DRUGS & SUPPLEMENTS

Rheonex-MF

advertisement
How long you have been taking the medicine?

Rheonex-MF uses

Rheonex-MF consists of Mefenamic Acid, Tranexamic Acid.

Mefenamic Acid:


INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of Rheonex-MF (Mefenamic Acid) and other treatment options before deciding to use Rheonex-MF (Mefenamic Acid). Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ).

Rheonex-MF (Mefenamic Acid) 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.

CONTRAINDICATIONS

Rheonex-MF (Mefenamic Acid) is contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to Rheonex-MF (Mefenamic Acid) or any components of the drug product (see WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reaction, Exacerbation of Asthma Related to Aspirin Sensitivity).
  • In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events ).

WARNINGS

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 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 Rheonex-MF (Mefenamic Acid), increases the risk of serious gastrointestinal (GI) events (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ).

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 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS).

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 Rheonex-MF in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Rheonex-MF (Mefenamic Acid) is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including Rheonex-MF (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 3-6 months, and in about 2-4% 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 ; 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

  • 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 Rheonex-MF (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 (see PRECAUTIONS; Drug Interactions ).

Hepatotoxicity

Elevations of ALT or AST 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 Rheonex-MF (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 Rheonex-MF (Mefenamic Acid) immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including Rheonex-MF (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 (see PRECAUTIONS; Drug Interactions ).

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 Rheonex-MF 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]) (see PRECAUTIONS; Drug Interactions ).

Avoid the use of Rheonex-MF (Mefenamic Acid) in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Rheonex-MF (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 Rheonex-MF in patients with advanced renal disease. The renal effects of Rheonex-MF (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 Rheonex-MF (Mefenamic Acid). Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Rheonex-MF (Mefenamic Acid) (see PRECAUTIONS; Drug Interactions ). Avoid the use of Rheonex-MF (Mefenamic Acid) in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Rheonex-MF (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

Rheonex-MF has been associated with anaphylactic reactions in patients with and without known hypersensitivity to Rheonex-MF (Mefenamic Acid) and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS , WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).

Seek emergency help if anaphylactic reaction occurs.

Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may 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 such aspirin-sensitive patients, Rheonex-MF (Mefenamic Acid) is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS ). When Rheonex-MF (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 Rheonex-MF, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (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 use of Rheonex-MF (Mefenamic Acid) at the first appearance of skin rash or any other sign of hypersensitivity. Rheonex-MF (Mefenamic Acid) is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS ).

Premature Closure of Fetal Ducts Arteriosus

Rheonex-MF (Mefenamic Acid) may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including Rheonex-MF (Mefenamic Acid), in pregnant women starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy ).

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 Rheonex-MF (Mefenamic Acid) has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Rheonex-MF (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) may increase this risk. Monitor these patients for signs of bleeding .

advertisement

PRECAUTIONS

General

Rheonex-MF 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 (Medication Guide) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with Rheonex-MF (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.

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 WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity. If these occur, instruct patients to stop Rheonex-MF (Mefenamic Acid) and seek immediate medical therapy (see WARNINGS; Hepatotoxicity ).

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema ).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction. Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATIONS, WARNINGS; Anaphylactic Reactions ).

Serious Skin Reactions

Advise patients to stop Rheonex-MF (Mefenamic Acid) immediately if they develop any type of rash and contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions ).

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Rheonex-MF, may be associated with a reversible delay in ovulation. .

Fetal Toxicity

Inform pregnant women to avoid use of Rheonex-MF (Mefenamic Acid) and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus ).

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of Rheonex-MF with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, PRECAUTIONS; Drug Interactions ). Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Rheonex-MF (Mefenamic Acid) until they talk to their healthcare provider .

Masking of Inflammation and Fever

The pharmacological activity of Rheonex-MF 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 WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity ).

Drug Interactions

Drugs That Interfere with Hemostasis
Clinical Impact:
  • Rheonex-MF (Mefenamic Acid) and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Rheonex-MF (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 Rheonex-MF (Mefenamic Acid) with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
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 Rheonex-MF (Mefenamic Acid) and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).

Rheonex-MF (Mefenamic Acid) is not a substitute for low dose aspirin for cardiovascular protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
  • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
  • During concomitant use of Rheonex-MF (Mefenamic Acid) and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of Rheonex-MF (Mefenamic Acid) and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function .
  • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of Rheonex-MF (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 Rheonex-MF (Mefenamic Acid) with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of Rheonex-MF (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 Rheonex-MF (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 Rheonex-MF (Mefenamic Acid) and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of Rheonex-MF (Mefenamic Acid) and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of Rheonex-MF (Mefenamic Acid) and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of Rheonex-MF (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 Rheonex-MF (Mefenamic Acid) with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of Rheonex-MF (Mefenamic Acid) and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity.
Intervention: During concomitant use of Rheonex-MF (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.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Antacid
Clinical Impact: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of Rheonex-MF (Mefenamic Acid) increased the Cmax and AUC of Rheonex-MF (Mefenamic Acid) by 125% and 36%, respectively.
Intervention: Concomitant use of Rheonex-MF (Mefenamic Acid) and antacids is not generally recommended because of possible increased adverse events.

Drug/Laboratory Test Interactions

Rheonex-MF (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 Rheonex-MF (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 Rheonex-MF have not been conducted.

Mutagenesis

Studies to evaluate the mutagenic potential of Rheonex-MF (Mefenamic Acid) have not been completed.

Impairment of Fertility

Dietary administration of Rheonex-MF 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/m2 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 Rheonex-MF, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Rheonex-MF (Mefenamic Acid), in pregnant women starting at 30 weeks of gestation (third trimester) .

There are no adequate and well-controlled studies of Rheonex-MF (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 2-4% for major malformations, and 15-20% 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 Rheonex-MF (Mefenamic Acid) 1.6-times and 0.6-times the maximum recommended human dose (MRHD), respectively. Dietary administration of Rheonex-MF (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 . 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 Rheonex-MF (Mefenamic Acid), resulted in increased pre- and post-implantation loss.

Data

Animal data

Pregnant rats administered 249 mg/kg of Rheonex-MF (1.6-times the MRHD of 1500 mg/day on a mg/m2 basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects.

Pregnant rabbits given 50 mg/kg of Rheonex-MF (Mefenamic Acid) (0.6-times the MRHD on a mg/m2 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 Rheonex-MF (Mefenamic Acid) at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m2 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 Rheonex-MF (Mefenamic Acid) at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m2 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 Rheonex-MF (Mefenamic Acid) on labor and delivery in pregnant women are unknown.

Nursing Mothers

Trace amounts of Rheonex-MF may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from Rheonex-MF (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 Rheonex-MF 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 Rheonex-MF (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 .

Clinical studies of Rheonex-MF (Mefenamic Acid) did not include 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 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, ADVERSE REACTIONS ).

advertisement

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Cardiovascular Thrombotic Events
  • GI Bleeding, Ulceration and Perforation (see WARNINGS)
  • Hepatotoxicity (see WARNINGS)
  • Hypertension (see WARNINGS)
  • Heart Failure and Edema (see WARNINGS))
  • Renal Toxicity and Hyperkalemia (see WARNINGS )
  • Anaphylactic Reactions (see WARNINGS)
  • Serious Skin Reactions (see WARNINGS)
  • Hematologic Toxicity (see WARNINGS)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In patients taking Rheonex-MF (Mefenamic Acid) 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 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

advertisement

OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare .

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).

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of Rheonex-MF (Mefenamic Acid) and other treatment options before deciding to use Rheonex-MF (Mefenamic Acid). Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ).

After observing the response to initial therapy with Rheonex-MF (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.

HOW SUPPLIED

Rheonex-MF (mefenamic acid) is available as 250 mg blue-banded, ivory capsules, imprinted with " FHPC 400" and "PONSTEL®".

Bottles of 30 NDC 59630-400-30

Dispense in a tight container as defined in the USP.

Image

Storage

Store at room temperature 20° to 25°C (68°to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured for:

Shionogi Inc.

Florham Park, NJ 07932

Manufactured by:

Halo Pharmaceutical Inc.

Whippany, NJ 07981

Rev. 05/2016

For inquires call 1-800-849-9707

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 05/16

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

NSAID can cause serious side effects, including:

  • Increase risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:
    • with increasing doses of NSAIDs
    • with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)". Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

  • Increase risk of bleeding, ulcers and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:
    • anytime during use
    • without warning symptoms
    • that may cause death

The risk of getting an ulcer or bleeding increases with:

  • past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
  • taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs"
  • increasing doses of NSAIDs
  • longer use of NSAIDs
  • smoking
  • drinking alcohol
  • older age
  • poor health
  • advanced liver disease
  • bleeding problems
NSAID should only be used:
  • exactly as prescribed
  • at the lowest dose possible for your treatment
  • or the shortest time needed
What are NSAIDs?

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDs:

  • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
  • right before or after heart bypass surgery.
Before taking NSAIDs, tell our healthcare provider about all of your medical conditions, including if you:
  • have liver or kidney problems
  • have high blood pressure
  • have asthma
  • are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy
  • are breastfeeding or plan to breastfeed

Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

  • new or worse high blood pressure
  • heart failure
  • liver problems including liver failure
  • kidney problem including kidney failure
  • low red blood cells (anemia)
  • life-threatening skin reactions
  • life-threatening allergic reactions
  • Other side effects if NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

Get emergency help right away if you get any of the following symptoms:

  • shortness of breath or trouble breathing
  • chest pain
  • weakness in one part or side of your body
  • slurred speech
  • swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:
  • nausea
  • more tired or weaker than usual
  • diarrhea
  • itching
  • your skin or eyes look yellow
  • indigestion or stomach pain
  • flu-like symptoms
  • vomit blood
  • there is blood in the bowel movement or it is black and sticky like tar
  • unusual weight gain
  • skin rash or blisters with fever
  • swelling of the arms, legs, hands, and feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about NSAIDs
  • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
  • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAID for more than 10 days.
General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

Manufactured for: SHIONOGI INC., Florham Park, NJ 07932

Manufactured by: HALO PHARMACEUTICAL INC., Whippany, NJ 07981

For more information, call 1-800-849-9707


NDC 59630-400-30

Rheonex-MF (Mefenamic Acid)®

(Mefenamic Acid Capsules, USP)

250 mg

Rx Only

30 CAPSULES

PHARMACIST: PLEASE DISPENSE

WITH MEDICATION GUIDE

SHIONOGI INC.

Tranexamic Acid:


RECENT MAJOR CHANGES

Contraindications (4.1) 10/2013

Warnings and Precautions (5.1) 10/2013

1 INDICATIONS AND USAGE

Rheonex-MF (Tranexamic Acid) tablets are indicated for the treatment of cyclic heavy menstrual bleeding [see Clinical Studies ( 14 )].

Prior to prescribing Rheonex-MF (Tranexamic Acid) tablets, exclude endometrial pathology that can be associated with heavy menstrual bleeding.

Rheonex-MF (Tranexamic Acid) tablets are an antifibrinolytic indicated for the treatment of cyclic heavy menstrual bleeding. (1)

2 DOSAGE AND ADMINISTRATION

  • 1,300 mg three times a day (3,900 mg/day) for a maximum of 5 days during monthly menstruation (2.1)
  • Renal impairment: Dosage adjustment is needed if serum creatinine concentration (Cr) is higher than 1.4 mg/dL (2.2)
    • Cr above 1.4 mg/dL and ≤ 2.8 mg/dL: 1,300 mg (two 650 mg tablets) two times a day (2,600 mg/day) for a maximum of 5 days during menstruation
    • Cr above 2.8 mg/dL and ≤ 5.7 mg/dL: 1,300 mg (two 650 mg tablets) once a day (1,300 mg/day) for a maximum of 5 days during menstruation
    • Cr above 5.7 mg/dL: 650 mg (one 650 mg tablet) once a day (650 mg/day) for a maximum of 5 days during menstruation

2.1 Recommended Dosage

The recommended dose of Rheonex-MF (Tranexamic Acid) tablets for women with normal renal function is two 650 mg tablets taken three times daily (3900 mg/day) for a maximum of 5 days during monthly menstruation. Rheonex-MF (Tranexamic Acid) tablets may be administered without regard to meals. Tablets should be swallowed whole and not chewed or broken apart.

2.2 Renal Impairment

In patients with renal impairment, the plasma concentration of Rheonex-MF (Tranexamic Acid) increased as serum creatinine concentration increased [see Clinical Pharmacology ( 12.3 )]. Dosage adjustment is needed in patients with serum creatinine concentration higher than 1.4 mg/dL (Table 1).

Rheonex-MF (Tranexamic Acid) Tablets
Serum Creatinine

(mg/dL)

Adjusted Dose Total Daily Dose
Cr above 1.4 and

≤ 2.8

1300 mg (two 650 mg tablets) two times a day for a maximum of 5 days during menstruation 2600 mg
Cr above 2.8 and

≤ 5.7

1300 mg (two 650 mg tablets) once a day for a maximum of 5 days during menstruation 1300 mg
Cr above 5.7 650 mg (one 650 mg tablet) once a day for a maximum of 5 days during menstruation 650 mg
advertisement

3 DOSAGE FORMS AND STRENGTHS

650 mg tablets

Tablets: 650 mg (3)

4 CONTRAINDICATIONS

  • Women who are using combination hormonal contraception
  • Women with active thromboembolic disease or a history or intrinsic risk of thrombosis or thromboembolism, including retinal vein or artery occlusion (4.1)

  • Hypersensitivity to Rheonex-MF (Tranexamic Acid) (4.2)

4.1 Thromboembolic Risk

Do not prescribe Rheonex-MF (Tranexamic Acid) tablets to women who are

  • using combination hormonal contraception
  • known to have any of the following conditions:
    • Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis)
    • A history of thrombosis or thromboembolism, including retinal vein or artery occlusion
    • An intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy)

Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, have been reported with Rheonex-MF (Tranexamic Acid).

4.2 Hypersensitivity to Rheonex-MF

Do not prescribe Rheonex-MF (Tranexamic Acid) tablets to women with known hypersensitivity to Rheonex-MF (Tranexamic Acid) [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )].

5 WARNINGS AND PRECAUTIONS

  • Concomitant use of Rheonex-MF tablets with Factor IX complex concentrates, anti-inhibitor coagulant concentrates or all-trans retinoic acid (oral tretinoin) may increase the risk of thrombosis. (5.1)
  • Visual or ocular adverse effects may occur with Rheonex-MF (Tranexamic Acid) tablets. Immediately discontinue use if visual or ocular symptoms occur. (5.1)
  • In case of severe allergic reaction, discontinue Rheonex-MF (Tranexamic Acid) tablets and seek immediate medical attention. (5.2)
  • Cerebral edema and cerebral infarction may be caused by use of Rheonex-MF (Tranexamic Acid) tablets in women with subarachnoid hemorrhage. (5.3)
  • Ligneous conjunctivitis has been reported in patients taking Rheonex-MF (Tranexamic Acid). (5.4)

5.1 Thromboembolic Risk

Concomitant Use of Hormonal Contraceptives

Combination hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because Rheonex-MF (Tranexamic Acid) tablets are antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when hormonal contraceptives are administered with Rheonex-MF (Tranexamic Acid) tablets. This is of particular concern in women who are obese or smoke cigarettes, especially smokers over 35 years of age.

Women using hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of Rheonex-MF (Tranexamic Acid) tablets, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of Rheonex-MF (Tranexamic Acid) tablets with hormonal contraceptives. However, there have been US postmarketing reports of venous and arterial thrombotic events in women who have used Rheonex-MF (Tranexamic Acid) tablets concomitantly with combination hormonal contraceptives. For this reason, concomitant use of Rheonex-MF (Tranexamic Acid) tablets with combination hormonal contraceptives is contraindicated. [see Contraindications (4.1) and Drug Interactions (7.1) ].

Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

Rheonex-MF (Tranexamic Acid) tablets is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ].

All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing Rheonex-MF (Tranexamic Acid) tablets to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ].

Ocular Effects

Retinal venous and arterial occlusion has been reported in patients using Rheonex-MF (Tranexamic Acid). Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed to discontinue Rheonex-MF (Tranexamic Acid) tablets immediately and should be referred to an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination, to exclude the possibility of retinal venous or arterial occlusion.

5.2 Severe Allergic Reaction

A case of severe allergic reaction to Rheonex-MF tablets was reported in the clinical trials, involving a subject who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus of Rheonex-MF (Tranexamic Acid).

5.3 Subarachnoid Hemorrhage

Cerebral edema and cerebral infarction may be caused by use of Rheonex-MF (Tranexamic Acid) tablets in women with subarachnoid hemorrhage.

5.4 Ligneous Conjunctivitis

Ligneous conjunctivitis has been reported in patients taking Rheonex-MF (Tranexamic Acid). The conjunctivitis resolved following cessation of the drug.

6 ADVERSE REACTIONS

Most common adverse reactions in clinical trials tablets subjects compared to placebo subjects) are headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia and fatigue. (6.1)



To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.



6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Short-term Studies

The safety of Rheonex-MF (Tranexamic Acid) tablets in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies ( 14 )]. One study compared the effects of two doses of Rheonex-MF (Tranexamic Acid) tablets (1950 mg and 3900 mg given daily for up to 5 days during each menstrual period) versus placebo over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one dose of 3900 mg/day of Rheonex-MF (Tranexamic Acid) tablets. A second study compared the effects of Rheonex-MF (Tranexamic Acid) tablets (3900 mg/day) versus placebo over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least one dose of Rheonex-MF (Tranexamic Acid) tablets. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥ 80 mL.

In these studies, subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21 to 35 days, and a BMI of approximately 32 kg/m2. On average, subjects had a history of HMB for approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were Caucasian, 25% were Black, and 5% were Asian, Native American, Pacific Islander, or Other. Seven percent (7%) of all subjects were of Hispanic origin. Women using hormonal contraception were excluded from the trials.

The rates of discontinuation due to adverse events during the two clinical trials were comparable between Rheonex-MF (Tranexamic Acid) tablets and placebo. In the 3-cycle study, the rate in the 3900 mg Rheonex-MF (Tranexamic Acid) tablets dose group was 0.8% as compared to 1.4% in the placebo group. In the 6-cycle study, the rate in the Rheonex-MF (Tranexamic Acid) tablets group was 2.4% as compared to 4.1% in the placebo group. Across the studies, the combined exposure to 3900 mg/day Rheonex-MF (Tranexamic Acid) tablets was 947 cycles and the average duration of use was 3.4 days per cycle.

A list of adverse events occurring in ≥ 5% of subjects and more frequently in Rheonex-MF (Tranexamic Acid) tablets treated subjects receiving 3900 mg/day compared to placebo is provided in Table 2.

Rheonex-MF (Tranexamic Acid)

Tablets

3900 mg/day n (%)

(N=232)

Placebo

n (%)

(N=139)

Total Number of Adverse Events 1500 923
Number of Subjects with at Least One Adverse Event 208 (89.7%) 122 (87.8%)
HEADACHE a 117 (50.4%) 65 (46.8%)
NASAL & SINUS SYMPTOMS b 59 (25.4%) 24 (17.3%)
BACK PAIN 48 (20.7%) 21 (15.1%)
ABDOMINAL PAIN c 46 (19.8%) 25 (18.0%)
MUSCULOSKELETAL PAIN d 26 (11.2%) 4 (2.9%)
ARTHRALGIA e 16 (6.9%) 7 (5.0%)
MUSCLE CRAMPS & SPASMS 15 (6.5%) 8 (5.8%)
MIGRAINE 14 (6.0%) 8 (5.8%)
ANEMIA 13 (5.6%) 5 (3.6%)
FATIGUE 12 (5.2%) 6 (4.3%)

a Includes headache and tension headache

b Nasal and sinus symptoms include nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis and sinus pain, and multiple allergies and seasonal allergies

c Abdominal pain includes abdominal tenderness and discomfort

d Musculoskeletal pain includes musculoskeletal discomfort and myalgia

e Arthralgia includes joint stiffness and swelling

Long-term Studies

Long-term safety of Rheonex-MF (Tranexamic Acid) tablets was studied in two open-label studies. In one study, subjects with physician-diagnosed heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse events. Women using hormonal contraception were excluded from the study. The total exposure in this study to 3900 mg/day Rheonex-MF (Tranexamic Acid) tablets was 10,213 cycles. The average duration of Rheonex-MF (Tranexamic Acid) tablets use was 2.9 days per cycle.

A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study through 9 menstrual cycles. A total of 2.1% of the subjects withdrew due to adverse events. The total exposure to 3900 mg/day Rheonex-MF (Tranexamic Acid) tablets in this study was 1,956 cycles. The average duration of Rheonex-MF (Tranexamic Acid) tablets use was 3.5 days per cycle.

The types and severity of adverse events in these two long-term open-label trials were similar to those observed in the double-blind, placebo-controlled studies although the percentage of subjects reporting them was greater in the 27-month study, most likely because of the longer study duration.

A case of severe allergic reaction to Rheonex-MF (Tranexamic Acid) tablets was reported in the extension trial, involving a subject on her fourth cycle of treatment, who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified from postmarketing experience with Rheonex-MF (Tranexamic Acid). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Based on US and worldwide postmarketing reports, the following have been reported in patients receiving Rheonex-MF (Tranexamic Acid) for various

Indications:

  • Nausea, vomiting, and diarrhea
  • Allergic skin reactions
  • Anaphylactic shock and anaphylactoid reactions
  • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction); cases have been associated with concomitant use of combination hormonal contraceptives
  • Impaired color vision and other visual disturbances
  • Dizziness

7 DRUG INTERACTIONS

No drug-drug interaction studies were conducted with Rheonex-MF tablets.

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both Rheonex-MF (Tranexamic Acid) tablets and tissue plasminogen activators. (7.2)

7.1 Hormonal Contraceptives

Because Rheonex-MF (Tranexamic Acid) tablets are antifibrinolytic, concomitant use of hormonal contraception and Rheonex-MF (Tranexamic Acid) tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. For this reason, concomitant use of Rheonex-MF (Tranexamic Acid) tablets with combination hormonal contraceptives is contraindicated [see Contraindications (4) and Warnings and Precautions ( 5.1 )].

7.2 Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both Rheonex-MF tablets and tissue plasminogen activators. Therefore, exercise caution if a woman taking Rheonex-MF (Tranexamic Acid) tablets therapy requires tissue plasminogen activators.

7.3 Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

Rheonex-MF (Tranexamic Acid) tablets are not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

7.4 All-Trans Retinoic Acid

Exercise caution when prescribing Rheonex-MF (Tranexamic Acid) tablets to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS

  • Geriatric Use: Rheonex-MF tablets are not indicated for use in postmenopausal women (8.5)
  • Renal impairment: Dosage adjustment is needed. (2.2, 8.6)

  • Hepatic impairment: No dosage adjustment is needed. (8.7)

8.1 Pregnancy(CategoryB)

Rheonex-MF (Tranexamic Acid) tablets are not indicated for use in pregnant women. Reproduction studies have been performed in mice, rats and rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to Rheonex-MF (Tranexamic Acid). However, Rheonex-MF (Tranexamic Acid) is known to cross the placenta and appears in cord blood at concentrations approximately equal to the maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Nonclinical Toxicology ( 13.1 )].

An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were conducted using Rheonex-MF (Tranexamic Acid). No adverse effects were observed in either study at doses up to 4 times the recommended human oral dose of 3900 mg/day based on mg/m2 (actual animal dose 1500 mg/kg/day).

8.3 Nursing Mothers

Rheonex-MF is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration. Rheonex-MF (Tranexamic Acid) tablets should be used during lactation only if clearly needed.

8.4 Pediatric Use

Rheonex-MF (Tranexamic Acid) tablets are indicated for women of reproductive age and are not intended for use in premenarcheal girls. Based on a pharmacokinetic study in 20 adolescent females, 12 to 16 years of age, no dose adjustment is needed in the adolescent population [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Rheonex-MF tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Rheonex-MF (Tranexamic Acid) tablets has not been studied. Because Rheonex-MF (Tranexamic Acid) is primarily eliminated via the kidneys by glomerular filtration with more than 95% excreted as unchanged in urine, dosage adjustment in patient with renal impairment is needed [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Rheonex-MF (Tranexamic Acid) tablets has not been studied. Because only a small fraction of the drug is metabolized, dosage adjustment in patients with hepatic impairment is not needed [see Clinical Pharmacology ( 12.3 )].

10 OVERDOSAGE

There are no known cases of intentional overdose with Rheonex-MF (Tranexamic Acid) tablets and no subjects in the clinical program took more than 2 times the prescribed amount of Rheonex-MF (Tranexamic Acid) tablets in a 24-hour period (>7800 mg/day). However, cases of overdose of Rheonex-MF (Tranexamic Acid) have been reported. Based on these reports, symptoms of overdose may include gastrointestinal (nausea, vomiting, diarrhea); hypotensive (e.g., orthostatic symptoms); thromboembolic (arterial, venous, embolic); visual impairment; mental status changes; myoclonus; or rash. No specific information is available on the treatment of overdose with Rheonex-MF (Tranexamic Acid) tablets. In the event of overdose, employ the usual supportive measures (e.g., clinical monitoring and supportive therapy) as dictated by the patient's clinical status.

11 DESCRIPTION

Rheonex-MF (Tranexamic Acid) tablets are an antifibrinolytic drug. The chemical name is trans-4-aminomethyl-cyclohexanecarboxylic acid. The structural formula is:

Rheonex-MF (Tranexamic Acid) is a white crystalline powder. It is freely soluble in water and in glacial acetic acid and is very slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C8H15N02 and the molecular weight is 157.2.

Rheonex-MF (Tranexamic Acid) tablets are provided as white to off-white, oval-shaped, film coated tablets, debossed with “WPI 3720” on one side of the tablet. The active ingredient in each tablet is 650 mg Rheonex-MF (Tranexamic Acid). The inactive ingredients contained in each tablet are: colloidal silicon dioxide, copovidone, crospovidone, eudragit, glyceryl behenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and triethyl citrate.

Structural Formula for Rheonex-MF (Tranexamic Acid)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rheonex-MF is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of Rheonex-MF (Tranexamic Acid), the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure.

The antifibrinolytic effects of Rheonex-MF (Tranexamic Acid) are mediated by reversible interactions at multiple binding sites within plasminogen. Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for Rheonex-MF (Tranexamic Acid) (Kd = 750 µmol/L) and 1 with high affinity (Kd = 1.1 µmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with Rheonex-MF (Tranexamic Acid) displaces plasminogen from the surface of fibrin. Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

12.2 Pharmacodynamics

Rheonex-MF (Tranexamic Acid), at in vitro concentrations of 25 to 100 M, reduces by 20 to 60% the maximal rate of plasmin lysis of fibrin catalyzed by tissue plasminogen activator (tPA).

Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of Rheonex-MF (Tranexamic Acid) on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving Rheonex-MF (Tranexamic Acid) total oral doses of 2 to 3 g/day for 5 days.

In healthy subjects, Rheonex-MF (Tranexamic Acid) at blood concentrations less than 10 mg/mL has no effect on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood. Rheonex-MF (Tranexamic Acid), however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time.

Cardiac Electrophysiology

The effect of Rheonex-MF (Tranexamic Acid) tablets on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 healthy females aged 18 to 49 years. Subjects received (1) Rheonex-MF (Tranexamic Acid) tablets 1300 mg (two 650 mg tablets), (2) Rheonex-MF (Tranexamic Acid) tablets 3900 mg (six 650 mg tablets; three times the recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo. There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration of either dose of Rheonex-MF (Tranexamic Acid) tablets. Moxifloxacin, the active control, was associated with a maximum 14.11 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

12.3 Pharmacokinetics

Absorption

After a single oral administration of two 650 mg tablets of Rheonex-MF tablets, the peak plasma concentration (Cmax) occurred at approximately 3 hours (Tmax). The absolute bioavailability of Rheonex-MF (Tranexamic Acid) tablets in women aged 18 to 49 is approximately 45%. Following multiple oral doses (two 650 mg tablets three times daily) administration of Rheonex-MF (Tranexamic Acid) tablets for 5 days, the mean Cmax increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (two 650 mg tablets). Plasma concentrations reached steady state at the 5th dose of Rheonex-MF (Tranexamic Acid) tablets on Day 2.

The mean plasma pharmacokinetic parameters of Rheonex-MF (Tranexamic Acid) determined in 19 healthy women following a single (two 650 mg tablets) and multiple (two 650 mg tablets three times daily for 5 days) oral dose of Rheonex-MF (Tranexamic Acid) tablets are shown in Table 3.

Parameter Arithmetic Mean (CV%)
Single dose Multiple dose
Cmax (mcg/mL) 13.83 (32.14) 16.41 (26.19)
AUCtldc (mcg-h/mL) 77.96 (31.14) 77.67 a (29.39)
AUCinf (mcg-h/mL) 80.19 (30.43) -
Tmax (h)b 2.5 (1 to 5) 2.5 (2 to 3.5)
t1/2 (h) 11.08 (16.94) -

Cmax = maximum concentration

AUCtldc = area under the drug concentration curve from time 0 to time of last determinable concentration

AUCinf = area under the drug concentration curve from time 0 to infinity

Tmax = time to maximum concentration

t1/2 = terminal elimination half-life

a AUC0-tau (mcg-h/mL) = area under the drug concentration curve from time 0 to 8 hours

b Data presented as median (range)

Effect of food: Rheonex-MF (Tranexamic Acid) tablets may be administered without regard to meals. A single dose administration (two 650 mg tablets) of Rheonex-MF (Tranexamic Acid) tablets with food increased both Cmax and AUC by 7% and 16%, respectively.

Distribution

Rheonex-MF (Tranexamic Acid) is 3% bound to plasma proteins with no apparent binding to albumin. Rheonex-MF (Tranexamic Acid) is distributed with an initial volume of distribution of 0.18 L/kg and steady-state apparent volume of distribution of 0.39 L/kg.

Rheonex-MF (Tranexamic Acid) crosses the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.

Rheonex-MF (Tranexamic Acid) concentration in cerebrospinal fluid is about one tenth of the plasma concentration.

The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of plasma concentrations.

Metabolism

A small fraction of the Rheonex-MF (Tranexamic Acid) is metabolized.

Excretion

Rheonex-MF (Tranexamic Acid) is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of Rheonex-MF (Tranexamic Acid) is about 90% at 24 hours after intravenous administration of 10 mg/kg. Most elimination post intravenous administration occurred during the first 10 hours, giving an apparent elimination half-life of approximately 2 hours. The mean terminal half-life of Rheonex-MF (Tranexamic Acid) tablets is approximately 11 hours. Plasma clearance of Rheonex-MF (Tranexamic Acid) is 110 to 116 mL/min.

Specific Populations

Pregnancy (Category B)

Rheonex-MF (Tranexamic Acid) tablets are not indicated for use in pregnant women. Rheonex-MF (Tranexamic Acid) is known to cross the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Use in Specific Populations ( 8.1 )].

Nursing Mothers

Rheonex-MF (Tranexamic Acid) is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentrations. Rheonex-MF (Tranexamic Acid) tablets should be used during lactation only if clearly needed [see Use in Specific Populations ( 8.3 )].

Pediatric Use

Rheonex-MF (Tranexamic Acid) tablets are indicated for women of reproductive age and are not intended for use in premenarcheal girls. In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg [two 650 mg tablets]), pharmacokinetics of Rheonex-MF (Tranexamic Acid) was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The Cmax and AUC values after a single oral dose of 650 mg in the adolescent females were 32 to 36% less than those after a single oral dose of 1,300 mg in the adolescent females. The Cmax and AUC values after a single oral dose of 1300 mg in the adolescent females were 20 to 25% less than those in the adult females given the same dose in a separate study. [See Use in Specific Populations (8.4)]

Geriatric Use

Rheonex-MF (Tranexamic Acid) tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

Renal Impairment

The effect of renal impairment on the disposition of Rheonex-MF (Tranexamic Acid) tablets has not been evaluated. Urinary excretion following a single intravenous injection of Rheonex-MF (Tranexamic Acid) declines as renal function decreases. Following a single 10 mg/kg intravenous injection of Rheonex-MF (Tranexamic Acid) in 28 patients, the 24-hour urinary fractions of Rheonex-MF (Tranexamic Acid) with serum creatinine concentrations 1.4 to 2.8, 2.8 to 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, respectively. The 24-hour Rheonex-MF (Tranexamic Acid) plasma concentrations for these patients demonstrated a direct relationship to the degree of renal impairment. Therefore, dose adjustment is needed in patients with renal impairment [see Dosage and Administration (2.2)].

Hepatic Impairment

The effect of hepatic impairment on the disposition of Rheonex-MF (Tranexamic Acid) tablets has not been evaluated. One percent and 0.5 percent of an oral dose are excreted as a dicarboxylic acid and acetylated metabolite, respectively. Because only a small fraction of the drug is metabolized, no dose adjustment is needed in patients with hepatic impairment.

Drug Interactions

No drug-drug interaction studies were conducted with Rheonex-MF (Tranexamic Acid) tablets.

Hormonal Contraceptives

Because Rheonex-MF (Tranexamic Acid) tablets are antifibrinolytic, concomitant use of hormonal contraception and Rheonex-MF (Tranexamic Acid) tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. For this reason, concomitant use of Rheonex-MF (Tranexamic Acid) tablets with combination hormonal contraceptives is contraindicated [see Contraindications (4) , Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )].

Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates

Rheonex-MF (Tranexamic Acid) tablets are not recommended in patients taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.3 ) ].

Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both Rheonex-MF (Tranexamic Acid) tablets and tissue plasminogen activators. Therefore, exercise caution if a patient taking Rheonex-MF (Tranexamic Acid) tablets therapy requires tissue plasminogen activators [see Drug Interactions ( 7.2 ) ].

All-Trans Retinoic Acid (Oral Tretinoin)

In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered all-trans retinoic acid plus intravenously administered Rheonex-MF (Tranexamic Acid), all-trans retinoic acid plus chemotherapy, or all-trans retinoic acid plus Rheonex-MF (Tranexamic Acid) plus chemotherapy, all 4 patients who were given all-trans retinoic acid plus Rheonex-MF (Tranexamic Acid) died, with 3 of the 4 deaths due to thrombotic complications. It appears that the procoagulant effect of all-trans retinoic acid may be exacerbated by concomitant use of Rheonex-MF (Tranexamic Acid). Therefore, exercise caution when prescribing Rheonex-MF (Tranexamic Acid) tablets to patients with acute promyelocytic leukemia taking all-trans retinoic acid [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.4 )].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies with Rheonex-MF in male mice at doses as high as 6 times the recommended human dose of 3900 mg/day showed an increased incidence of leukemia which may have been related to treatment. Female mice were not included in this experiment.

The dose multiple referenced above is based on body surface area (mg/m2). Actual daily dose in mice was up to 5000 mg/kg/day in food.

Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver.

Mutagenesis

Rheonex-MF (Tranexamic Acid) was neither mutagenic nor clastogenic in the in vitro Bacterial Reverse Mutation Assay (Ames test), in vitro chromosome aberration test in Chinese hamster cells, and in in vivo chromosome aberration tests in mice and rats.

Impairment of Fertility

Reproductive studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to Rheonex-MF (Tranexamic Acid).

In a rat embryo-fetal developmental toxicity study, Rheonex-MF (Tranexamic Acid) had no adverse effects on embryo-fetal development when administered during the period of organogenesis (from gestation days 6 through 17) at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. In a perinatal-postnatal study in rats, Rheonex-MF (Tranexamic Acid) had no adverse effects on pup viability, growth or development when administered from gestation day 6 through postnatal day 20 at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day.

The dose multiples referenced above are based on body surface area (mg/m2). Actual daily doses in rats were 300, 750 or 1500 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology

Ocular Effects

In a 9-month toxicology study, dogs were administered Rheonex-MF (Tranexamic Acid) in food at doses of 0, 200, 600, or 1200 mg/kg/day. These doses are approximately 2, 5, and 6 times, respectively, the recommended human oral dose of 3900 mg/day based on AUC. At 6 times the human dose, some dogs developed reversible reddening and gelatinous discharge from the eyes. Ophthalmologic examination revealed reversible changes in the nictitating membrane/conjunctiva. In some female dogs, the presence of inflammatory exudate over the bulbar conjunctival mucosa was observed. Histopathological examinations did not reveal any retinal alteration. No adverse effects were observed at 5 times the human dose.

In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats following oral or intravenous Rheonex-MF (Tranexamic Acid) doses at 6 to 40 times the recommended usual human dose based on mg/m2 (actual animal doses between 250 to 1600 mg/kg/day).

14 CLINICAL STUDIES

The efficacy and safety of Rheonex-MF tablets in the treatment of heavy menstrual bleeding (HMB) was demonstrated in one 3-cycle treatment and one 6-cycle treatment, randomized, double-blind, placebo-controlled study [see Adverse Reactions ( 6 .1 )]. In these studies, HMB was defined as an average menstrual blood loss of ≥ 80 mL as assessed by alkaline hematin analysis of collected sanitary products over two baseline menstrual cycles. Subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21 to 35 days, and a BMI of approximately 32 kg/m2. On average, subjects had an HMB history of approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were Caucasian, 25% were Black, and 5% were Asian, Native American, Pacific Islander, or Other. Seven percent (7%) of all subjects were of Hispanic origin.

In these studies, the primary outcome measure was menstrual blood loss (MBL), measured using the alkaline hematin method. The endpoint was change from baseline in MBL, calculated by subtracting the mean MBL during treatment from the mean pretreatment MBL.

The key secondary outcome measures were based on specific questions concerning limitations in social or leisure activities (LSLA) and limitations in physical activities (LPA). Large stains (soiling beyond the undergarment) were also included as a key secondary outcome measure.

14.1 Three-Cycle Treatment Study

This study compared the effects of two doses of Rheonex-MF (Tranexamic Acid) tablets (1950 mg and 3900 mg given daily for up to 5 days during each menstrual period) versus placebo on MBL over a 3-cycle treatment duration. Of the 294 evaluable subjects, 115 Rheonex-MF (Tranexamic Acid) tablets 1950 mg/day subjects, 112 Rheonex-MF (Tranexamic Acid) tablets 3900 mg/day subjects and 67 placebo subjects took at least one dose of study drug and had post-treatment data available.

Results are shown in Table 4. MBL was statistically significantly reduced in patients treated with 3900 mg/day Rheonex-MF (Tranexamic Acid) tablets compared to placebo. Study success also required achieving a reduction in MBL that was determined to be clinically meaningful to the subjects. The 1950 mg/day Rheonex-MF (Tranexamic Acid) tablets dose did not meet the criteria for success.

Treatment Arm N Baseline Mean

MBL (mL)

Least

Squares Mean

Reduction

in MBL (mL)

Percent

Reduction

in MBL

Rheonex-MF (Tranexamic Acid)

tablets 3900

mg/day

112 169 65* 39%
Rheonex-MF (Tranexamic Acid)

tablets 1950

mg/day

115 178 44 25%
Placebo 67 154 7 5%

* p<0.001 versus placebo

Rheonex-MF (Tranexamic Acid) tablets also statistically significantly reduced limitations on social, leisure, and physical activities in the 3900 mg/day dose group compared to placebo (see Table 5). No statistically significant treatment difference was observed in response rates on the number of large stains.

Outcome Measure N Baseline

Mean a

Least

Squares Mean

Reduction b

Social and Leisure Activities
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

112 3.00 0.98c
Placebo 66 2.85 0.39
Physical Activities
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

112 3.07 0.94c
Placebo 66 2.96 0.34
N Responders d
Reduction in Large Stains
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

111 64%e
Placebo 67 52%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline.

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains.

e Non-significant difference versus placebo

14.2 Six-Cycle Treatment Study

This study compared the effects of Rheonex-MF tablets 3900 mg/day given daily for up to 5 days during each menstrual period versus placebo on MBL over a 6-cycle treatment duration. Of the 187 evaluable subjects, 115 Rheonex-MF (Tranexamic Acid) tablets subjects and 72 placebo subjects took at least one dose of study drug and had post-treatment data available.

Results are shown in Table 6. MBL was statistically significantly reduced in patients treated with 3900 mg/day Rheonex-MF (Tranexamic Acid) tablets compared to placebo. Study success also required achieving a reduction in MBL that was determined to be clinically meaningful to the subjects.

Treatment Arm N Baseline Mean

MBL (mL)

Least

Squares Mean

Reduction

in MBL (mL)

Percent

Reduction in

MBL

Rheonex-MF (Tranexamic Acid) tablets

3900 mg/day

115 172 66* 38%
Placebo 72 153 18 12%

* p<0.001 versus placebo

Limitations on social, leisure, and physical activities were also statistically significantly reduced in the Rheonex-MF (Tranexamic Acid) tablets group compared to placebo (see Table 7). No statistically significant treatment difference was observed in response rates on the number of large stains.

Outcome Measure N Baseline

Mean a

Least

Squares Mean

Reduction b

Social and Leisure Activities
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

115 2.92 0.85c
Placebo 72 2.74 0.44
Physical Activities
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

115 3.05 0.87c
Placebo 72 2.90 0.40
N Responders d
Reduction in Large Stains
3900 mg/day

Rheonex-MF (Tranexamic Acid) tablets

115 57%e
Placebo 72 51%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains

e Non-significant difference versus placebo

14.3 MBL Results over Time

The efficacy of Rheonex-MF (Tranexamic Acid) tablets 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated versus placebo in the double-blind, placebo-controlled efficacy studies (see Figure 1). The change in MBL from baseline was similar across all post-baseline treatment cycles.

Figure 1: MBL Levels over Duration of Therapy

Figure 1 - The efficacy of Rheonex-MF (Tranexamic Acid) tablets 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated versus placebo in the double-blind, placebo-controlled efficacy studies.

16 HOW SUPPLIED/STORAGE AND HANDLING

Rheonex-MF (Tranexamic Acid) tablets are provided as white to off-white, oval-shaped, film coated tablets. Each tablet is debossed with “WPI 3720” on one side of the tablet and are supplied as:


Quantity


Package Type


NDC Number


30 tablets


HDPE Bottle


0591-3720-30


1000 tablets


HDPE Bottle


0591-3720-10


Storage

Store at 20º to 25º C (68º to 77º F)..

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information)

Instruct patients that the usual schedule is to take two tablets with liquids, three times a day during menstruation. Patients should be instructed not to exceed 3 doses (6 tablets) in a 24-hour period or to take for more than 5 days in any menstrual cycle.

Inform patients that they should immediately stop Rheonex-MF (Tranexamic Acid) tablets if they notice any eye symptoms or change in their vision. Instruct them to report any such problems promptly to their physician and to follow-up with an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination of the retina.

Inform patients that they should stop Rheonex-MF (Tranexamic Acid) tablets and seek immediate medical attention if they notice symptoms of a severe allergic reaction (e.g., shortness of breath or throat tightening).

Instruct patients that common side effects of Rheonex-MF (Tranexamic Acid) tablets include headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia and fatigue.

Advise patients to contact their healthcare provider if their heavy menstrual bleeding symptoms persist or worsen.

Remind patients to read the Patient Labeling carefully.

PATIENT INFORMATION

Tranexamic (tran-eks-am-ik) acid tablets

Read the Patient Information that comes with Rheonex-MF (Tranexamic Acid) tablets before you start using the drug and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What are Rheonex-MF (Tranexamic Acid) tablets ?

Rheonex-MF (Tranexamic Acid) tablets are a prescription medicine used to treat your heavy monthly period (menstruation) when your bleeding gets in the way of social, leisure and physical activities. Rheonex-MF (Tranexamic Acid) tablets do not contain any hormones. On average, Rheonex-MF (Tranexamic Acid) tablets have been shown to lower the amount of blood lost during your monthly period by about one-third, but it is not meant to stop your period.

Rheonex-MF (Tranexamic Acid) tablets are taken only during your period and are not meant to treat pre-menstrual symptoms (symptoms that occur before your bleeding starts). Rheonex-MF (Tranexamic Acid) tablets do not affect your fertility and cannot be used as birth control. Rheonex-MF (Tranexamic Acid) tablets do not protect you against diseases that you may get if you have unprotected sex.

Rheonex-MF (Tranexamic Acid) tablets have not been studied in adolescents younger than 18 years of age.

Rheonex-MF (Tranexamic Acid) tablets are not for women who have already gone through menopause (post-menopausal).

Who should not take t ranexamic acid tablets ?

Do not take Rheonex-MF (Tranexamic Acid) tablets if you:

  • Are using a form of birth control that contains estrogen and a progestin (like a birth control pill, patch, or vaginal ring). Ask your healthcare provider before taking Rheonex-MF (Tranexamic Acid) tablets if you are not sure if your birth control method contains estrogen and a progestin.
  • Currently have a blood clot
  • Have ever had a blood clot
  • Have been told that you are at risk of having a blood clot
  • Are allergic to Rheonex-MF (Tranexamic Acid) tablets or Rheonex-MF (Tranexamic Acid)

What should I tell my healthcare provider before taking t ranexamic acid tablets ?

Before taking Rheonex-MF (Tranexamic Acid) tablets, tell your healthcare provider about all of your medical conditions, including whether:

  • You have ever had a blood clot or been told that you are at risk of having a blood clot
  • You are using a form of birth control that contains estrogen and a progestin (like a birth control pill, patch, or vaginal ring). Using hormonal birth control along with Rheonex-MF (Tranexamic Acid) tablets may increase your chance of having a serious blood clot, stroke, or heart attack. For this reason, do not use Rheonex-MF (Tranexamic Acid) tablets if you use a form of birth control that contains estrogen and a progestin.
  • You are pregnant or think you may be pregnant
  • You are breastfeeding or plan to breastfeed. Tranexamic acid can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Rheonex-MF (Tranexamic Acid) tablets.
  • The time between the start of your periods is less than 21 days or more than 35 days
  • You have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rheonex-MF (Tranexamic Acid) tablets and other medicines can affect each other, causing side effects. Rheonex-MF (Tranexamic Acid) tablets can affect the way other medicines work and other medicines can affect how Rheonex-MF (Tranexamic Acid) tablets work.

Especially tell your healthcare provider if you take:

  • Birth control pills or other hormonal birth control
  • Medicines used to help your blood form clots
  • Medicines used to break up blood clots
  • Any medicines to treat leukemia

Ask your healthcare provider if you are not sure if your medicine is one that is described above.

How should I take t ranexamic acid tablets ?

  • Take Rheonex-MF (Tranexamic Acid) tablets exactly as your healthcare provider tells you.
  • Do not take Rheonex-MF (Tranexamic Acid) tablets until your period has started.
  • Do not take Rheonex-MF (Tranexamic Acid) tablets for more than 5 days in a row.
  • Do not take Rheonex-MF (Tranexamic Acid) tablets when you do not have your period.
  • Once your period has started, take 2 tablets of Rheonex-MF (Tranexamic Acid) tablets three times per day (e.g., in the morning, afternoon, and evening).
  • Rheonex-MF (Tranexamic Acid) tablets should be swallowed whole and not chewed or broken apart.
  • Rheonex-MF (Tranexamic Acid) tablets may be taken with or without food.
  • Do not take more than 6 tablets of Rheonex-MF (Tranexamic Acid) tablets in a day. If you take more than 6 tablets, call your healthcare provider.
  • If you miss a dose, take it when you remember, and then take your next dose at least six hours later. Do not take more than two tablets at a time to make up for missed doses.
  • If Rheonex-MF (Tranexamic Acid) tablets do not help to lessen bleeding with your periods after 2 cycles or seems to stop working, talk to your healthcare provider.

What are the possible side effects of t ranexamic acid tablets ?

Rheonex-MF (Tranexamic Acid) tablets can cause serious side effects, including:

  • Blood clots. You may have a higher risk of having serious blood clots if you take Rheonex-MF (Tranexamic Acid) tablets with:
    • medicines used to help your blood form clots
    • some medicines used to treat leukemia
  • Eye changes. Stop taking Rheonex-MF (Tranexamic Acid) tablets and promptly report any eye problems you have while taking Rheonex-MF (Tranexamic Acid) tablets. Your doctor will refer you to an eye doctor who will examine your eyes.
  • Allergic reaction. If you have severe shortness of breath and your throat feels tight, stop taking Rheonex-MF (Tranexamic Acid) tablets and get medical care right away.

The most common side effects of Rheonex-MF (Tranexamic Acid) tablets include:

  • Headaches
  • Sinus and nasal problems
  • Back pain
  • Pain in your abdomen
  • Pain in your muscles or joints
  • Anemia
  • Fatigue

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of Rheonex-MF (Tranexamic Acid) tablets. For more information, ask your healthcare provider or pharmacist.

If you notice a change in your usual bleeding pattern that worries you, or your heavy bleeding continues, contact your healthcare provider right away. This may be a sign of a more serious condition .

Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Actavis at 1-800-272-5525.

How should I store t ranexamic acid tablets ?

Store Rheonex-MF (Tranexamic Acid) tablets at room temperature between 20º to 25º C (68º to 77º F).

Keep t ranexamic acid tablets and all medicines out of the reach of children.

General information about t ranexamic acid tablets

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information Leaflets. Do not use Rheonex-MF (Tranexamic Acid) tablets for a condition for which it was not prescribed. Do not give Rheonex-MF (Tranexamic Acid) tablets to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about Rheonex-MF (Tranexamic Acid) tablets. If you would like more information about Rheonex-MF (Tranexamic Acid) tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Rheonex-MF (Tranexamic Acid) tablets that is written for healthcare professionals. For more information, go to www.actavis.com or call 1-800-272-5525.

What are the ingredients of Rheonex-MF (Tranexamic Acid) tablets ?

Active ingredient: Rheonex-MF (Tranexamic Acid)

Inactive ingredients: colloidal silicon dioxide, copovidone, crospovidone, eudragit, glyceryl behenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and triethyl citrate.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: November 2014 197511-2

NDC 0591-3720-30


Rheonex-MF (Tranexamic Acid) Tablets 650 mg

PHARMACIST: PLEASE DISPENSE IN THIS CHILD-RESISTANT

CONTAINER WITH PATIENT INFORMATION LEAFLET PROVIDED.

Watson 30 Tablets Rx only

NDC 0591-3720-30 Rheonex-MF (Tranexamic Acid) Tablets 650 mg PHARMACIST: PLEASE DISPENSE IN THIS CHILD-RESISTANT CONTAINER WITH PATIENT INFORMATION LEAFLET PROVIDED. Watson 30 Tablets Rx only

Rheonex-MF pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Rheonex-MF available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Rheonex-MF destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Rheonex-MF Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Rheonex-MF pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


advertisement

References

  1. Dailymed."PONSTEL (MEFENAMIC ACID) CAPSULE [SHIONOGI INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."TRANEXAMIC ACID TABLET, FILM COATED [ACTAVIS PHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."TRANEXAMIC ACID: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Rheonex-MF?

Depending on the reaction of the Rheonex-MF after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Rheonex-MF not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Rheonex-MF addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

advertisement

Review

sDrugs.com conducted a study on Rheonex-MF, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Rheonex-MF consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reviews


There are no reviews yet. Be the first to write one!


Your name: 
Email: 
Spam protection:  < Type 21 here

The information was verified by Dr. Arunabha Ray, MD Pharmacology

© 2002 - 2019 "sDrugs.com". All Rights Reserved