5.11 ) Fetal Toxicity : Limit use of NSAIDs, including diclofenac potassium for oral solution, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus ( 5.12 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.13 , 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 to 14 days following CABG surgery found an increased inciden…

4 CONTRAINDICATIONS Diclofenac potassium for oral solution 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 NSAIDs 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 potassium for oral solution 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 ( 5.13 ) ] 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 ) and Clinical Pharmacology ( 12.3 ) ]. Intervention: Concomitant use of diclofenac potassium for oral solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.13 ) ]. 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 potassium for oral solution and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac potassium for oral solution 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 )] . 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 potassium for oral solution 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 potassium for oral solution 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 potassium for oral soluti…

8.1 Pregnancy Risk Summary Use of NSAIDs, including diclofenac potassium for oral solution, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac potassium for oral solution use between about 20 and 30 weeks of gestation, and avoid diclofenac potassium for oral solution use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) . Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac potassium for oral solution, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal studies, oral administration of diclofenac sodium to pregnant mice, rats, and rabbits resulted in adverse effects on development (embryofetal mortality, reduced fetal growth) at doses similar to those used clinically. 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 potassium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac potassium for oral solution, can cause premature closure of the fetal ductus arteriosus (see Data) . Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac potassium for oral solution treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac potassium for oral solution and follow up according to clinical practice (see Data) . Labor or Delivery The effects of diclofenac potassium on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impair…

6 ADVERSE REACTIONS The following serious 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 ) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.10 )] Medication Overuse Headache [see Warnings and Precautions ( 5.11 )] Hematologic Toxicity [ see Warnings and Precautions ( 5.13 ) ] Most common adverse reactions (≥1% and >placebo) were nausea and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. The safety of a single dose of diclofenac potassium for oral solution was evaluated in 2 placebo-controlled trials with a total of 634 migraine patients treated with diclofenac potassium for oral solution for a single migraine headache. Following treatment with diclofenac potassium (either diclofenac potassium for oral solution or diclofenac potassium immediate-release tablets [as a control]), 5 subjects (0.8%) withdrew from the studies; following placebo exposure, 1 subject (0.2%) withdrew. The most common adverse reactions (i.e., that occurred in 1% or more of diclofenac potassium for oral solution -treated patients) and more frequent with diclofenac potassium for oral solution than with placebo were nausea and dizziness (see Table 1). Table 1: Adverse Reactions With Incidence >1% and Greater Than Placebo in Studies 1 and 2 Combined Adverse Reactions Diclofenac Potassium for Oral Solution N=634 Placebo N=646 Gastrointestinal Nausea 3% 2% Nervous System Dizziness 1% 0.5% The most common adverse events resulting in discontinuation of patients following diclofenac potassium for oral solution dosing in controlled clinical trials were urticaria (0.2%) and flushing (0.2%). No withdrawals were due to a serious reaction. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of diclofenac or other NSAIDs. 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. Adverse Reactions Reported With Diclofenac and Other NSAIDs In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1% to 10% of patients are: GI reactions (including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers [gastric/duodenal], and vomiting), abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus. Other less frequently occurring adverse reactions identified during post approval use of diclofenac and other NSAIDs include fixed drug eruption [see Warnings and Precautions (5.9)]. Additional adverse reactions reported in patients taking NSAIDs include occasionally: Body as a Whole: Fever, infection, sepsis Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope Digestive System: Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal b…