Mefenamic Acid Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes .................................................................................................... 2

Table of Contents .................................................................................................................... 2

Part 1: Healthcare Professional Information ............................................................................ 5

1. 1.

   Indications ........................................................................................................................ 5

   1.1. Pediatrics ................................................................................................................... 5

   1.2. Geriatrics ................................................................................................................... 5

2. 2. Contraindications ............................................................................................................. 5
3. 3. Serious Warnings and Precautions Box ............................................................................. 6
4. 4.

   Dosage and Administration ............................................................................................... 7

   4.1. Dosing Considerations ............................................................................................... 7

   4.2. Recommended Dose and Dosage Adjustment .......................................................... 8

   4.4. Administration ........................................................................................................... 8

   4.5. Missed Dose .............................................................................................................. 8

5. 5. Overdose .......................................................................................................................... 8
6. 6. Dosage Forms, Strengths, Composition, and Packaging .................................................... 9
7. 7.

   Warnings and Precautions .............................................................................................. 10

   Carcinogenesis and Genotoxicity ......................................................................................... 10

   Cardiovascular ..................................................................................................................... 10

   Endocrine and Metabolism .................................................................................................. 11

   Gastrointestinal ................................................................................................................... 11

   Genitourinary ...................................................................................................................... 12

   Hematologic ........................................................................................................................ 12

   Hepatic/Biliary/Pancreatic ................................................................................................... 13

   Immune ............................................................................................................................... 13

   Monitoring and Laboratory Tests ........................................................................................ 14

   Neurologic ........................................................................................................................... 15

   Ophthalmologic ................................................................................................................... 15

   Perioperative Considerations .............................................................................................. 15

   Psychiatric ............................................................................................................................ 15

   Renal ................................................................................................................................ 15

   Reproductive Health ............................................................................................................ 16

   Respiratory .......................................................................................................................... 17

   Skin ................................................................................................................................ 17

   7.1. Special Populations ................................................................................................. 17

   7.1.1. Pregnancy ................................................................................................................ 17

   7.1.2. Breastfeeding .......................................................................................................... 19

   7.1.3. Pediatrics ................................................................................................................. 19

   7.1.4. Geriatrics ................................................................................................................. 19

8. 8.

   Adverse Reactions .......................................................................................................... 19

   8.1. Adverse Reaction Overview ..................................................................................... 19

   8.2. Clinical Trial Adverse Reactions ............................................................................... 20

   8.3. Less Common Clinical Trial Adverse Reactions ........................................................ 20

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................ 20

   8.5. Post-Market Adverse Reactions .............................................................................. 20

9. 9.

   Drug Interactions ............................................................................................................ 22

   9.2. Drug Interactions Overview ..................................................................................... 22

   9.3. Drug-Behaviour Interactions ................................................................................... 22

   9.4. Drug-Drug Interactions ............................................................................................ 22

   9.5. Drug-Food Interactions............................................................................................ 27

   9.6. Drug-Herb Interactions ............................................................................................ 27

   9.7. Drug-Laboratory Test Interactions .......................................................................... 27

10. 10.

    Clinical Pharmacology ..................................................................................................... 27

    10.1. Mechanism of Action ............................................................................................... 27

    10.2. Pharmacodynamics ................................................................................................. 27

    10.3. Pharmacokinetics .................................................................................................... 28

11. 11. Storage, Stability, and Disposal ....................................................................................... 29

Part 2: Scientific Information ................................................................................................. 30

1. 13. Pharmaceutical Information ........................................................................................... 30
2. 14. Clinical Trials ................................................................................................................... 30
3. 15. Microbiology .................................................................................................................. 30
4. 16. Non-Clinical Toxicology ................................................................................................... 30
5. 17. Supporting Product Monographs .................................................................................... 32

Patient Medication Information ............................................................................................ 33

Part 1: Healthcare Professional Information

1. Indications

Adult (>18 years old)

MEFENAMIC ACID (mefenamic acid) is indicated for the relief of pain of moderate severity in conditions such as:

• muscular aches and pains
• primary dysmenorrhea
• headache
• dental pain

For patients with an increased risk of developing CV and/or GI adverse events, other management strategies that do NOT include the use of NSAIDs should be considered first (see 2 Contraindications and 7 Warnings and Precautions, Cardiovascular, and 7 Warnings and Precautions, Gastrointestinal).

Use of MEFENAMIC ACID should be limited to the lowest effective dose for the shortest possible duration of treatment in order to minimize the potential risk for cardiovascular or gastrointestinal adverse events (see 2 Contraindications and 7 Warnings and Precautions, Cardiovascular, and 7 Warnings and Precautions, Gastrointestinal).

MEFENAMIC ACID, as a NSAID, does NOT treat clinical disease or prevent its progression.

MEFENAMIC ACID, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient continues to take it.

1.1. Pediatrics

Pediatrics (< 18 years of age): MEFENAMIC ACID is contraindicated in the pediatric population (see 2 Contraindications and 7.1.3 Pediatrics).

1.2. Geriatrics

Geriatrics (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness (see 7.1.4 Geriatrics).

2. Contraindications

MEFENAMIC ACID is contraindicated in:

• Children and adolescents less than 18 years of age.
• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• The peri-operative setting of coronary artery bypass graft surgery (CABG). Although mefenamic acid has NOT been studied in this patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an increased incidence of cardiovascular/thromboembolic events, deep surgical infections and sternal wound complications.
• During the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition (see 7.1.1 Pregnancy).
• Women who are breastfeeding, because of the potential for serious adverse reactions in breastfeeding infants (see 7.1.2 Breastfeeding).
• Severe uncontrolled heart failure (see 7 Warnings and Precautions, Cardiovascular).
• History of asthma, bronchospasm, urticaria, or allergic-type reactions after taking ASA or other NSAIDs (i.e. complete or partial syndrome of ASA-intolerance - rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions have occurred in such individuals. Individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. The potential for cross-reactivity between different NSAIDs must be kept in mind (see 7 Warnings and Precautions, Immune, Anaphylactoid Reactions).
• Active gastric / duodenal / peptic ulcer, active GI bleeding (see 7 Warnings and Precautions, Gastrointestinal).
• Cerebrovascular bleeding or other bleeding disorders.
• Inflammatory bowel disease.
• Severe liver impairment or active liver disease (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).
• Severe renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored) (see 7 Warnings and Precautions, Renal).
• Known hyperkalemia (see 7 Warnings and Precautions, Renal, Fluid and Electrolyte Balance).
• Serious Warnings and Precautions Box

Serious Warnings and Precautions

4. Dosage and Administration

4.1. Dosing Considerations

• Use of MEFENAMIC ACID should be limited to the lowest effective dose for the shortest possible duration of treatment (see 1 Indications).

• MEFENAMIC ACID is NOT recommended for use with other NSAIDs, including COX-2 inhibitors, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for

  • additive adverse reactions (see 9.4 Drug-Drug Interactions, Acetylsalicylic acid (ASA) or other NSAIDS).
• For geriatric patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision (see 7 Warnings and Precautions, Cardiovascular, 7 Warnings and Precautions, Gastrointestinal and 7 Warnings and Precautions, Renal).

4.2. Recommended Dose and Dosage Adjustment

Treatment of Acute Pain in Adults:

MEFENAMIC ACID 250 mg capsules: 500 mg (2 capsules) as an initial dose, followed by 250 mg (1 capsule) every 6 hours as needed. Treatment usually should not exceed one week.

Treatment of Primary Dysmenorrhea:

MEFENAMIC ACID 250 mg capsules: 500 mg (2 capsules) as an initial dose, followed by 250 mg (1 capsule) every 6 hours.

Treatment may start with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days.

Pediatrics (< 18 years of age): MEFENAMIC ACID is contraindicated for use in pediatric patients (see 2 Contraindications and 7.1.3 Pediatrics).

4.4. Administration

Administration is by the oral route, preferably with food.

4.5. Missed Dose

If a dose is missed, patient should take it as soon as they remember. If it is near the time of the next dose, the missed dose should be skipped and the usual dosing schedule should be resumed. The dose should not be doubled to catch up.

5. Overdose

Symptoms of overdosage are related to the amount of drug ingested and range from gastrointestinal discomfort and diarrhoea to seizures, acute renal failure, coma and death. Plasma levels of up to 210 mcg/mL (therapeutic range 1 to 10 mcg/mL) have been reported resulting in repeated generalised convulsions, but are not generally useful for evaluation and management of overdosage.

There is no specific antidote for mefenamic acid overdose. Treatment is symptomatic and supportive, including fluid replacement and IV access especially to patients who are dehydrated or unable to ingest adequate fluids. Avoiding intravascular fluid depletion will help prevent development of renal failure.

In cases of severe toxicity, activated charcoal may reduce absorption of the drug if given within one to two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube ensuring that the airway is protected. In clinically severe overdoses, full blood count, electrolytes, glucose, renal function, liver function tests, arterial blood gases and coagulation studies should be monitored for abnormalities. Because mefenamic acid and its metabolites are firmly bound to plasma proteins, hemodialysis, hemoperfusion and peritoneal dialysis may be of little value.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Each yellow opaque body, aqua blue opaque cap, hard gelatin capsule, imprinted “250” in black ink with white to off-white powder fill, contains mefenamic acid 250 mg.

MEFENAMIC ACID is available in bottles of 100 and 500 capsules.

7. Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

Carcinogenesis and Genotoxicity

No data is available.

Cardiovascular

MEFENAMIC ACID is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing MEFENAMIC ACID to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (NOT an exhaustive list)

• Hypertension
• Dyslipidemia / Hyperlipidemia
• Diabetes Mellitus
• Congestive Heart Failure (NYHA I)
• Coronary Artery Disease (Atherosclerosis)
• Peripheral Arterial Disease
• Smoking
• Creatinine Clearance < 60 mL/min or 1 mL/sec

Use of NSAID, such as MEFENAMIC ACID, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing MEFENAMIC ACID should hypertension either develop or worsen with its use.

Use of NSAID, such as MEFENAMIC ACID, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism (see 7 Warnings and Precautions, Renal, Fluid and Electrolyte Balance).

For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.

Endocrine and Metabolism

Corticosteroids: MEFENAMIC ACID is NOT a substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids (see 9.4 Drug-Drug Interactions, Glucocorticoids).

Gastrointestinal

Serious gastrointestinal (GI) toxicity (sometimes fatal), such as peptic / duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAID, such as MEFENAMIC ACID. Minor upper GI problems, such as dyspepsia, commonly occur at any time. Healthcare professionals should remain alert for ulceration and bleeding in patients treated with MEFENAMIC ACID, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered (see 7.1.4 Geriatrics).

Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using MEFENAMIC ACID and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g. age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

If diarrhea occurs, the dosage should be reduced or temporarily suspended (see 8 Adverse Reactions and 4 Dosage and Administration). Certain patients who develop diarrhea may be unable to tolerate the drug because of recurrence of the symptoms on subsequent exposure.

Caution should be taken if prescribing MEFENAMIC ACID to patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

• Anti-coagulants (e.g. warfarin)
• Anti-platelet agents (e.g. ASA, clopidogrel)
• Oral corticosteroids (e.g. prednisone)
• Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline)

Genitourinary

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with a NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with MEFENAMIC ACID should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.

Hematologic

NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anti-coagulants or suffering from haemophilia or platelet disorders should be carefully observed when MEFENAMIC ACID is administered.

Anti-coagulants: Numerous studies have shown that the concomitant use of NSAIDs and anti-coagulants increases the risk of bleeding. Concurrent therapy of MEFENAMIC ACID with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur (see 9.4 Drug-Drug Interactions, Anticoagulants).

Mefenamic acid 500 mg and ASA 650 mg 4 times a day both caused significant further lowering of the prothrombin concentration (mefenamic acid 3.48% and ASA 2.75%) in patients in whom the concentration had been initially lowered by anticoagulant therapy. Caution, therefore, should be exercised in administering MEFENAMIC ACID to patients on anticoagulant therapy and should not be given when prothrombin concentration is in the range of 10 to 20% normal. Careful monitoring of blood coagulation factors is recommended.

Anti-platelet Effects: NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible.

Mefenamic acid and other NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA (see 9.4 Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or other NSAIDs). Concomitant administration of MEFENAMIC ACID with low dose ASA increases the risk of GI ulceration and associated complications.

Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

Anemia is sometimes seen in patients receiving NSAIDs, including MEFENAMIC ACID. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including MEFENAMIC ACID, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

Hepatic/Biliary/Pancreatic

As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.

MEFENAMIC ACID should be used with caution in patients with hepatic impairment.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with MEFENAMIC ACID. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with NSAIDs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.), MEFENAMIC ACID should be discontinued.

If there is a need to prescribe MEFENAMIC ACID in the presence of impaired liver function, it must be done under strict observation.

Immune

Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to mefenamic acid. In post-marketing experience, rare cases of anaphylactic / anaphylactoid reactions and angioedema have been reported in patients receiving mefenamic acid. MEFENAMIC ACID should NOT be given to patients with the ASA-triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see 2 Contraindications).

ASA-Intolerance: MEFENAMIC ACID should NOT be given to patients with complete or partial syndrome of ASA- intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see 2 Contraindications).

Cross-sensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.

Infection: MEFENAMIC ACID, in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.

Aseptic Meningitis: Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the healthcare professional must be vigilant to the development of this complication.

Monitoring and Laboratory Tests

A false-positive reaction for urinary bile, using the diazo tablet test, may result after MEFENAMIC ACID administration. If biliuria is suspected other diagnostic procedures, such as the Harrison spot test, should be performed.

Hematology: MEFENAMIC ACID may prolong prothrombin time. Therefore, when the drug is administered to patients receiving oral anticoagulant therapy, frequent monitoring of prothrombin time is necessary. The concurrent use of NSAIDs and warfarin has been associated with severe, sometimes fatal haemorrhage. Mefenamic acid like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation and may prolong prothrombin time in patients on warfarin therapy. Mefenamic acid has been show to displace warfarin from protein binding sites and may enhance the response to oral anticoagulants. Concurrent administration of MEFENAMIC ACID with oral anticoagulant drugs requires frequent prothrombin time monitoring.

It is recommended that estimations of hemoglobin and blood counts be carried out at regular intervals.

Pregnancy: If MEFENAMIC ACID is administered in the middle (approximately 20 weeks) to the end of the second trimester, it is recommended that pregnant women on MEFENAMIC ACID be closely monitored for amniotic fluid volume since MEFENAMIC ACID may result in reduction of amniotic fluid volume and even oligohydramnios (see 7.1.1 Pregnancy). MEFENAMIC ACID is contraindicated for use in the third trimester of pregnancy.

Neurologic

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, with the use of NSAIDs, such as MEFENAMIC ACID. If patients experience such adverse reaction(s), they should exercise caution in carrying out activities that require alertness.

Ophthalmologic

Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms develop MEFENAMIC ACID should be discontinued and an ophthalmologic examination performed.

Ophthalmologic examination should be carried out at periodic intervals in any patient receiving MEFENAMIC ACID for an extended period of time.

Perioperative Considerations

See 2 Contraindications, Coronary Artery Bypass Graft Surgery.

Psychiatric

Some patients may experience insomnia or depression with the use of NSAIDs, such as MEFENAMIC ACID (see 7 Warnings and Precautions, Neurologic).

Renal

Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis, hematuria, low grade proteinuria and occasionally nephrotic syndrome.

In chronic animal toxicity studies, mefenamic acid at 7 to 28 times the recommended human dose, caused minor microscopic renal papillary necrosis in rats, edema and blunting of the renal papilla in dogs, and renal papillary edema in monkeys (see 16 Non-Clinical Toxicology). In humans, there have been reports of acute interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome.

Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to reduction in renal blood flow or blood volume. Under these circumstances, renal prostaglandins help maintain renal perfusion and glomerular filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR < 60 mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, and those who are elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate a NSAID under stable conditions may decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment state.

In normal human volunteers, BUN levels were slightly elevated following prolonged administration of mefenamic acid at greater than therapeutic doses. Since MEFENAMIC ACID is eliminated primarily by the kidneys, it should not be administered to patients with significantly impaired renal function.

Caution should be used when initiating treatment with NSAIDs, such as MEFENAMIC ACID, in patients with considerable dehydration. Such patients should be rehydrated prior to initiation of therapy. Caution is also recommended in patients with pre-existing kidney disease.

Advanced Renal Disease: See 2 Contraindications.

Fluid and Electrolyte Balance: Use of NSAIDs, such as MEFENAMIC ACID, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing MEFENAMIC ACID in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see 7 Warnings and Precautions, Cardiovascular).

Use of NSAIDs, such as MEFENAMIC ACID, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

Electrolytes should be monitored periodically (see 2 Contraindications).

Reproductive Health

• Fertility

The use of MEFENAMIC ACID, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of MEFENAMIC ACID should be considered.

Respiratory

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

MEFENAMIC ACID should be used with caution in known asthmatics.

Skin

Serious skin reactions: Use of some NSAIDs, such as MEFENAMIC ACID, have been associated with rare post-market cases of serious, fatal or otherwise life-threatening skin reactions, including:

• drug reaction with eosinophilia and systemic symptoms (DRESS),
• Stevens-Johnson syndrome,
• toxic epidermal necrolysis,
• exfoliative dermatitis,
• erythema multiforme,
• fixed drug eruption (FDE) and
• generalized bullous fixed drug eruption (GBFDE).

Patients appear to be at higher risk for these events early in the course of therapy, with the onset of cases usually occurring within the first month of treatment. These reactions may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that they should discontinue their NSAID at the first appearance of a skin rash, mucosal lesions or any other sign of hypersensitivity, and contact their physician immediately for assessment and advice, including which therapies to discontinue.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection, and eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

7.1. Special Populations

7.1.1. Pregnancy

MEFENAMIC ACID is contraindicated for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition (see 2 Contraindications and 16 Non-Clinical Toxicology, Reproductive and Developmental Toxicology). Caution is recommended in prescribing MEFENAMIC ACID during the first and second trimesters of pregnancy, particularly from the middle to end of the second trimester of pregnancy (onset at approximately 20 weeks) due to possible fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment or failure (see 16 Non-Clinical Toxicology, Reproductive and Developmental Toxicology).

Published studies and post-marketing reports describe maternal NSAID use at approximately 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment or failure. NSAIDs were shown to cause significant reduction in fetal urine production prior to reduction of amniotic fluid volume. There have also been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction and renal impairment without oligohydramnios, some of which were irreversible, even after treatment discontinuation.

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. Complications of prolonged oligohydramnios may for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If after careful consideration of the benefit-risk, NSAID treatment is considered necessary to be administered anywhere from the middle (onset at approximately 20 weeks) to the end of the second trimester of pregnancy, the use should be limited to the lowest effective dose and shortest duration possible. It is also recommended that ultrasound monitoring of amniotic fluid be considered if MEFENAMIC ACID treatment extends beyond 48 hours and that NSAIDs treatment be discontinued if oligohydramnios occurs, followed by appropriate medical follow up.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryofoetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

It is not known if mefenamic acid or its metabolites crosses the placenta. Since there are no adequate and well controlled studies in pregnant women, mefenamic acid should be used only if the potential benefits to the mother justify the possible risks to the foetus.

Women on MEFENAMIC ACID therapy should consult their physician if they decide to become pregnant.

7.1.2. Breastfeeding

Trace amounts of mefenamic acid may be present in breast milk and transmitted to the breastfeeding infant; thus MEFENAMIC ACID should not be taken by the breastfeeding mother because of the effects of this class of drugs on the infant cardiovascular system (see 2 Contraindications).

7.1.3. Pediatrics

Pediatrics (<18 years of age): MEFENAMIC ACID is contraindicated for use in pediatric patients (see 2 Contraindications).

7.1.4. Geriatrics

Geriatrics (>65 years of age): Patients older than 65 years (referred to in this document as older or elderly) and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding. For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. For high risk patients, alternate therapies that do not involve MEFENAMIC ACID should be considered (see 4.1 Dosage and Administration, Dosing Considerations, 7 Warnings and Precautions, Cardiovascular, 7 Warnings and Precautions, Gastrointestinal and 7 Warnings and Precautions, Renal).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly. Gastrointestinal adverse events can develop at any time in the course of the therapy. (See 7 Warnings and Precautions, Gastrointestinal).

In patients taking mefenamic acid or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are:

Gastrointestinal experiences including - 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

8.2. Clinical Trial Adverse Reactions

No data are available at the time of authorization.

8.3. Less Common Clinical Trial Adverse Reactions

No data are available at the time of authorization.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Cases of autoimmune hemolytic anemia have been associated with the continuous administration of NSAIDs, including MEFENAMIC ACID, for 12 months or longer. In such cases the Coombs test results are positive, with evidence of both accelerated RBC production and RBC destruction. The process is reversible upon termination of mefenamic acid administration.

Decreases in hematocrit have been noted in 2 to 5% of patients and primarily in those who have received prolonged therapy.

Leukopenia, eosinophilia, thrombocytopenic purpura, agranulocytosis, pancytopenia, bone marrow hypoplasia and aplastic anemia have also been occasionally reported with NSAID treatment.

8.5. Post-Market Adverse Reactions

Additional reports of serious adverse events temporally associated with mefenamic acid during worldwide post-marketing experience are included below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to mefenamic acid exposure.

Body as a whole: fever, infection, sepsis, asthenia, malaise, death.

Cardiac disorders: Palpitation, arrhythmia, myocardial infarction, palpitations, congestive heart failure, tachycardia, syncope.

Ear and labyrinth disorders: Ear pain, hearing impairment.

Eye disorders: Blurred vision, eye irritation, conjunctivitis, reversible loss of color vision.

Gastrointestinal disorders: The most frequently reported adverse reactions associated with the use of mefenamic acid involve the gastrointestinal tract. In controlled studies for up to 8 months, the following disturbances were reported in decreasing order of frequency: diarrhea (approximately 5% of patients), nausea with or without vomiting, other gastrointestinal symptoms and abdominal pain.

In certain patients, the diarrhea was of sufficient severity to require discontinuation of medication. The occurrence of diarrhea is usually dose related, generally subsides on reduction of dosage and rapidly disappears on termination of therapy.

Other gastrointestinal reactions less frequently reported were pyrosis, flatulence, constipation, enterocolitis, colitis, steatorrhea, pancreatitis.

Gastrointestinal ulceration with or without hemorrhage, rectal bleeding, pancreatitis, melena, dry mouth, stomatitis, eructation, esophagitis, gastritis, glossitis, hematemesis have been reported.

Hematologic: eosinophilia, leukopenia, thrombocytopenia, agranulocytosis, pancytopenia, hemolytic anemia, aplastic anemia.

Hepatobiliary disorders: Cholestatic jaundice, hepatitis, liver failure, hepatorenal syndrome and mild hepatic toxicity have been reported less frequently.

Immune system disorders: Facial edema, angioedema, edema of the larynx, anaphylaxis and anaphylactoid reactions have been reported.

Lymphatic system: lymphadenopathy.

Metabolism and nutrition disorders: Anorexia, weight changes, appetite changes, hyperglycemia, glucose intolerance in diabetic patients has been reported.

Mild hepatic toxicity and increased need for insulin in a diabetic patient have been reported.

Nervous system disorders: Aseptic meningitis, coma, hallucinations, reversible leukoencephalopathy, dizziness, drowsiness, vertigo, convulsions, tremors, paresthesia, and headache have occurred.

Psychiatric disorders: Insomnia, somnolence, anxiety, nervousness, confusion, depression, dream abnormalities, have occurred.

Renal and urinary disorders: As with other NSAID agents, renal failure, including papillary necrosis, has been reported. In elderly patients, renal failure has occurred after taking mefenamic acid for 2 to 6 weeks. The renal damage may not be completely reversible. Hematuria, dysuria, cystitis, interstitial nephritis, oliguria/polyuria, proteinuria and hyponatremia have also been reported with mefenamic acid.

Respiratory, thoracic and mediastinal disorders: Asthma, dyspnea, respiratory depression, pneumonia.

Skin and subcutaneous tissue disorders: Urticaria, fixed drug eruption (FDE), rash, angioedema, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), erythema multiforme, exfoliative dermatitis, alopecia, photosensitivity, pruritus, ecchymosis, purpura, and perspiration have been reported.

Vascular disorders: Hypotension, hypertension, vasculitis.

9. Drug Interactions

9.2. Drug Interactions Overview

Mefenamic acid is highly protein bound in plasma. It is metabolised by CYP2C9, and its metabolites, as well as mefenamic acid directly, can be glucuronidated. A number of compounds are inhibitors of CYP2C9. Drug interactions studies of mefenamic acid and these compounds have not been conducted. The possibility of altered safety and efficacy should be considered when MEFENAMIC ACID is used concomitantly with these drugs.

9.3. Drug-Behaviour Interactions

Alcoholic beverages while taking MEFENAMIC ACID make it more likely to develop gastrointestinal problems.

MEFENAMIC ACID is contraindicated in heavy drinkers (see 2 Contraindications).

9.4. Drug-Drug Interactions

The drugs listed in Table 2 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

A false-positive reaction for urinary bile, using the diazo tablet test, may result after MEFENAMIC ACID administration. If biliuria is suspected other diagnostic procedures, such as the Harrison spot test, should be performed.

10. Clinical Pharmacology

10.1. Mechanism of Action

MEFENAMIC ACID (mefenamic acid), an anthranilic acid derivative, is a nonsteroidal anti-inflammatory drug (NSAID) with demonstrated anti-inflammatory, analgesic and antipyretic activity in laboratory animals. Its mode of action is not completely understood, but may be related to prostaglandin synthetase inhibition. In animal studies, the drug was found to inhibit prostaglandin synthesis and to compete for binding at the prostaglandin receptor site.

10.2. Pharmacodynamics

The analgesic and anti-inflammatory activities of mefenamic acid have been demonstrated in laboratory animals. Using the threshold amount of pressure on the rat’s tail required to elicit a squeak, mefenamic acid was 1.4 times as potent as aminopyrine as an analgesic agent.

Utilizing the ultraviolet-induced erythema method in guinea pigs, mefenamic acid was 0.5, 5 and 3.8 times as potent as phenylbutazone, ASA and aminopyrine, respectively, as an anti-inflammatory agent.

Experimental inflammatory granulation tissue growth was inhibited in both intact and adrenalectomized rats by mefenamic acid, indicating that its effects are not mediated via corticosteroids. In contrast with hydrocortisone, which caused significant dose-related adrenal atrophy, thymus involution, and retarded growth, mefenamic acid did not exert such effects at pharmacologically active doses.

Mefenamic acid and phenylbutazone both showed a pronounced and comparable antipyretic action in rats when tested against yeast-induced fever.

Mefenamic acid did not relieve morphine abstinence signs in abstinent, morphine-habituated monkeys.

10.3. Pharmacokinetics

Absorption

Mefenamic acid appears to be rapidly absorbed from the gastrointestinal tract following oral administration to humans.

Distribution

Peak plasma levels were reached 1 to 2 hours after administration of two 250 mg capsules; the C_max of free mefenamic acid was 3.5 mcg/mL and the half-life in plasma was about 3 to 4 hours. Following a single 1000 mg oral dose, peak plasma levels of 10 mcg/mL occurred in 2 to 4 hours, with a half-life of 2 hours.

Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. Repeated administration of mefenamic acid (250 mg capsules four times a day (q.i.d) yielded peak plasma levels of 3.7 to 6.7 mcg/mL within 1 to 2.5 hours after administration of each dose.

Metabolism

Mefenamic acid has two distinct metabolic products, namely a hydroxymethyl and a carboxy derivative; both have been identified in both plasma and urine. The parent drug and the metabolites are conjugated with glucuronic acid and excreted primarily in the urine but to a lesser extent also in the feces.

Elimination

Following a single dose, 67% of the total dose is excreted in the urine as unchanged drug or as one of two metabolites. Twenty to twenty-five per cent of the dose is excreted in the feces during the first 3 days.

Special populations and conditions

• Pediatrics: The safety and efficacy of mefenamic acid in pediatric patients has not been established. See 2 Contraindications.
• Geriatrics: See 7.1.4 Geriatrics.
• Sex: This information is not available for this drug product.
• Pregnancy and Breastfeeding: See 7.1.1 Pregnancy and 7.1.2 Breastfeeding.
• Genetic Polymorphism: This information is not available for this drug product.
• Ethnic Origin: This information is not available for this drug product.
• Hepatic Insufficiency: See 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic.
• Renal Insufficiency: See 7 Warnings and Precautions, Renal.
• Obesity: This information is not available for this drug product.
• Storage, Stability, and Disposal

Store at room temperature 15°C - 30°C. Protect from moisture.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance:

Mefenamic acid

Chemical name:

Benzoic acid, 2-[(2,3- dimethylphenyl)amino]-;

N-2,3-Xylylanthranilic acid.

Molecular formula and molecular mass:

C₁₅H₁₅N0₂; 241.29 g/mol

Structural formula:

Physicochemical properties:

White to off-white, crystalline powder. Melts at about 230°C, with decomposition. Soluble in solutions of alkali hydroxides; sparingly soluble in chloroform; slightly soluble in alcohol and in methanol; practically insoluble in water.

14. Clinical Trials

No information available.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General Toxicology

Acute Toxicity

Acute oral toxicity studies were carried out in mice and rats. The median lethal dose for mice and rats by the oral and parenteral route is summarized in the following table:

Table 3 - Summary of Oral and Parenteral Toxicity

Chronic Toxicity

Rats: In a 78-week chronic oral toxicity study three groups of 12 male and 12 female albino rats were given mefenamic acid in the diet at dose levels of approximately 23, 50, or 100 mg/kg. The fourth group served as control. In all treated groups, there was a mild depression of food intake and a moderate depression of weight gain. At doses of 50 to 100 mg/kg/day, there was evidence of intolerance.

Abnormal biochemical values, reflecting the clinical condition of moribund animals, were seen terminally.

Gross and microscopic examination revealed drug-related changes in the kidneys and small intestine. Minor papillary necrosis and epithelial cellular degeneration of the collecting tubules were found in the higher dose animals. Lesions of the small intestine, ranging from superficial mucosal erosions to massive ulceration, likewise occurred only in the higher dose groups.

Dogs: Dogs were given mefenamic acid for one year at relatively large doses ranging from 50 to 200 mg/kg/day. Vomiting and occasional diarrhea, with no clear cut evidence of a dose relationship, appeared throughout the experiment. The only significant hematologic, biochemical, or tissue evidence of intolerance was hepatocellular hydropic vacuolation in one animal and renal papillary edema in another. A dose of 400 mg/kg/day given to 2 dogs for 10 days was discontinued because of intolerance.

Monkeys: In a chronic toxicity study, monkeys tolerated the compound well at doses of 200 mg/kg/day for periods of 367 to 722 days, but at doses of 400 and 600 mg/kg/day, episodes of vomiting, convulsions and ataxia were seen in several animals. Three monkeys showed periodic transaminase value elevation. After sacrifice, microscopic lesions were detected in the kidney, heart, liver, psoas muscle, colon and stomach in animals receiving the highest dose (600 mg/kg). In the mid-dose animals (400 mg/kg), similar lesions were seen in the kidney, heart, stomach and pylorus.

Reproductive and Developmental Toxicology

Reproduction studies with mefenamic acid have been performed in rats, rabbits and dogs. Rats given up to 10 times the human dose showed decreased fertility, delay in parturition and a decreased rate of survival to weaning. No drug-related gross abnormalities were seen either in the mother or offspring. Rabbits at 2.5 times the human dose showed an increase in the number of resorptions. There were no fetal anomalies observed in these studies nor in dogs at up to 10 times the human dose.

17. Supporting Product Monographs

1. 1. PONSTAN® (Capsules, 250 mg), control 303286, product monograph, AA Pharma Inc. (2026-04-02)