Mefenamic Acid

1 INDICATIONS AND USAGE Mefenamic acid capsules are a nonsteroidal anti-inflammatory drug indicated for: For management of mild to moderate pain in patient 14 years of age and older, when therapy will not exceed one week (7 days). ( 1.1 ) For treatment of primary dysmenorrhea. ( 1.2 ) 1.1 Mild to Moderate Pain Mefenamic acid capsules are indicated for management of mild to moderate pain in adults and pediatric patients 14 years of age and older, when therapy will not exceed one week (7 days). 1.2 Dysmenorrhea Mefenamic acid capsules are indicated for treatment of primary dysmenorrhea.

2 DOSAGE AND ADMINISTRATION Adults and adolescents 14 years of age and older: 500 mg given orally as an initial dose followed by 250 mg every 6 hours as needed ( 2.2 ) For the treatment of primary dysmenorrhea: 500 mg given orally as an initial dose followed by 250 mg every 6 hours ( 2.3 ) 2.1 Important Dosage and Administration Information Carefully consider the potential benefits and risks of mefenamic acid capsules and other treatment options before deciding to use mefenamic acid capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5.2 )] . After observing the response to initial therapy with mefenamic acid capsules, the dose and frequency should be adjusted to suit an individual patient's needs. 2.2 For the Management of Mild to Moderate Pain The recommended dosage in adults and pediatric patients 14 years of age and older is 500 mg given orally as an initial dose followed by 250 mg every 6 hours as needed. 2.3 Dysmenorrhea The recommended dose is 500 mg given orally as an initial dose followed by 250 mg every 6 hours starting with the onset of bleeding and associated symptoms.

3 DOSAGE FORMS AND STRENGTHS 250 mg size '1' capsules having ivory cap and ivory body imprinted with "LU" on cap and "R31" on body in black ink Capsule: 250 mg of mefenamic acid ( 3 )

4 CONTRAINDICATIONS Mefenamic acid capsules are contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to mefenamic acid or any components of the drug product [see Warnings and Precautions ( 5.7 )] . 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 , 5.9 )] . In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions ( 5.1 )] . Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to mefenamic acid or any components of the drug product ( 4 ) 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 ( 4 ) In the setting of coronary artery bypass graft (CABG) surgery ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions ( 5.1 )] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions ( 5.2 )] Hepatotoxicity [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Heart Failure and Edema [see Warnings and Precautions ( 5.5 )] Renal Toxicity and Hyperkalemia [see Warnings and Precautions ( 5.6 )] Anaphylactic Reactions [see Warnings and Precautions ( 5.7 )] Serious Skin Reactions [see Warnings and Precautions ( 5.9 , 5.10 )] Hematologic Toxicity [see Warnings and Precautions ( 5.12 )] 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 following adverse reactions associated with the use of mefenamic acid were identified in clinical studies or post- marketing reports. Because some of these reactions were 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 In patients taking mefenamic acid or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1 to10 % of patients are: Gastrointestinal - Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting Auditory System - Tinnitus Genitourinary System - Abnormal renal function Hepatic System - Elevated liver enzymes Dermatologic - Pruritus, rashes Cardiovascular - Anemia, edema Central Nervous System - Dizziness, headache Hematopoetic and lymphatic system - Increased bleeding time Additional adverse experiences reported less frequently and listed here by body system include: General - anaphylactoid reactions, appetite changes, death, fever, infection, sepsis Cardiovascular - congestive heart failure, hypertension, tachycardia, syncope arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Gastrointestinal system - dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice, eructation, liver failure, pancreatitis Hematopoetic and lymphatic system - ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia, agranulocytosis, hemolytic anemia, aplastic anemia, lymph-adenopathy, pancytopenia Metabolic - weight changes, hyperglycemia Central Nervous System - anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness; insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo, convulsions, coma, hallucinations, meningitis Respiratory system - asthma, dyspnea, respiratory depression, pneumonia Dermatologic - alopecia, photosensitivity, pruritus, sweat, angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, fixed drug eruption (FDE), urticaria Special senses - blurred vision, conjunctivitis, hearing impairment Genitourinary system - cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure In patients taking mefenamic acid or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1 to 10 % of patients are: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800 399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS 7.1 Drug Interactions See Table 1 for clinically significant drug interactions with mefenamic acid. Table1: Clinically Significant Drug Interactions with Mefenamic Acid Drugs That Interfere with Hemostasis Clinical Impact: Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid 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 mefenamic acid 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 ( 5.12 )] . Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2 )] . Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.12 )] . Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of mefenamic acid 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 mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [See Clinical Pharmacology ( 12.3 )] . Intervention: During …

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of mefenamic acid in women who have difficulty conceiving. ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including mefenamic acid, 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 mefenamic acid capsules use between about 20 and 30 weeks of gestation, and avoid mefenamic acid capsules 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 mefenamic acid capsules, 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 reproduction studies, administration of mefenamic acid to pregnant rats during organogenesis through lactation resulted in perinatal death and smaller litter sizes at exposures comparable to the Maximum Recommended Human Dose (MRHD) (see Data) . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as mefenamic acid, 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. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, 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. Clinical Considerations 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 mefenamic acid, 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 mefenamic acid capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue mefenamic acid capsules and follow up according to clinical practice (see Data ) . Labor or Delivery There are no studies on the effects of mefenamic acid during labor or delivery. In animal studies, NSAIDs, including mefenamic acid, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. 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, …

12.1 Mechanism of Action Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid 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 mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

11 DESCRIPTION Mefenamic acid capsules, USP contains active moiety mefenamic acid, USP which is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name of mefenamic acid, USP is N-2,3-xylylanthranilic acid. The molecular weight is 241.29 g/mol. Its molecular formula is C 15 H 15 N0 2 and the structural formula of mefenamic acid is: Mefenamic acid, USP is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230° to 231°C and water solubility of 0.004% at pH 7.1. Mefenamic acid capsule, USP is for oral administration. Each capsule contains 250 mg of mefenamic acid, USP and lactose monohydrate. The capsule shell contains D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, sodium lauryl sulfate, titanium dioxide, black iron oxide, propylene glycol & shellac. mefenamic-structure.jpg

OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see Warnings ; Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation , Hypertension , Renal Toxicity and Hyperkalemia ). 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 overdose (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).

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Mefenamic acid capsules USP, 250 mg are available as size '1' capsules having ivory cap and ivory body imprinted with "LU" on cap and "R31" on body in black ink, containing white to off white granular powder. They are supplied as follows: NDC 68180-185-06 Bottles of 30's Dispense in a tight container as defined in the USP. 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

16.1 How Supplied Mefenamic acid capsules USP, 250 mg are available as size '1' capsules having ivory cap and ivory body imprinted with "LU" on cap and "R31" on body in black ink, containing white to off white granular powder. They are supplied as follows: NDC 68180-185-06 Bottles of 30's Dispense in a tight container as defined in the USP.