DRUGS & SUPPLEMENTS

Emthexate

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Emthexate uses

Emthexate consists of Methotrexate, Methotrexate Sodium.

Methotrexate:


WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

Emthexate (Methotrexate) can cause the following severe or fatal adverse reactions.

Monitor closely and modify dose or discontinue Emthexate (Methotrexate) as appropriate.

  • Bone marrow suppression
  • Serious infections
  • Renal toxicity and increased toxicity with renal impairment
  • Gastrointestinal toxicity
  • Hepatic toxicity
  • Pulmonary toxicity
  • Hypersensitivity and dermatologic reactions
  • Emthexate (Methotrexate) can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of Emthexate (Methotrexate) and risks to the fetus when prescribing Emthexate (Methotrexate) to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with Emthexate (Methotrexate) .

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • Emthexate (Methotrexate) can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression (5.1), infection (5.2), renal (5.3), gastrointestinal (5.4), hepatic (5.5), pulmonary (5.6), hypersensitivity and dermatologic (5.7).
  • Emthexate (Methotrexate) can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of Emthexate (Methotrexate) and risks to the fetus when prescribing Emthexate (Methotrexate) to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with Emthexate (Methotrexate) (5.9, 8.1, 8.3).
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1 INDICATIONS AND USAGE

Emthexate is a folate analog metabolic inhibitor indicated for the:

  • Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen (1.1)
  • Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy (1.2)

1.1 Acute Lymphoblastic Leukemia

Emthexate (Methotrexate) is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

1.2 Polyarticular Juvenile Idiopathic Arthritis

Emthexate (Methotrexate) is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

2 DOSAGE AND ADMINISTRATION

  • Use another formulation of Emthexate for patients requiring dosing via routes of administration other than oral (2.1).
  • Measure with an accurate measuring device (2.1).

Recommended

Dosage:

  • ALL: 20 mg/m2 one time weekly (2.2)
  • pJIA: Starting dose of 10 mg/m2 one time weekly (2.3)

2.1 Important Administration Information

Emthexate (Methotrexate) is intended for oral use only. Use another formulation of Emthexate (Methotrexate) for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

It is important that Emthexate (Methotrexate) be measured with an accurate measuring device . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

2.2 Acute Lymphoblastic Leukemia

The recommended starting dose of Emthexate, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2 given one time weekly. After initiating Emthexate (Methotrexate), continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.

2.3 Polyarticular Juvenile Idiopathic Arthritis

The recommended starting dose of Emthexate (Methotrexate) is 10 mg/m2 given one time weekly.

Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week in pediatric patients, doses greater than 20 mg/m2/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if Emthexate (Methotrexate) is administered by an alternative route using another formulation.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Certain side effects such as mouth sores may be reduced by folate supplementation with Emthexate (Methotrexate) in pJIA.

2.4 Evaluations Prior to Starting Emthexate

Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with Emthexate (Methotrexate) [see Warnings and Precautions (5.1, 5.3, 5.5, 5.7, 5.14 )]. Exclude pregnancy in females of reproductive potential before starting Emthexate (Methotrexate) .

2.5 Handling Information

Emthexate (Methotrexate) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

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3 DOSAGE FORMS AND STRENGTHS

Emthexate (Methotrexate) is a clear yellow to orange oral solution that contains 2.5 mg of Emthexate (Methotrexate) per milliliter.

Oral solution: 2.5 mg/mL (3)

4 CONTRAINDICATIONS

Emthexate (Methotrexate) is contraindicated in the following:

  • Pregnancy in patients with non-malignant diseases. Emthexate (Methotrexate) can cause embryo-fetal toxicity and fetal death when administered during pregnancy .
  • Patients with severe hypersensitivity to Emthexate (Methotrexate) .
  • Pregnancy (patients with pJIA) (4)
  • Severe hypersensitivity to Emthexate (Methotrexate) (4)

5 WARNINGS AND PRECAUTIONS

  • Secondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue Emthexate before starting treatment for lymphoma (5.8).
  • Immunizations may be ineffective (5.10).
  • Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).

5.1 Bone Marrow Suppression

Emthexate (Methotrexate) suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.

Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue Emthexate (Methotrexate) as needed.

5.2 Serious Infections

Patients treated with Emthexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections.

Monitor patients for the signs and symptoms of infection during and after treatment with Emthexate (Methotrexate) and treat promptly. Consider dose modification or discontinuation of Emthexate (Methotrexate) in patients who develop serious infections .

5.3 Renal Toxicity and Increased Toxicity with Renal Impairment

Emthexate (Methotrexate) can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.

Consider administration of glucarpidase in patients with toxic plasma Emthexate (Methotrexate) concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function .

5.4 Gastrointestinal Toxicity

Emthexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.

Interrupt or discontinue Emthexate (Methotrexate) and institute appropriate supportive care as needed.

Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of Emthexate (Methotrexate) (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) .

5.5 Hepatic Toxicity

Emthexate (Methotrexate) can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of Emthexate (Methotrexate) in patients with chronic liver disease.

Assess liver function prior to initiating Emthexate (Methotrexate) and monitor liver function tests during treatment. Interrupt or discontinue Emthexate (Methotrexate) as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.

Other risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age.

5.6 Pulmonary Toxicity

Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue Emthexate as appropriate.

5.7 Hypersensitivity and Dermatologic Reactions

Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with Emthexate (Methotrexate). Discontinue Emthexate (Methotrexate) if severe dermatologic reactions occur.

Anaphylaxis can occur with Emthexate (Methotrexate). If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Emthexate (Methotrexate) and institute appropriate therapy. Emthexate (Methotrexate) is contraindicated for use in patients with a history of severe hypersensitivity.

Radiation dermatitis and sunburn may be “recalled” by the use of Emthexate (Methotrexate).

5.8 Secondary Malignancies

Secondary malignancies can occur at all dose levels of Emthexate.

There have been instances of lymphoproliferative disease associated with low-dose oral Emthexate (Methotrexate) which have regressed completely following withdrawal of Emthexate (Methotrexate) without institution of antineoplastic therapy. Discontinue Emthexate (Methotrexate) first and institute appropriate treatment if the lymphoma does not regress.

5.9 Embryo-Fetal Toxicity

Based on published reports and methotrexate’s mechanism of action, Emthexate (Methotrexate) can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, Emthexate (Methotrexate) is contraindicated. Consider the benefits and risks of Emthexate (Methotrexate) and risks to the fetus when prescribing Emthexate (Methotrexate) to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final Emthexate (Methotrexate) dose .

5.10 Ineffective Immunization and Risks Associated with Live Vaccines

Immunization may be ineffective when given during Emthexate therapy.

Immunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving Emthexate (Methotrexate) therapy.

5.11 Effects on Reproduction

Based on published reports, Emthexate (Methotrexate) can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients .

5.12 Increased Toxicity Due to ThirdSpace Accumulation

Emthexate can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Emthexate (Methotrexate) administration .

5.13 Soft Tissue and Bone Toxicity with Radiation Therapy

Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with Emthexate (Methotrexate).

5.14 Laboratory Tests

Closely monitor patients undergoing Emthexate therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1, 5.3, 5.5)].

Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated Emthexate (Methotrexate) blood levels (e.g., dehydration).

Liver Function Tests

Transient liver function test abnormalities are observed frequently after Emthexate (Methotrexate) administration and are usually not cause for modification of Emthexate (Methotrexate) therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation .

Pulmonary Function Tests

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available .

5.15 Risk of Improper Dosing

Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

Advise patients to measure Emthexate (Methotrexate) with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .

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6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Bone Marrow Suppression
  • Serious Infections
  • Renal Toxicity and Increased Toxicity with Renal Impairment
  • Gastrointestinal Toxicity
  • Hepatic Toxicity
  • Pulmonary Toxicity
  • Hypersensitivity and Dermatologic Reactions
  • Secondary Malignancies
  • Ineffective Immunization and Risks Associated with Live Vaccines
  • Infertility
  • Increased Toxicity Due to Third‑Space Accumulation
  • Soft Tissue and Bone Toxicity with Radiation Therapy

Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection (6).

To report SUSPECTED ADVERSE REACTIONS, contact Silvergate Pharmaceuticals at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase Emthexate (Methotrexate) toxicity.

Polyarticular Juvenile Idiopathic Arthritis

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of Emthexate (Methotrexate) (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.

6.2 Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of Emthexate (Methotrexate) are listed below by organ system.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphaden-opathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia

Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of Emthexate (Methotrexate).

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens‑Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.

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7 DRUG INTERACTIONS

  • Oral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly.
  • Hepatotoxins: May increase risk of hepatotoxicity. Monitor patients accordingly (7.1).
  • Probenecid: May increase Emthexate (Methotrexate) exposure. Consider alternative drugs (7.1).
  • Theophylline: May reduce theophylline clearance. Monitor theophylline levels (7.2).

7.1 Effect of Other Drugs on Emthexate (Methotrexate)

Oral Antibiotics

Penicillins may reduce the renal clearance of Emthexate (Methotrexate); increased serum concentrations of Emthexate (Methotrexate) with concomitant hematologic and gastrointestinal toxicity have been observed with Emthexate (Methotrexate). Monitor patients accordingly .

Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving Emthexate (Methotrexate). Monitor patients accordingly .

Hepatotoxins

The potential for increased hepatotoxicity when Emthexate (Methotrexate) is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving Emthexate (Methotrexate) with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.

Probenecid

Probenecid may reduce renal elimination of Emthexate (Methotrexate). Consider alternative drugs.

7.2 Effect of Emthexate on Other Drugs

Theophylline

Emthexate (Methotrexate) may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with Emthexate (Methotrexate).

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed.

8.1 Pregnancy

Risk Summary

Based on published reports and methotrexate’s mechanism of action, Emthexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman . In pregnant women with non-malignant disease, Emthexate (Methotrexate) is contraindicated. Consider the benefits and risks of Emthexate (Methotrexate) and risks to the fetus when prescribing Emthexate (Methotrexate) to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Published data from cases, literature reviews, and observational studies report that Emthexate (Methotrexate) exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Emthexate (Methotrexate) exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because Emthexate (Methotrexate) is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception Emthexate (Methotrexate) exposure.

A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking Emthexate (Methotrexate) less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to Emthexate (Methotrexate) was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to Emthexate (Methotrexate) after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to Emthexate (Methotrexate) after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

Risk Summary

Limited published literature report the presence of Emthexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of Emthexate (Methotrexate) on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from Emthexate (Methotrexate) in breastfed infants, advise women not to breastfeed during Emthexate (Methotrexate) therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Test for pregnancy prior to initiating therapy with Emthexate.

Contraception

Females

Emthexate (Methotrexate) can cause fetal harm when administered to a pregnant woman .

Advise females of reproductive potential to use effective contraception during and for 6 months after the final Emthexate (Methotrexate) dose.

Males

Emthexate (Methotrexate) can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final Emthexate (Methotrexate) dose.

Infertility

Females

Based on published reports of female infertility after therapy with Emthexate, advise females of reproductive potential that Emthexate (Methotrexate) can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after therapy with Emthexate (Methotrexate), advise males of reproductive potential that Emthexate (Methotrexate) can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

8.4 Pediatric Use

Safety and effectiveness of Emthexate (Methotrexate) in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) .

8.6 Renal Impairment

Emthexate elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue Emthexate (Methotrexate) administration .

8.7 Hepatic Impairment

The effect of hepatic impairment on Emthexate (Methotrexate) pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.

10 OVERDOSAGE

Manifestations

Fatal overdosage has occurred with Emthexate (Methotrexate). Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.

Management

Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of Emthexate (Methotrexate). Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum Emthexate (Methotrexate) concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum Emthexate (Methotrexate) concentrations may cause renal damage leading to acute renal failure.

Glucarpidase is indicated for the treatment of toxic Emthexate (Methotrexate) concentrations in patients with delayed Emthexate (Methotrexate) clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of Emthexate (Methotrexate) and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve Emthexate (Methotrexate) elimination. However, effective clearance of Emthexate (Methotrexate) has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION

Emthexate (Methotrexate) contains Emthexate (Methotrexate), a folate analog metabolic inhibitor.

Chemically Emthexate (Methotrexate) is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:

NDC 52652-2001-1

Emthexate (Methotrexate)

(methotrexate)

Oral Solution

2.5 mg/mL

For Oral Use Only

READY TO USE

120 mL

Silvergate

Pharmaceuticals Inc.

Rx Only

Each 1 mL contains 2.5 mg

Emthexate (Methotrexate) (equivalent to

2.74 mg Emthexate (Methotrexate) sodium).

Usual Dose:

See prescribing information.

Store refrigerated

2° - 8°C (36° - 46°F).

After dispensing, may be

stored at room temperature

15° - 30°C (59° - 86°F)

for 60 days.

KEEP THIS AND ALL

MEDICATIONS OUT OF THE

REACH OF CHILDREN

Manufactured for:

Silvergate Pharmaceuticals, Inc.

Greenwood Village, CO 80111

Lot:

EXp:

Methotrexate Sodium:


WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

Emthexate (Methotrexate Sodium) can cause the following severe or fatal adverse reactions.

Monitor closely and modify dose or discontinue Emthexate (Methotrexate Sodium) as appropriate.

  • Bone marrow suppression
  • Serious infections
  • Renal toxicity and increased toxicity with renal impairment
  • Gastrointestinal toxicity
  • Hepatic toxicity
  • Pulmonary toxicity
  • Hypersensitivity and dermatologic reactions
  • Emthexate (Methotrexate Sodium) can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of Emthexate (Methotrexate Sodium) and risks to the fetus when prescribing Emthexate (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with Emthexate (Methotrexate Sodium) .

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • Emthexate (Methotrexate Sodium) can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression (5.1), infection (5.2), renal (5.3), gastrointestinal (5.4), hepatic (5.5), pulmonary (5.6), hypersensitivity and dermatologic (5.7).
  • Emthexate (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of Emthexate (Methotrexate Sodium) and risks to the fetus when prescribing Emthexate (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with Emthexate (Methotrexate Sodium) (5.9, 8.1, 8.3).

1 INDICATIONS AND USAGE

Emthexate is a folate analog metabolic inhibitor indicated for the:

  • Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen (1.1)
  • Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy (1.2)

1.1 Acute Lymphoblastic Leukemia

Emthexate (Methotrexate Sodium) is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

1.2 Polyarticular Juvenile Idiopathic Arthritis

Emthexate (Methotrexate Sodium) is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

2 DOSAGE AND ADMINISTRATION

  • Use another formulation of Emthexate for patients requiring dosing via routes of administration other than oral (2.1).
  • Measure with an accurate measuring device (2.1).

Recommended

Dosage:

  • ALL: 20 mg/m2 one time weekly (2.2)
  • pJIA: Starting dose of 10 mg/m2 one time weekly (2.3)

2.1 Important Administration Information

Emthexate (Methotrexate Sodium) is intended for oral use only. Use another formulation of Emthexate (Methotrexate Sodium) for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

It is important that Emthexate (Methotrexate Sodium) be measured with an accurate measuring device . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

2.2 Acute Lymphoblastic Leukemia

The recommended starting dose of Emthexate, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2 given one time weekly. After initiating Emthexate (Methotrexate Sodium), continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.

2.3 Polyarticular Juvenile Idiopathic Arthritis

The recommended starting dose of Emthexate (Methotrexate Sodium) is 10 mg/m2 given one time weekly.

Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week in pediatric patients, doses greater than 20 mg/m2/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if Emthexate (Methotrexate Sodium) is administered by an alternative route using another formulation.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Certain side effects such as mouth sores may be reduced by folate supplementation with Emthexate (Methotrexate Sodium) in pJIA.

2.4 Evaluations Prior to Starting Emthexate

Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with Emthexate (Methotrexate Sodium) [see Warnings and Precautions (5.1, 5.3, 5.5, 5.7, 5.14 )]. Exclude pregnancy in females of reproductive potential before starting Emthexate (Methotrexate Sodium) .

2.5 Handling Information

Emthexate (Methotrexate Sodium) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

3 DOSAGE FORMS AND STRENGTHS

Emthexate (Methotrexate Sodium) is a clear yellow to orange oral solution that contains 2.5 mg of Emthexate (Methotrexate Sodium) per milliliter.

Oral solution: 2.5 mg/mL (3)

4 CONTRAINDICATIONS

Emthexate (Methotrexate Sodium) is contraindicated in the following:

  • Pregnancy in patients with non-malignant diseases. Emthexate (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death when administered during pregnancy .
  • Patients with severe hypersensitivity to Emthexate (Methotrexate Sodium) .
  • Pregnancy (patients with pJIA) (4)
  • Severe hypersensitivity to Emthexate (Methotrexate Sodium) (4)

5 WARNINGS AND PRECAUTIONS

  • Secondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue Emthexate before starting treatment for lymphoma (5.8).
  • Immunizations may be ineffective (5.10).
  • Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).

5.1 Bone Marrow Suppression

Emthexate (Methotrexate Sodium) suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.

Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue Emthexate (Methotrexate Sodium) as needed.

5.2 Serious Infections

Patients treated with Emthexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections.

Monitor patients for the signs and symptoms of infection during and after treatment with Emthexate (Methotrexate Sodium) and treat promptly. Consider dose modification or discontinuation of Emthexate (Methotrexate Sodium) in patients who develop serious infections .

5.3 Renal Toxicity and Increased Toxicity with Renal Impairment

Emthexate (Methotrexate Sodium) can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.

Consider administration of glucarpidase in patients with toxic plasma Emthexate (Methotrexate Sodium) concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function .

5.4 Gastrointestinal Toxicity

Emthexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.

Interrupt or discontinue Emthexate (Methotrexate Sodium) and institute appropriate supportive care as needed.

Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of Emthexate (Methotrexate Sodium) (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) .

5.5 Hepatic Toxicity

Emthexate (Methotrexate Sodium) can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of Emthexate (Methotrexate Sodium) in patients with chronic liver disease.

Assess liver function prior to initiating Emthexate (Methotrexate Sodium) and monitor liver function tests during treatment. Interrupt or discontinue Emthexate (Methotrexate Sodium) as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.

Other risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age.

5.6 Pulmonary Toxicity

Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue Emthexate as appropriate.

5.7 Hypersensitivity and Dermatologic Reactions

Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with Emthexate (Methotrexate Sodium). Discontinue Emthexate (Methotrexate Sodium) if severe dermatologic reactions occur.

Anaphylaxis can occur with Emthexate (Methotrexate Sodium). If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Emthexate (Methotrexate Sodium) and institute appropriate therapy. Emthexate (Methotrexate Sodium) is contraindicated for use in patients with a history of severe hypersensitivity.

Radiation dermatitis and sunburn may be “recalled” by the use of Emthexate (Methotrexate Sodium).

5.8 Secondary Malignancies

Secondary malignancies can occur at all dose levels of Emthexate.

There have been instances of lymphoproliferative disease associated with low-dose oral Emthexate (Methotrexate Sodium) which have regressed completely following withdrawal of Emthexate (Methotrexate Sodium) without institution of antineoplastic therapy. Discontinue Emthexate (Methotrexate Sodium) first and institute appropriate treatment if the lymphoma does not regress.

5.9 Embryo-Fetal Toxicity

Based on published reports and methotrexate’s mechanism of action, Emthexate (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, Emthexate (Methotrexate Sodium) is contraindicated. Consider the benefits and risks of Emthexate (Methotrexate Sodium) and risks to the fetus when prescribing Emthexate (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final Emthexate (Methotrexate Sodium) dose .

5.10 Ineffective Immunization and Risks Associated with Live Vaccines

Immunization may be ineffective when given during Emthexate therapy.

Immunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving Emthexate (Methotrexate Sodium) therapy.

5.11 Effects on Reproduction

Based on published reports, Emthexate (Methotrexate Sodium) can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients .

5.12 Increased Toxicity Due to ThirdSpace Accumulation

Emthexate can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Emthexate (Methotrexate Sodium) administration .

5.13 Soft Tissue and Bone Toxicity with Radiation Therapy

Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with Emthexate (Methotrexate Sodium).

5.14 Laboratory Tests

Closely monitor patients undergoing Emthexate therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1, 5.3, 5.5)].

Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated Emthexate (Methotrexate Sodium) blood levels (e.g., dehydration).

Liver Function Tests

Transient liver function test abnormalities are observed frequently after Emthexate (Methotrexate Sodium) administration and are usually not cause for modification of Emthexate (Methotrexate Sodium) therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation .

Pulmonary Function Tests

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available .

5.15 Risk of Improper Dosing

Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

Advise patients to measure Emthexate (Methotrexate Sodium) with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Bone Marrow Suppression
  • Serious Infections
  • Renal Toxicity and Increased Toxicity with Renal Impairment
  • Gastrointestinal Toxicity
  • Hepatic Toxicity
  • Pulmonary Toxicity
  • Hypersensitivity and Dermatologic Reactions
  • Secondary Malignancies
  • Ineffective Immunization and Risks Associated with Live Vaccines
  • Infertility
  • Increased Toxicity Due to Third‑Space Accumulation
  • Soft Tissue and Bone Toxicity with Radiation Therapy

Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection (6).

To report SUSPECTED ADVERSE REACTIONS, contact Silvergate Pharmaceuticals at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase Emthexate (Methotrexate Sodium) toxicity.

Polyarticular Juvenile Idiopathic Arthritis

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of Emthexate (Methotrexate Sodium) (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.

6.2 Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of Emthexate (Methotrexate Sodium) are listed below by organ system.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphaden-opathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia

Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of Emthexate (Methotrexate Sodium).

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens‑Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.

7 DRUG INTERACTIONS

  • Oral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly.
  • Hepatotoxins: May increase risk of hepatotoxicity. Monitor patients accordingly (7.1).
  • Probenecid: May increase Emthexate (Methotrexate Sodium) exposure. Consider alternative drugs (7.1).
  • Theophylline: May reduce theophylline clearance. Monitor theophylline levels (7.2).

7.1 Effect of Other Drugs on Emthexate (Methotrexate Sodium)

Oral Antibiotics

Penicillins may reduce the renal clearance of Emthexate (Methotrexate Sodium); increased serum concentrations of Emthexate (Methotrexate Sodium) with concomitant hematologic and gastrointestinal toxicity have been observed with Emthexate (Methotrexate Sodium). Monitor patients accordingly .

Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving Emthexate (Methotrexate Sodium). Monitor patients accordingly .

Hepatotoxins

The potential for increased hepatotoxicity when Emthexate (Methotrexate Sodium) is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving Emthexate (Methotrexate Sodium) with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.

Probenecid

Probenecid may reduce renal elimination of Emthexate (Methotrexate Sodium). Consider alternative drugs.

7.2 Effect of Emthexate on Other Drugs

Theophylline

Emthexate (Methotrexate Sodium) may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with Emthexate (Methotrexate Sodium).

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed.

8.1 Pregnancy

Risk Summary

Based on published reports and methotrexate’s mechanism of action, Emthexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman . In pregnant women with non-malignant disease, Emthexate (Methotrexate Sodium) is contraindicated. Consider the benefits and risks of Emthexate (Methotrexate Sodium) and risks to the fetus when prescribing Emthexate (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Published data from cases, literature reviews, and observational studies report that Emthexate (Methotrexate Sodium) exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Emthexate (Methotrexate Sodium) exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because Emthexate (Methotrexate Sodium) is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception Emthexate (Methotrexate Sodium) exposure.

A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking Emthexate (Methotrexate Sodium) less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to Emthexate (Methotrexate Sodium) was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to Emthexate (Methotrexate Sodium) after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to Emthexate (Methotrexate Sodium) after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

Risk Summary

Limited published literature report the presence of Emthexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of Emthexate (Methotrexate Sodium) on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from Emthexate (Methotrexate Sodium) in breastfed infants, advise women not to breastfeed during Emthexate (Methotrexate Sodium) therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Test for pregnancy prior to initiating therapy with Emthexate.

Contraception

Females

Emthexate (Methotrexate Sodium) can cause fetal harm when administered to a pregnant woman .

Advise females of reproductive potential to use effective contraception during and for 6 months after the final Emthexate (Methotrexate Sodium) dose.

Males

Emthexate (Methotrexate Sodium) can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final Emthexate (Methotrexate Sodium) dose.

Infertility

Females

Based on published reports of female infertility after therapy with Emthexate, advise females of reproductive potential that Emthexate (Methotrexate Sodium) can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after therapy with Emthexate (Methotrexate Sodium), advise males of reproductive potential that Emthexate (Methotrexate Sodium) can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

8.4 Pediatric Use

Safety and effectiveness of Emthexate (Methotrexate Sodium) in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) .

8.6 Renal Impairment

Emthexate elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue Emthexate (Methotrexate Sodium) administration .

8.7 Hepatic Impairment

The effect of hepatic impairment on Emthexate (Methotrexate Sodium) pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.

10 OVERDOSAGE

Manifestations

Fatal overdosage has occurred with Emthexate (Methotrexate Sodium). Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.

Management

Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of Emthexate (Methotrexate Sodium). Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum Emthexate (Methotrexate Sodium) concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum Emthexate (Methotrexate Sodium) concentrations may cause renal damage leading to acute renal failure.

Glucarpidase is indicated for the treatment of toxic Emthexate (Methotrexate Sodium) concentrations in patients with delayed Emthexate (Methotrexate Sodium) clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of Emthexate (Methotrexate Sodium) and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve Emthexate (Methotrexate Sodium) elimination. However, effective clearance of Emthexate (Methotrexate Sodium) has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION

Emthexate (Methotrexate Sodium) contains Emthexate (Methotrexate Sodium), a folate analog metabolic inhibitor.

Chemically Emthexate (Methotrexate Sodium) is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:

NDC 52652-2001-1

Emthexate (Methotrexate Sodium)

(methotrexate)

Oral Solution

2.5 mg/mL

For Oral Use Only

READY TO USE

120 mL

Silvergate

Pharmaceuticals Inc.

Rx Only

Each 1 mL contains 2.5 mg

Emthexate (Methotrexate Sodium) (equivalent to

2.74 mg Emthexate (Methotrexate Sodium) sodium).

Usual Dose:

See prescribing information.

Store refrigerated

2° - 8°C (36° - 46°F).

After dispensing, may be

stored at room temperature

15° - 30°C (59° - 86°F)

for 60 days.

KEEP THIS AND ALL

MEDICATIONS OUT OF THE

REACH OF CHILDREN

Manufactured for:

Silvergate Pharmaceuticals, Inc.

Greenwood Village, CO 80111

Lot:

EXp:

Emthexate 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.


Emthexate 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.


Emthexate 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.


Emthexate 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.


Emthexate 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.


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References

  1. Dailymed."METHOTREXATE (METHOTREXATE SODIUM) INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."XATMEP (METHOTREXATE) SOLUTION [SILVERGATE PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."METHOTREXATE SODIUM: 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 Emthexate?

Depending on the reaction of the Emthexate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Emthexate 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 Emthexate 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.

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Review

sDrugs.com conducted a study on Emthexate, 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 Emthexate 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

One visitor reported useful

How is the drug Emthexate useful in reducing or relieving the symptoms? How useful is it?
According to the survey conducted by the website sDrugs.com, there are variable results and below are the percentages of the users that say the medicine is useful to them and that say it is not helping them much. It is not ideal to continue taking the medication if you feel it is not helping you much. Contact your healthcare provider to check if there is a need to change the medicine or if there is a need to re-evaluate your condition. The usefulness of the medicine may vary from patient to patient, depending on the other diseases he is suffering from and slightly depends on the brand name.
Visitors%
Useful1
100.0%

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

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