Diclofenac Potassium

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 Ascend Laboratories, LLC at 1-877-ASCRX01 (877-272-7901) or FDA at 1-800-FDA-1088 or 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. 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. 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 bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: Weight changes Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: Asthma, dyspnea Skin and Appendages: Alopecia, photosensitivity, sweating increased Special Senses: Blurred Vision Urogenital System: Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions in patients taking NSAIDs, which occur rarely, are: Body as a Whole : Anaphylactic reactions, appetite changes, death Cardiovascular System : Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System : Colitis, eructation, liver failure, pancreatitis Hemic and Lymphatic System : Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional : Hyperglycemia Nervous System : Convulsions, coma, hallucinations, meningitis Respiratory System: Respiratory depression, pneumonia Skin and Appendages : Angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses : Conjunctivitis, hearing impairment

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)

11 DESCRIPTION Diclofenac potassium for oral solution, USP is a nonsteroidal anti-inflammatory drug, available as a buffered soluble powder, designed to be mixed with water prior to oral administration. Diclofenac potassium for oral solution, USP is a white to off-white, peppermint flavored powder for oral solution packaged in individual unit dose packets. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid monopotassium salt. The molecular weight is 334.25. Its molecular formula is C 14 H 10 Cl 2 NKO 2 , and it has the following structure. The inactive ingredients in diclofenac potassium for oral solution, USP include: Glyceryl behenate, mannitol, peppermint flavor, potassium bicarbonate, and sucralose. diclo-stru

2 DOSAGE & ADMINISTRATION Single 50 mg dose; mix single packet contents with 1 to 2 ounces or 2 to 4 tablespoons (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 or 2 to 4 tablespoons (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.

1 INDICATIONS & 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

10 OVERDOSAGE Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and, coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). Anaphylactic reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

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 solution 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 potassium for oral solution and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac potassium for oral solution and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of diclofenac potassium for oral solution 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 and Precautions (5.2) ]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac potassium for oral solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NSAIDs 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. Inhibitors of Cytochrome P450 2C9 Clinical Impact: Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co- administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [ see Clinical Pharmacology (12.3) ] Intervention: During concomitant use of diclofenac potassium for oral solution and drugs that inhibit CYP2C9, an increase in the duration between diclofenac potassium for oral solution doses for subsequent migraine attacks may be necessary. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking diclofenac potassium for oral solution with drugs that interfere with hemostasis. Concomitant use of diclofenac potassium for oral solution and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors and ARBs : Concomitant use with diclofenac potassium for oral solution 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 loop and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) Digoxin : Concomitant use with diclofenac potassium for oral solution can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac potassium for oral solution has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac potassium for oral solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to intravenous administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. In fasting volunteers, measurable plasma levels were observed within 5 minutes of dosing with diclofenac potassium for oral solution. Peak plasma levels were achieved at approximately 0.25 hour in fasting normal volunteers, with a range of 0.17 to 0.67 hours. High fat food had no significant effect on the extent of diclofenac absorption, but there was a reduction in peak plasma levels of approximately 70% after a high fat meal. Decreased C max may be associated to decreased effectiveness. Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4’- hydroxy-, 5-hydroxy-, 3’-hydroxy-, 4’,5-dihydroxy- and 3’-hydroxy-4’-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxydiclofenac, has very weak pharmacologic activity. The formation of 4’- hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. In patients with renal impairment, peak concentrations of metabolites 4’­ hydroxy-and 5- hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Specific Populations Race: There are no pharmacokinetic differences due to race. Hepatic Impairment: The liver metabolizes almost 100% of diclofenac; there is insufficient information available to support dosing recommendations for diclofenac potassium for oral solution in patients with hepatic insufficiency [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] . Renal Impairment: In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6) and Use in Specific Populations ( 8.7) ] . Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ].

12.1 Mechanism of Action Diclofenac potassium for oral solution has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac potassium for oral solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to intravenous administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. In fasting volunteers, measurable plasma levels were observed within 5 minutes of dosing with diclofenac potassium for oral solution. Peak plasma levels were achieved at approximately 0.25 hour in fasting normal volunteers, with a range of 0.17 to 0.67 hours. High fat food had no significant effect on the extent of diclofenac absorption, but there was a reduction in peak plasma levels of approximately 70% after a high fat meal. Decreased C max may be associated to decreased effectiveness. Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4’- hydroxy-, 5-hydroxy-, 3’-hydroxy-, 4’,5-dihydroxy- and 3’-hydroxy-4’-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxydiclofenac, has very weak pharmacologic activity. The formation of 4’- hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. In patients with renal impairment, peak concentrations of metabolites 4’­ hydroxy-and 5- hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Specific Populations Race: There are no pharmacokinetic differences due to race. Hepatic Impairment: The liver metabolizes almost 100% of diclofenac; there is insufficient information available to support dosing recommendations for diclofenac potassium for oral solution in patients with hepatic insufficiency [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] . Renal Impairment: In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6) and Use in Specific Populations ( 8.7) ] . Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ].

20221021

4

3 DOSAGE FORMS & STRENGTHS Diclofenac potassium for oral solution, USP is available in individual packets each designed to deliver a 50 mg dose when mixed in water. Packets: Each containing buffered diclofenac potassium 50 mg in a soluble powder (3)

Diclofenac Potassium Diclofenac Potassium DICLOFENAC POTASSIUM DICLOFENAC GLYCERYL DIBEHENATE MANNITOL POTASSIUM BICARBONATE SUCRALOSE PEPPERMINT White Powder

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Carcinogenesis Long term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m 2 ] basis) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid- dose treated (0.5 mg/kg/day or 3 mg/m 2 /day) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (less than the RHD on a mg/m 2 basis) in males and 1 m/kg/day (less than the RHD on a mg/m 2 basis) in females did not reveal any oncogenic potential. Mutagenesis Diclofenac sodium was not genotoxic in in vitro (reverse mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including dominant lethal and male germinal epithelial chromosomal aberration in Chinese hamster) assays. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (less than the RHD on a mg/m 2 basis) did not affect fertility.

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Carcinogenesis Long term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m 2 ] basis) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid- dose treated (0.5 mg/kg/day or 3 mg/m 2 /day) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (less than the RHD on a mg/m 2 basis) in males and 1 m/kg/day (less than the RHD on a mg/m 2 basis) in females did not reveal any oncogenic potential. Mutagenesis Diclofenac sodium was not genotoxic in in vitro (reverse mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including dominant lethal and male germinal epithelial chromosomal aberration in Chinese hamster) assays. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (less than the RHD on a mg/m 2 basis) did not affect fertility.

ANDA216635

Diclofenac Potassium

Diclofenac Potassium

67877-772

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 67877-772-49 Diclofenac Potassium for Oral Solution, 50 mg Rx Only NDC 67877-772-58 Diclofenac Potassium for Oral Solution, 50 mg Rx Only Diclofenac Potassium for Oral Solution USP Sachet Label Diclofenac Potassium for Oral Solution USP Carton Label

Warnings and Precautions ( 5.10 , 5.12 ) 4/2021

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac potassium for oral solution and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Diclofenac potassium for oral solution, like other NSAIDS, can cause GI discomfort and more serious GI adverse events such as ulcers and bleeding, which may result in hospitalization and even death. Inform patients of the increased risk, and advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. Inform patients of the importance of follow-up in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis [ see Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac potassium for oral solution and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 )]. Serious Skin Reactions, Including DRESS Advise patients to stop taking diclofenac potassium for oral solution immediately if they develop any type of rash, blisters, fever or other signs of hypersensitivity such as itching and to contact their healthcare provider as soon as possible. Diclofenac potassium for oral solution, like other NSAIDs, can cause serious skin reactions such as exfoliative dermatitis, Steven-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and DRESS, which may result in hospitalizations and even death [ see Warnings and Precautions ( 5.9 , 5.10 ) ]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [ see Warnings and Precautions ( 5.11 ) ]. Fetal Toxicity Inform pregnant women to avoid use of diclofenac potassium for oral solution and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac potassium for oral solution is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions ( 5.12 and Use in Specific Populations ( 8.1 ) ]. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in specific Populations ( 8.2 )] . Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac potassium for oral solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [ see Use in Specific Populations ( 8.3 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of diclofenac potassium for oral solution with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with diclofenac potassium for oral solution until they talk to their healthcare provider [see Drug Interactions ( 7 ) ]. Manufactured by: Alkem Laboratories Ltd., INDIA. Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: July, 2022

MEDICATION GUIDE Diclofenac Potassium (dye-KLOE-fen-ak poe-TAS-ee-um) for oral solution What is the most important information I should know about diclofenac potassium for oral solution? Diclofenac potassium for oral solution contains diclofenac (a non-steroidal anti-inflammatory drug or NSAID). NSAIDs, including diclofenac potassium for oral solution, 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 NSAIDs, including diclofenac potassium for oral solution right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs, including diclofenac potassium for oral solution, 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 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 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 o older age longer use of NSAIDs o poor health smoking o advanced liver disease drinking alcohol o bleeding problems Diclofenac potassium for oral solution should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What is diclofenac potassium for oral solution? Diclofenac potassium for oral solution is a prescription medicine used to treat migraine attacks in adults. It does not prevent or lessen the number of migraines you have, and it is not for other types of headaches. Diclofenac potassium for oral solution contains diclofenac potassium (a non-steroidal anti-inflammatory drug or NSAID). How should I take diclofenac potassium for oral solution? Take diclofenac potassium for oral solution exactly as your healthcare provider tells you to take it. Take 1 dose of diclofenac potassium for oral solution to treat your migraine headache: take a single dose packet open packet only when you are ready to use it empty contents of packet into 1 to 2 ounces or 2 to 4 tablespoons (30 to 60 mL) of water mix well and drink the water and powder mixture throw away empty packet in a safe place and out of the reach of children. 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 do not take more diclofenac potassium for oral solution than directed by your healthcare provider. In case of overdose, get medical help or contact a Poison Control Center right away Who should not take diclofenac potassium for oral solution? Do not take diclofenac potassium for oral solution: if you have had an asthma attack, hives, or other allergic reaction with aspirin, diclofenac, or any other NSAIDs. right before or after heart bypass surgery. Before taking diclofenac potassium for oral solution, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have a history of stomach ulcer or bleeding in your stomach or intestines have any allergies to any medicines have chest pain, shortness of breath, irregular heartbeats have high blood pressure have asthma are pregnant, think you might be pregnant, or are trying to become pregnant. Taking NSAIDs, including diclofenac potassium for oral solution, 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. have a headache that is different from your usual migraine Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs, like diclofenac potassium for oral solution, 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. Especially tell your doctor if you take: aspirin any anticoagulant medicines (warfarin, Coumadin, Jantoven) Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. What are the possible side effects of diclofenac potassium for oral solution? Diclofenac potassium for oral solution can cause serious side effects, including: See “What is the most important information I should know about diclofenac potassium for oral solution?” new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure bleeding and ulcers in the stomach and intestine low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions asthma attacks in people who have asthma medication overuse headaches. Some people who use too much diclofenac potassium for oral solution may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with diclofenac potassium for oral solution. 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 slurred speech chest pain swelling of the face or throat weakness in one part or side of your body Stop taking diclofenac potassium for oral solution and call your healthcare provider right away if you get any of the following symptoms nausea that seems out of proportion to your migraine vomit blood sudden or severe pain in your belly there is blood in your bowel movement or it is black and sticky like tar more tired or weaker than usual unusual weight gain diarrhea more tired or weaker than usual itching skin rash or blisters with fever your skin or eyes look yellow swelling of the arms, legs, hands and feet indigestion or stomach pain flu-like symptoms If you take too much of your NSAID, 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. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured by: Alkem Laboratories Ltd., INDIA. Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 7/2022 PT-9123

14 CLINICAL STUDIES The efficacy of diclofenac potassium for oral solution in the acute treatment of migraine headache was demonstrated in two randomized, double-blind, placebo-controlled trials. Patients enrolled in these two trials were predominantly female (85%) and white (86%), with a mean age of 40 years (range: 18 to 65). Patients were instructed to treat a migraine of moderate to severe pain with 1 dose of study medication. Patients evaluated their headache pain 2 hours later. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. In addition, the proportion of patients who were “sustained pain free”, defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours post- dose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours post-dose, was also evaluated. In these studies, the percentage of patients achieving pain freedom 2 hours after treatment and sustained pain freedom from 2 to 24 hours post-dose was significantly greater in patients who received diclofenac potassium for oral solution compared with those who received placebo (see Table 3). The percentage of patients achieving pain relief 2 hours after treatment (defined as a reduction in headache severity from moderate or severe pain to mild or no pain) was also significantly greater in patients who received diclofenac potassium for oral solution compared with those who received placebo (see Table 3). Table 3: Percentage of Patients with 2-Hour Pain Freedom, Sustained Pain Freedom 2-24 Hours, and 2-Hour Pain Relief Following Treatment Study 1 Diclofenac Potassium for Oral Solution (n=265) Placebo (n=257) 2-Hour Pain Free 24% 13% 2-24h Sustained Pain Free 22% 10% 2-Hour Pain Relief 48% 27% Study 2 Diclofenac Potassium for Oral Solution (n=343) Placebo (n=347) 2-Hour Pain Free 25% 10% 2-24h Sustained Pain Free 19% 7% 2-Hour Pain Relief 65% 41% The estimated probability of achieving migraine headache pain freedom within 2 hours following treatment with diclofenac potassium for oral solution is shown in Figure 1. Figure 1: Percentage of Patients with Initial Headache Pain Freedom within 2 Hours There was a decreased incidence of nausea, photophobia and phonophobia following administration of diclofenac potassium for oral solution, compared to placebo. The efficacy and safety of diclofenac potassium for oral solution was unaffected by age or gender of the patient. diclo-clinical

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2, 5.3 , 5.6 , 5.15 ) ]. Clinical studies of diclofenac potassium for oral solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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 2-4% and 15-20%, 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 for oral solution 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 Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Oral administration of diclofenac sodium to pregnant mice and rabbits during organogenesis resulted in embryofetal toxicity at oral doses of up to 20 and 10 mg/kg/day (up to approximately 2 and 4 times, respectively, the recommended human dose [RHD] of 50 mg/day, based on body surface area [mg/m 2 ]). In rats, oral administration of diclofenac at doses of up to 10 mg/kg/day (up to approximately 2 times the RHD on a mg/m 2 basis) during organogenesis resulted in increased embryofetal mortality and reduced fetal body weights.

8 USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of diclofenac potassium for oral solution in women who have difficulties conceiving ( 8.3 ) 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 2-4% and 15-20%, 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 for oral solution 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 Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Oral administration of diclofenac sodium to pregnant mice and rabbits during organogenesis resulted in embryofetal toxicity at oral doses of up to 20 and 10 mg/kg/day (up to approximately 2 and 4 times, respectively, the recommended human dose [RHD] of 50 mg/day, based on body surface area [mg/m 2 ]). In rats, oral administration of diclofenac at doses of up to 10 mg/kg/day (up to approximately 2 times the RHD on a mg/m 2 basis) during organogenesis resulted in increased embryofetal mortality and reduced fetal body weights. 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac potassium for oral solution and any potential adverse effects on the breastfed infant from diclofenac potassium for oral solution or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac potassium for oral solution, 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 potassium for oral solution, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2, 5.3 , 5.6 , 5.15 ) ]. Clinical studies of diclofenac potassium for oral solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Because hepatic metabolism accounts for almost 100% of diclofenac elimination, patients with hepatic impairment should be considered for treatment with diclofenac potassium for oral solution only if the benefits outweigh the risks. There is insufficient information available to support dosing recommendations for diclofenac potassium for oral solution in patients with hepatic insufficiency [ see Clinical Pharmacology ( 12.3 ) ]. 8.7 Renal Impairment No information is available from controlled clinical studies regarding the use of diclofenac potassium for oral solution in patients with advanced renal disease. Therefore, treatment with diclofenac potassium for oral solution is not recommended in patients with advanced renal disease. If diclofenac potassium for oral solution therapy must be initiated, close monitoring of the patient’s renal function is advisable.

16 HOW SUPPLIED/STORAGE AND HANDLING Diclofenac potassium for oral solution, USP 50 mg, is a white to off-white, peppermint flavored powder for oral solution, supplied as individual dose packets. Each individual packet is designed to deliver a dose of 50 mg diclofenac potassium when mixed in water. NDC 67877-772- 49 Individual diclofenac potassium for oral solution, USP packets NDC 67877-772- 58 Boxes of nine (9) diclofenac potassium for oral solution, USP packets Storage Store at 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL 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 [ see Warnings and Precautions ( 5.1 ) ]. Diclofenac potassium for oral solution is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications (4) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning Non-steroidal 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 ( 5.1 ) Diclofenac potassium for oral solution is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 )