PONSTEL

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).
• PONSTEL® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (See WARNINGS).

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (See WARNINGS).

Ponstel^® (mefenamic acid) is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each blue-banded, ivory capsule 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°-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 C₁₅H₁₅N0₂ and the structural formula of mefenamic acid is:

Each capsule also contains lactose, NF. The capsule shell and/or band contains citric acid, USP; D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, NF; glycerol monooleate; silicon dioxide, NF; sodium benzoate, NF; sodium lauryl sulfate, NF; titanium dioxide, USP.

Ponstel is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Ponstel, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

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).^1,2   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 10-20 mcg/mL³ 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 PRECAUTIONS, Drug Interactions).¹
 
Distribution: Mefenamic acid has been reported as being greater than 90% bound to albumin.⁹ The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vz_ss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg.²
 
Based on its physical and chemical properties, Ponstel is expected to be excreted in
human breast milk.
 
Metabolism: Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite l). Further oxidation to a 3-carboxymefenamic acid (Metabolite ll) may occur.¹⁰ 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 6-8 hours for the carboxy metabolite and its glucuronide.³
 
 
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.³
 
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.³  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 excretion are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Ponstel should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function.
 

Pediatric: Ponstel has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean Cmax in this study was 4 mcg/mL (range 2.9-6.1). The mean time to maximum concentration (Tmax) was 8 hours (range 2-18 hrs).¹¹
 
Race: Pharmacokinetic differences due to race have not been identified.
 
Hepatic Insufficiency: Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of Ponstel compared to patients with normal hepatic function.
 
Renal Insufficiency: Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Ponstel should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function.

In controlled, double-blind, clinical trials, Ponstel 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 Ponstel, 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. Ponstel was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated.

Carefully consider the potential benefits and risks of PONSTEL and other treatment options before deciding to use PONSTEL.  Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
 
PONSTEL is indicated:

• For relief of mild to moderate pain in patients ≥14 years of age, when therapy will not exceed one week (7 days).
• For treatment of primary dysmenorrhea.

PONSTEL is contraindicated in patients with known hypersensitivity to Mefenamic acid. 
 
PONSTEL should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.  Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).
 
PONSTEL is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
 
Ponstel is contraindicated in patients with active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract.
 
Ponstel should not be used in patients with preexisting renal disease.

PONSTEL 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 mate to discontinue corticosteroids.
 
 
The pharmacological activity of PONSTEL in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including PONSTEL.  These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy.  Notable elevations of ALT and AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs.  In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
 
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with PONSTEL.  If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), PONSTEL should be discontinued.
 

Anemia is sometimes seen in patients receiving NSAIDs, including PONSTEL.  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 PONSTEL, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.  NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.  Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving PONSTEL who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Patients with asthma may have aspirin-sensitive asthma.  The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal.  Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, PONSTEL should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.  Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• PONSTEL, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
• PONSTEL, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulceration and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
• PONSTEL, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and bulers, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g. nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling in the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, PONSTEL should be avoided because it may cause premature closure of the ductus arteriosus.

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.  Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically.  If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver test persist or worsen, PONSTEL should be discontinued.

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 Ponstel is used concomitantly with these drugs.

Ponstel may prolong prothrombin time.⁴ 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.

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred.  The effects of PONSTEL on labor and delivery in pregnant women are unknown.

Trace amounts of Ponstel may be present in breast milk and transmitted to the nursing infant.⁷  Because of the potential for serious adverse reactions in nursing infants from PONSTEL, 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.

Safety and effectiveness in pediatric patients below the age of 14 have not been established.

Clinical studies of Ponstel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.  As with any NSAIDs, caution should be exercised in treating the elderly (65 years or older).
 
 
This drug is known to be substantially excreted by the kidney, and the risk of 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 (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).

In patients taking Ponstel or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% 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 uled 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,
lymphadenopathy, 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

Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
 
 
Patients should be managed by symptomatic and supportive care following an NSAID
overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Carefully consider the potential benefits and risks of PONSTEL and other treatment options before deciding to use PONSTEL.  Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
 
After observing the response to initial therapy with PONSTEL, the dose and frequency should be adjusted to suit an individual patients 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.⁴
 
 
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 effect treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days.⁵

Ponstel (mefenamic acid) is available as 250 mg blue-banded, ivory capsules, imprinted with " FHPC 400" and "PONSTEL®”.
 
Bottles of 100          NDC 59630-400-10
 
Storage
Store at 20- 25°C (68- 77°F); excursions permitted to 15-30°C  (59-86°F) [See USP Controlled Room Temperature].

• Neuvonen PJ, Kivisto KT: Enhancement of drug absorption by antacids. An unrecognized drug interaction. Clin Pharmacokinet. 27:120-8, Aug 1994.
• Tall AR, Mistilits SP: Studies on Ponstan (mefenamic acid): I. Gastro-intestinal blood loss; II. Absorption and excretion of a new formulation. J Int Med Res (UK). 1975, 3 (3) p176-82.
• Winder CV, Kaump DH, Glazko et al: Experimental observations of flufenamic, mefenamic, and meclofenamic acids. AnnPhys Med (Eng), Suppl p7-49.1967.
• Glazko AJ: Experimental observations of flufenamic, mefenamic, and meclofenamic acids. Part III. Metabolic disposition, in Fenamates in Medicine. A Symposium, London, 1966. Annals of Physical Medicine, Supplement, pp 23-36, 1967.
• Data on file, First Horizon (Protocol 356).
• Budoff PW: Use of mefenamic acid in the treatment of primary dysmenorrheal. JAMA. 241: 2713-2716, 1979.
• Buchanan RA, et al. The breast milk excretion of mefenamic acid. Curr Ther Res. 10:592, 1968.
• Corby DG, Decker WJ: Management of acute poisoning with activated charcoal. Pediatrics. 54:324, 1974.
• Champion GD, Graham GG: Pharmacokinetics of non-steriodal anti-inflammatory agents. Aust NZ J Med. 8 (Supp 1): 94-100, Jun 1978
• McGurk KA, Remmel RP, Hosagrahara VP, Tosh D, Burchell B: Reactivity of mefenamic acid 1- o- acyl glucuronide with proteins in vitro and ex vivo. Drug Metab Dispos. Aug 1996, 24 (8) p842-9.
• Ito K, Niida Y, Sato J et al: Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus. Acta Paediatr JPN. 36 (4): 387-91, 1994.

Distributed by: