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Mefenamic acid
Overview
What is Mefenamic acid?
Mefenamic Acid Capsules are a member of the fenamate group of nonsteroidal anti- inflammatory drugs (NSAIDs). Each Size '1' Yellow-Yellow capsule, with 'ML' imprinted on the cap & '250' imprinted on the body, contains 250 mg of mefenamic acid for oral administration. Mefenamic acid 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. The chemical name is N-2,3-xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C
H
NO
and the structural formula of mefenamic acid is:
Each capsule also contains 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.
What does Mefenamic acid look like?
What are the available doses of Mefenamic acid?
Sorry No records found.
What should I talk to my health care provider before I take Mefenamic acid?
Sorry No records found
How should I use Mefenamic acid?
Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (
).
Mefenamic acid is indicated:
Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals
).
After observing the response to initial therapy with mefenamic acid, the dose and frequency should be adjusted to suit an individual patient's needs.
For the relief of acute pain in adults and adolescents ≥14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week.
For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting 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.
What interacts with Mefenamic acid?
- Mefenamicacid is 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 ( .
- Historyof 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 (
- In the setting of coronary artery bypass graft (CABG) surgery (see )
What are the warnings of Mefenamic acid?
Safe use of methocarbamol has not been established with regard to possible adverse effects upon fetal development. There have been reports of fetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore, methocarbamol tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgment of the physician the potential benefits outweigh the possible hazards (see ).
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see
).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
).
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs
).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs])
).
Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see
). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic Reactions
Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma
Seek emergency help if anaphylactic reaction occurs.
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients withasthmamay have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in suchaspirin-sensitivepatients,mefenamicacid is contraindicated in patients with thisform of aspirin sensitivity
). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis,Stevens-JohnsonSyndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the useofmefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous seriousskinreactionstoNSAIDs
).
Premature Closure of Fetal Ducts Arteriosus
Mefenamic acid may cause prematureclosure of the ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnantwomen starting at 30 weeks of gestation (third trimester)
).
Hematological Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia,monitorhemoglobin or hematocrit.
NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)mayincrease this risk. Monitor these patients for signs of bleeding
- Use the lowest effective dosage for the shortest possible duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue mefenamic acid until a serious GI adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding ).
What are the precautions of Mefenamic acid?
General
Mefenamic acid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
Information for Patients
Advise the patient to read the FDA-approved patient labeling (
) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with mefenamic acid 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 healthcare provider immediately (see
).
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see
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 mefenamic acid and seek immediate medical therapy (see
).
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
).
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
).
Serious Skin Reactions
Advise patients to stop mefenamic acid immediately if they develop any type of rash and contact their healthcare provider as soon as possible (see
).
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including mefenamic acid, may be associated with a reversible delay in ovulation.
Fetal Toxicity
Inform pregnant women to avoid use of mefenamic acid and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus
).
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased riskofgastrointestinaltoxicity,and little or no increase in efficacy
).Alertpatients that NSAIDsmay be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Informpatientsnot to use low-dose aspirin concomitantly with mefenamic acid until they talk to their healthcare provider
Masking of Inflammation and Fever
The pharmacological activity of mefenamic acid in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile checked periodically (see
).
Drug Interactions
See Table 2 for clinically significant drug interactions with mefenamic acid.
Table 2: 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 . | 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 . |
| Intervention: | Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see 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). |
| 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. |
| 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 | 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. 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 mefenamic acid 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 mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. | Cyclosporine |
| Clinical Impact: | Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. | NSAIDs and Salicylates |
| Clinical Impact: | Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
| Intervention: | The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. | Pemetrexed |
| Clinical Impact: | Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. |
| Clinical Impact: | In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C and AUC of mefenamic acid by 125% and 36%, respectively. |
| Intervention: | Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. |
Drug/Laboratory Test Interactions
Mefenamic acid may prolong prothrombin time. Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of mefenamic acid have not been conducted.
Mutagenesis
Studies to evaluate the mutagenic potential of mefenamic acid have not been completed.
Impairment of Fertility
Dietary administration of mefenamic acid to male rats 61 days- and to female rats 15 days- prior to mating through to Gestation Day (GD) 21 at a dose of 155 mg/kg/day (equivalent to the Maximum Recommended Human Dose [MRHD] of 1500 mg/day on a mg/m basis) resulted in decreased corpora lutea.
In another study, rats administered up to 10-times a human dose of 250 mg showed decreased fertility.
Pregnancy
Risk Summary
Use of NSAIDs, including mefenamic acid, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester)
There are no adequate and well-controlled studies of mefenamic acid in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies in rats and rabbits when dosed throughout gestation, there were no evidence of developmental effects at a dose of mefenamic acid 1.6-times and 0.6-times the maximum recommended human dose (MRHD), respectively. Dietary administration of mefenamic acid at a dose 1.2-times the MRHD from gestation day (GD) 15 to weaning or at a dose equivalent to the MRHD from 15 days prior to mating through to weaning resulted in greater incidences of perinatal death [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.
Data
Animal data
Pregnant rats administered 249 mg/kg of mefenamic acid (1.6-times the MRHD of 1500 mg/day on a mg/m basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects.
Pregnant rabbits given 50 mg/kg of mefenamic acid (0.6-times the MRHD on a mg/m basis) from GD 6 to GD 18 did not result in any clear treatment-related adverse developmental effects. However, incidences of resorption were greater in treated compared to control animals. This dose was associated with some evidence of maternal toxicity with 4 of 18 rabbits exhibiting diarrhea and weight loss.
Dietary administration of mefenamic acid at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m basis) to pregnant rats from GD 15 to weaning resulted in an increased incidence of perinatal death. Treated dams were associated with decreased weight gain and delayed parturition. In another study, dietary administration of mefenamic acid at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m basis) to females 15 days prior to mating through to weaning resulted in smaller average litter sizes and higher incidence of perinatal death.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, decreased pup survival occurred and increased the incidence of stillbirth. The effects of mefenamic acid on labor and delivery in pregnant women are unknown.
Nursing Mothers
Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including mefenamic acid 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 in 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 mefenamic acid, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 14 have not been established.
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, start dosing at the low end of the dosing range, and monitor patients for adverse effects
Clinicalstudies of mefenamic acid did notinclude sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
This drug is known to besubstantially excreted by the kidney, and the riskof toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function ).
What are the side effects of Mefenamic acid?
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,adversereaction 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.
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
Additional adverse experiences reported occasionally and listed here by body system include:
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, pruritus, sweat
Special senses - blurred vision
Urogenital system - cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions, which occur rarely are:
Body as a whole - anaphylactoid reactions, appetite changes, death
Cardiovascular system - arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive system - eructation, liver failure, pancreatitis
Hemic and lymphatic system - agranulocytosis, hemolytic anemia, aplastic anemia, lymph adenopathy, pancytopenia
Metabolic and nutritional - hyperglycemia
Nervous system - convulsions, coma, hallucinations, meningitis
Respiratory - respiratory depression, pneumonia
Skin and appendages - angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens - Johnson syndrome, urticaria
Special senses - conjunctivitis, hearing impairment
- Cardiovascular Thrombotic Events (
- GIBleeding, Ulceration and Perforation (
- Hepatotoxicity(
- Hypertension(
- Heart Failure and Edema (
- Renal Toxicity and Hyperkalemia( )
- Anaphylactic Reactions(
- SeriousSkinReactions (
- HematologicToxicity (
What should I look out for while using Mefenamic acid?
Mefenamicacid is contraindicated in the following patients:
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see
).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
).
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs
).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs])
).
Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see
). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic Reactions
Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma
Seek emergency help if anaphylactic reaction occurs.
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients withasthmamay have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in suchaspirin-sensitivepatients,mefenamicacid is contraindicated in patients with thisform of aspirin sensitivity
). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis,Stevens-JohnsonSyndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the useofmefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous seriousskinreactionstoNSAIDs
).
Premature Closure of Fetal Ducts Arteriosus
Mefenamic acid may cause prematureclosure of the ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnantwomen starting at 30 weeks of gestation (third trimester)
).
Hematological Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia,monitorhemoglobin or hematocrit.
NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)mayincrease this risk. Monitor these patients for signs of bleeding
What might happen if I take too much Mefenamic acid?
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
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).
How should I store and handle Mefenamic acid?
RISPERDAL Tablets should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and moisture. Keep out of reach of children.RISPERDAL Tablets should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and moisture. Keep out of reach of children.Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017Mefenamic Acid Capsules USP 250 mg are Size ‘1’ yellow-yellow capsules with ‘ML’ imprinted on the cap & ‘250’ imprinted on the body. They are supplied as follows:Bottles of 30 NDC 42571-258-30Bottles of 100 NDC 42571-258-01 Dispense in a tight container as defined in the USP.Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Made in IndiaManufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920 Revised: 12/2017
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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
. Mefenamic acid concentrations reached during therapy have produced
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.
Pharmacokinetics
Absorption
Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17% CV). The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied.
Following a single 1-gram oral dose, mean peak plasma levels ranging from 10 to 20 mcg/mL have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n= 6) receiving 1-gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life.
The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see
).
Distribution
Mefenamic acid has been reported as being greater than 90% bound to albumin. The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vzss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg.
Based on its physical and chemical properties, mefenamic acid is expected to be excreted in human breast milk
).
Elimination
Metabolism
Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur. The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n= 6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6 to 8 hours for the carboxy metabolite and its glucuronide.
Excretion
Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3 carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.
The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound. The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretions are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (
.
TABLE 1. Pharmacokinetic Parameter Estimates for Mefenamic Acid
Special Populations
Pediatric:
Race:
Hepatic Impairment
(see
).
Renal Impairment
see
Drug
Interaction
Studies
Aspirin:
see
.
Clinical Studies
In controlled, double-blind, clinical trials, mefenamic acid was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either mefenamic acid, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Mefenamic acid was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated.
Non-Clinical Toxicology
Mefenamicacid is contraindicated in the following patients:Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see ).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see ).
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs ).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) ).
Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see ). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic Reactions
Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma
Seek emergency help if anaphylactic reaction occurs.
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients withasthmamay have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in suchaspirin-sensitivepatients,mefenamicacid is contraindicated in patients with thisform of aspirin sensitivity ). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis,Stevens-JohnsonSyndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the useofmefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous seriousskinreactionstoNSAIDs ).
Premature Closure of Fetal Ducts Arteriosus
Mefenamic acid may cause prematureclosure of the ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnantwomen starting at 30 weeks of gestation (third trimester) ).
Hematological Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia,monitorhemoglobin or hematocrit.
NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)mayincrease this risk. Monitor these patients for signs of bleeding
See Table 2 for clinically significant drug interactions with mefenamic acid.
Table 2: Clinically Significant Drug Interactions with Mefenamic Acid
Mefenamic acid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,adversereaction 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.
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
Additional adverse experiences reported occasionally and listed here by body system include:
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, pruritus, sweat
Special senses - blurred vision
Urogenital system - cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions, which occur rarely are:
Body as a whole - anaphylactoid reactions, appetite changes, death
Cardiovascular system - arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive system - eructation, liver failure, pancreatitis
Hemic and lymphatic system - agranulocytosis, hemolytic anemia, aplastic anemia, lymph adenopathy, pancytopenia
Metabolic and nutritional - hyperglycemia
Nervous system - convulsions, coma, hallucinations, meningitis
Respiratory - respiratory depression, pneumonia
Skin and appendages - angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens - Johnson syndrome, urticaria
Special senses - conjunctivitis, hearing impairment
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).