ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oHypersensitivity Reactions [see Warnings and Precautions (5.2)]oMyelosuppression [see Warnings and Precautions (5.3)]oGastrointestinal Toxicity [see Warnings and Precautions (5.4)]oHepatotoxicity [see Warnings and Precautions (5.5)]oPulmonary Toxicity [see Warnings and Precautions (5.6)]oDermatologic Reactions [see Warnings and Precautions (5.7)]oRenal Toxicity [see Warnings and Precautions (5.8)]oSerious Infections [see Warnings and Precautions (5.11)]oNeurotoxicity [see Warnings and Precautions (5.12)]oSecondary Malignancies [see Warnings and Precautions (5.13)]oTumor Lysis Syndrome [see Warnings and Precautions (5.14)]oIncreased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)]. oHypersensitivity Reactions [see Warnings and Precautions (5.2)]. oMyelosuppression [see Warnings and Precautions (5.3)]. oGastrointestinal Toxicity [see Warnings and Precautions (5.4)]. oHepatotoxicity [see Warnings and Precautions (5.5)]. oPulmonary Toxicity [see Warnings and Precautions (5.6)]. oDermatologic Reactions [see Warnings and Precautions (5.7)]. oRenal Toxicity [see Warnings and Precautions (5.8)]. oSerious Infections [see Warnings and Precautions (5.11)]. oNeurotoxicity [see Warnings and Precautions (5.12)]. oSecondary Malignancies [see Warnings and Precautions (5.13)]. oTumor Lysis Syndrome [see Warnings and Precautions (5.14)]. oIncreased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)]. Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.. Rheumatoid Arthritis. The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n 128) with rheumatoid arthritis are listed below. Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received corticosteroids. Hepatic histology was not examined in these short-term studies.Incidence >= 10%: Elevated liver tests 15%, nausea/vomiting 10%Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count 100,000/mm3)Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count 3000/mm3), pancytopenia, dizzinessTwo other controlled trials of patients (n 680) with rheumatoid arthritis who received methotrexate 7.5 mg to 15 mg orally once weekly showed the following serious adverse reaction:Incidence 1%: Interstitial pneumonitisOther less common adverse reactions were: anemia, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge.. Polyarticular Juvenile Idiopathic Arthritis (pJIA). The most common adverse reactions reported in patients to 18 years of age with pJIA treated with methotrexate mg/m2 to 20 mg/m2 orally once weekly or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver tests 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea) 11%; stomatitis 2%; leukopenia 2%; headache 1.2%; alopecia 0.5%; dizziness 0.2%; rash 0.2%. Most patients received concomitant NSAIDs and some also received corticosteroids.. Psoriasis. In two published series of adults with psoriasis (n 204, 248) who received methotrexate up to 25 mg per week for up to years, adverse reaction rates were similar to those in patients with rheumatoid arthritis, except for alopecia, photosensitivity, and burning of skin lesions (3% to 10% each). Painful plaque erosions have been reported.. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden deathEndocrine: DiabetesEye: Optic neuropathy, blurred vision, ocular pain, conjunctivitis, xerophthalmiaGastrointestinal: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration Hematology: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia Hepatobiliary: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis Immune system: Anaphylaxis, anaphylactoid reactions, vasculitis Metabolism: HyperglycemiaMusculoskeletal: Stress fracture, soft tissue and bone necrosis, arthralgia, myalgia, osteoporosis Nervous system: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, and convulsions.Renal: Azotemia, hematuria, proteinuria, cystitisReproductive: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction Respiratory: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis.

BOXED WARNING SECTION.


WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS AND SEVERE ADVERSE REACTIONS oMethotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].oMethotrexate tablets are contraindicated in patients with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4), Warnings and Precautions (5.2)].oSerious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7, 5.8)].. oMethotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].. oMethotrexate tablets are contraindicated in patients with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4), Warnings and Precautions (5.2)].. oSerious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7, 5.8)].. WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, and SEVERE ADVERSE REACTIONS See full prescribing information for complete boxed warning.oMethotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to fetus and to use effective contraception (4, 5.1, 8.1, 8.3). oMethotrexate tablets are contraindicated in patients with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis (4, 5.2). oSerious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate (5.3, 5.4, 5.5, 5.6, 5.7, 5.8).. oMethotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to fetus and to use effective contraception (4, 5.1, 8.1, 8.3). oMethotrexate tablets are contraindicated in patients with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis (4, 5.2). oSerious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate (5.3, 5.4, 5.5, 5.6, 5.7, 5.8).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNULL synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.. 12.3 Pharmacokinetics Absorption. At doses of 30 mg/m2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized.. Effect of Food Food has been shown to delay absorption and reduce peak concentration.. Distribution. Methotrexate in serum is approximately 50% protein bound.Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.. Elimination. The elimination half-life of methotrexate is approximately to 10 hours.Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors.Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg.. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration.Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate.. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration.Biliary excretion accounts for <= 10% of the methotrexate dose.. Specific Populations. The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown.. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (Cmax 0.11 to 2.3 micromolar after 20 mg/m2 dose) was 20-fold. The time to peak concentration (Tmax 0.67 to hours after 15 mg/m2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m2 is significantly less than that of lower doses.In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m2/week to 11.2 mg/m2/week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at hour, 0.44 micromolar (0.01 to 1.00) at hours, and 0.29 micromolar (0.06 to 0.58) at hours.In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m2 to 30 mg/m2) or for JIA (3.75 mg/m2 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively.. Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Methotrexate tablets are contraindicated in:oPregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].oPatients with history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate [see Warnings and Precautions (5.2)].. oPregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].. oPatients with history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate [see Warnings and Precautions (5.2)].. oIn pregnancy for non-neoplastic diseases (4) oHistory of severe hypersensitivity to methotrexate (4). oIn pregnancy for non-neoplastic diseases (4) oHistory of severe hypersensitivity to methotrexate (4).

DESCRIPTION SECTION.


11 DESCRIPTION Methotrexate is dihydrofolate reductase inhibitor with the chemical name of N-[4-[[(2,4 diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L glutamic acid. The molecular formula is C20H22N8O5 and the molecular weight is 454.4 g/mol. The structural formula is:Methotrexate Tablets, USP for oral use are available in bottles of 100 tablets. Each methotrexate tablet contains 2.5 mg methotrexate equivalent to 2.74 mg methotrexate sodium and the following inactive ingredients: colloidal silicon dioxide, FD&C Red No. 40 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium carbonate (monohydrate), sodium lauryl sulfate and sodium starch glycolate (potato).. Methotrexate Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION oInstruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (2.1, 5.9) oVerify pregnancy status in females of reproductive potential before starting methotrexate tablets (4, 5.1). oALL: The recommended dosage is 20 mg/m2 orally once weekly as part of combination chemotherapy maintenance regimen. (2.2) oMycosis fungoides: The recommended dosage is 25 to 75 mg orally once weekly as monotherapy; 10 mg/m2 orally twice weekly as part of combination chemotherapy. (2.2) oRelapsed or refractory non-Hodgkin lymphoma: The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (2.2) oRheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response (2.3) opJIA: The recommended starting dosage is 10 mg/m2 orally once weekly; adjust dose to achieve an optimal response (2.4) oPsoriasis: The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved. (2.5) oInstruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (2.1, 5.9) oVerify pregnancy status in females of reproductive potential before starting methotrexate tablets (4, 5.1). oALL: The recommended dosage is 20 mg/m2 orally once weekly as part of combination chemotherapy maintenance regimen. (2.2) oMycosis fungoides: The recommended dosage is 25 to 75 mg orally once weekly as monotherapy; 10 mg/m2 orally twice weekly as part of combination chemotherapy. (2.2) oRelapsed or refractory non-Hodgkin lymphoma: The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (2.2) oRheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response (2.3) opJIA: The recommended starting dosage is 10 mg/m2 orally once weekly; adjust dose to achieve an optimal response (2.4) oPsoriasis: The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved. (2.5) 2.1Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets [see Contraindications (4), Warnings and Precautions (5.1)].Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9)].When switching the dosing regimen from oral administration to intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary.Do not administer to patients who are unable to swallow tablet.Methotrexate tablets are cytotoxic drug. Follow applicable special handling and disposal procedures.1 2.2Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia. The recommended starting dosage of methotrexate tablets is 20 mg/m2 orally once weekly, as part of combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at desirable level and for excessive myelosuppression.. Mycosis Fungoides. The recommended dosage of methotrexate tablets is 25 to 75 mg orally once weekly when administered as single agent or 10 mg/m2 orally twice weekly as part of combination chemotherapy regimen.. Relapsed or Refractory Non-Hodgkin Lymphomas. The recommended dosage of methotrexate tablets is 2.5 mg orally to times per week (maximum 10 mg per week) as part of metronomic combination chemotherapy regimen.. 2.3 Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of methotrexate tablets is 7.5 mg orally once weekly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between and weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)]. 2.4Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of methotrexate tablets is 10 mg/m2 orally once weekly with escalation to achieve optimal response. Dosages of more than 30 mg/m2 once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between and weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)]. 2.5 Recommended Dosage for Psoriasis The recommended dosage of methotrexate tablets is 10 to 25 mg orally once weekly until an adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed dose of 30 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen.Administer folic acid or folinic acid supplementation to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)].. 2.6Dosage Modifications for Adverse Reactions Discontinue methotrexate tablets for: oAnaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2)]oLymphoproliferative disease [see Warnings and Precautions (5.13)]Withhold, dose reduce or discontinue methotrexate tablets as appropriate for: oMyelosuppression [see Warnings and Precautions (5.3)]Withhold or discontinue methotrexate tablets as appropriate for: oSevere gastrointestinal toxicity [see Warnings and Precautions (5.4)]oHepatotoxicity [see Warnings and Precautions (5.5)]oPulmonary toxicity [see Warnings and Precautions (5.6)]oSevere dermatologic reactions [see Warnings and Precautions (5.7)]oSevere renal toxicity [see Warnings and Precautions (5.8)]oSerious infections [see Warnings and Precautions (5.11)]oNeurotoxicity [see Warnings and Precautions (5.12)]. oAnaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2)]. oLymphoproliferative disease [see Warnings and Precautions (5.13)]. oMyelosuppression [see Warnings and Precautions (5.3)]. oSevere gastrointestinal toxicity [see Warnings and Precautions (5.4)]. oHepatotoxicity [see Warnings and Precautions (5.5)]. oPulmonary toxicity [see Warnings and Precautions (5.6)]. oSevere dermatologic reactions [see Warnings and Precautions (5.7)]. oSevere renal toxicity [see Warnings and Precautions (5.8)]. oSerious infections [see Warnings and Precautions (5.11)]. oNeurotoxicity [see Warnings and Precautions (5.12)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Methotrexate Tablets, USP are available containing 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium. oThe 2.5 mg tablets are orange, round, scored tablets debossed with above the score and 14 below the score on one side of the tablet and blank on the other side of the tablet. oThe 2.5 mg tablets are orange, round, scored tablets debossed with above the score and 14 below the score on one side of the tablet and blank on the other side of the tablet. Tablets: 2.5 mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with methotrexate. (7) 7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure. Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with:oOral antibiotics (including neomycin)oOral or intravenous penicillin or sulfonamide antibioticsoHighly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines)oProbencidoAntifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides)oAspirin and other nonsteroidal anti-inflammatory drugsoHepatotoxic productsoProton pump inhibitorsoWeak acids (e.g., salicylates)oNephrotoxic products. oOral antibiotics (including neomycin). oOral or intravenous penicillin or sulfonamide antibiotics. oHighly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines). oProbencid. oAntifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides). oAspirin and other nonsteroidal anti-inflammatory drugs. oHepatotoxic products. oProton pump inhibitors. oWeak acids (e.g., salicylates). oNephrotoxic products. Nitrous Oxide. Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.. Folic Acid. Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.10)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1)]. Pregnancy Testing. Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate tablets [see Contraindications (4), Use in Specific Populations (8.1)]. Contraception. Females Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose.. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose.. Infertility. Females Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected females.. Males Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected males.

GERIATRIC USE SECTION.


8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Methotrexate Tablets, USP are available containing 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium. The 2.5 mg tablets are orange, round, scored tablets debossed with above the score and 14 below the score on one side of the tablet and blank on the other side of the tablet. They are available as follows: NDC 0378-0014-01bottles of 100 tabletsStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F). [See USP Controlled Room Temperature.]Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.Methotrexate tablets are cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Methotrexate tablets are dihydrofolate reductase inhibitor indicated for the: oTreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen (1.1) oTreatment of adults with mycosis fungoides (1.1) oTreatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of metronomic combination regimen (1.1) oTreatment of adults with rheumatoid arthritis (1.2) oTreatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) oTreatment of adults with severe psoriasis (1.4) oTreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen (1.1) oTreatment of adults with mycosis fungoides (1.1) oTreatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of metronomic combination regimen (1.1) oTreatment of adults with rheumatoid arthritis (1.2) oTreatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) oTreatment of adults with severe psoriasis (1.4) 1.1Neoplastic Diseases Methotrexate tablets are indicated for the:otreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen.otreatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as single agent or as part of combination chemotherapy regimen.otreatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of metronomic combination chemotherapy regimen.. otreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen.. otreatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as single agent or as part of combination chemotherapy regimen.. otreatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of metronomic combination chemotherapy regimen.. 1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.. 1.3Polyarticular Juvenile Idiopathic Arthritis Methotrexate tablets are indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).. 1.4 Psoriasis Methotrexate tablets are indicated for the treatment of adults with severe psoriasis.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Embryo-Fetal ToxicityoAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1)].oAdvise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose [see Use in Specific Populations (8.3)].oAdvise males of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose [see Use in Specific Populations (8.3)].Hypersensitivity Reactions: Advise patients and their caregivers of the potential risk of hypersensitivity and that methotrexate tablets are contraindicated in patients with history of hypersensitivity reactions to methotrexate. Instruct patients to seek immediate medical attention for signs of hypersensitivity reaction [see Warnings and Precautions (5.2)].Myelosuppression and Serious Infections: Inform patients and their caregivers that methotrexate tablets can cause myelosuppression and the need for frequent monitoring of blood cell counts. Advise patients and their caregivers to immediately report new onset fever, symptoms of infection, easy bruising or persistent bleeding to their healthcare provider [see Warnings and Precautions (5.3, 5.11)].Gastrointestinal Toxicity: Advise patients and their caregivers to report new or worsening diarrhea, vomiting, or stomatitis to their healthcare provider. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.4)].Hepatotoxicity: Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.5)].Pulmonary Toxicity: Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see Warnings and Precautions (5.6)].Dermatologic Reactions: Advise patients and their caregivers that methotrexate tablets can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients and their caregivers to avoid excessive sun exposure and use sun protection measures [see Warnings and Precautions (5.7)].Renal Toxicity: Advise patients and their caregivers to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.8)].Risk of Serious Adverse Reactions with Medication Error: For patients who are prescribed once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see Warnings and Precautions (5.9)].Neurotoxicity: Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions (5.12)].Secondary Malignancies: Advise patients on the risk of second primary malignancies during treatment with methotrexate tablets [see Warnings and Precautions (5.13)].Lactation: Instruct women not to breastfeed during treatment with methotrexate tablets and for week after the final dose [see Use in Specific Populations (8.2)].Infertility: Advise females and males of reproductive potential that methotrexate may impair fertility [see Warnings and Precautions (5.16), Use in Specific Populations (8.3)].Drug Interactions: Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].. oAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1)].. oAdvise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose [see Use in Specific Populations (8.3)].. oAdvise males of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose [see Use in Specific Populations (8.3)].

LACTATION SECTION.


8.2 Lactation Risk Summary. Limited published literature report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for week after the final dose.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNULL synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

OVERDOSAGE SECTION.


10 OVERDOSAGE Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.9)]. Manifestations: Manifestations of methotrexate overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported.Management: Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy. Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information.Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (> micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional dosage information.Administer concomitant hydration and urinary alkalinization.Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, methotrexate has been effectively cleared with acute, intermittent hemodialysis using high-flux dialyzer.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0378-0014-01MethotrexateTablets, USP2.5 mgEach tablet contains 2.5 mg methotrexate, USP equivalent to2.74 mg methotrexate sodium.Dispense in tight, light-resistant container as defined in the USPusing child-resistant closure.Keep container tightly closed.Keep this and all medication out of the reach of children. Store at 20C to 25C (68F to 77F); excursions permitted to15oC to 30oC (59oF to 86oF). [See USP Controlled Room Temperature.]Protect from light.Recommended Dosage: See accompanying prescribing information.Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Mylan.comRM0014A15. Methotrexate Tablets 2.5 mg Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use The safety and effectiveness of methotrexate tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1), Dosage and Administration (2)]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)]. The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1)].

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics Absorption. At doses of 30 mg/m2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized.. Effect of Food Food has been shown to delay absorption and reduce peak concentration.. Distribution. Methotrexate in serum is approximately 50% protein bound.Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.. Elimination. The elimination half-life of methotrexate is approximately to 10 hours.Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors.Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg.. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration.Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate.. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration.Biliary excretion accounts for <= 10% of the methotrexate dose.. Specific Populations. The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown.. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (Cmax 0.11 to 2.3 micromolar after 20 mg/m2 dose) was 20-fold. The time to peak concentration (Tmax 0.67 to hours after 15 mg/m2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m2 is significantly less than that of lower doses.In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m2/week to 11.2 mg/m2/week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at hour, 0.44 micromolar (0.01 to 1.00) at hours, and 0.29 micromolar (0.06 to 0.58) at hours.In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m2 to 30 mg/m2) or for JIA (3.75 mg/m2 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively.. Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk Summary. Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)], methotrexate can cause embryo-fetal toxicity and fetal death when administered to pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. 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 methotrexate is widely distributed and persists in the body for prolonged period, there is potential risk to the fetus from preconception methotrexate exposure.A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmune disease (17%; 95% CI: 13, 23). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI: 0.6, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

REFERENCES SECTION.


15 REFERENCES 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.. 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

RISKS.


Risk Summary. Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)], methotrexate can cause embryo-fetal toxicity and fetal death when administered to pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information Methotrexate Tablets, USP(meth oh trex ate) What is the most important information should know about methotrexate tablets Methotrexate tablets can cause serious side effects that may be severe and lead to death, including: Harm to an unborn baby, including birth defects or death of an unborn baby. Females who can become pregnant:oYour healthcare provider should do pregnancy test before you start taking methotrexate tablets to see if you are pregnant.oIf you are being treated for medical condition other than cancer, do not take methotrexate tablets if you are pregnant. See Who should not take methotrexate tabletsoIf you are taking methotrexate tablets to treat your cancer, you and your healthcare provider will decide if you will take methotrexate tablets if you are pregnant.oUse effective birth control (contraception) during treatment and for months after your final dose of methotrexate tablets. Ask your healthcare provider what forms of birth control you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with methotrexate tablets. Males with female partners who are able to become pregnant:oUse effective birth control during treatment and for months after your final dose of methotrexate tablets. Tell your healthcare provider right away if your female partner becomes pregnant during treatment with methotrexate tablets. Severe allergic reactions. Severe allergic reactions can happen with methotrexate tablets. Signs and symptoms of severe allergic reaction may include:oskin rash, itching and hivesoswelling of the face, lips, tongue, or throatodizzinessotrouble breathingowheezingofast heart rateofeeling faintostomach-area painovomiting or diarrheaDo not take methotrexate tablets if you have had severe allergic reaction to methotrexate in the past. Get medical help right away if you develop any of the signs or symptoms of severe allergic reaction listed above. Decreased blood cell counts. Methotrexate tablets can affect your bone marrow and cause decreases in red blood counts, white blood cell counts, and platelets that can be severe and life-threatening.oYour healthcare provider will check your blood cell counts when you start and during treatment with methotrexate tablets.Call your healthcare provider right away if you develop any of the following:oa new feverosymptoms of infectionoEasy bruising or bleeding that will not stop (persistent bleeding)Severe stomach and intestine problems (gastrointestinal) problems.oDiarrhea, vomiting, nausea, and mouth sores can happen in people who take methotrexate tablets.oInflammation of the intestine with severe bleeding and tear in the intestinal wall (perforation) have happened with methotrexate tablets and cause death.oPeople who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have greater risk of developing severe stomach or intestine problems with methotrexate tablets.Tell your healthcare provider if you develop new or worsening diarrhea, vomiting, or mouth sores during treatment with methotrexate tablets. Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools. Liver problems. Methotrexate tablets can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. oIn people with psoriasis who take methotrexate tablets, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases as with the amount of methotrexate tablets that you take over time. oYour healthcare provider will do tests to monitor your liver function before you start and during treatment with methotrexate tablets.Tell your healthcare provider if you have any signs or symptoms of liver problems during treatment with methotrexate tablets, including:otirednessoeasy bleeding or bruisingoloss of appetiteonauseaodifficulty thinking clearlyoswelling in your legs, feet or anklesoweight lossoitchy skinoyellowing of your skin or the white part of your eyesoweaknessLung problems. Lung problems can happen suddenly (acute) with methotrexate tablets or they can develop over long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death. Tell your healthcare provider if you have any new or worsening symptoms including: cough (especially dry cough), fever, or trouble breathing. Severe skin reactions. Severe skin reactions can happen with methotrexate tablets and can lead to death. oIn people with psoriasis: Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light. oMethotrexate tablets can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall dermatitis) and cause sunburn to come back (photodermatitis).Limit sunlight exposure during treatment with methotrexate tablets. Use sunscreen and wear protective clothing when you will be exposed to sunlight during treatment with methotrexate tablets. Tell your healthcare provider right away about any new or worsening skin rash during treatment with methotrexate tablets. Kidney problems. Kidney problems can happen with methotrexate tablets, including kidney failure which can happen suddenly (acute) and may not go away (irreversible). Your healthcare provider will check your kidney function before you start and during treatment with methotrexate tablets. Tell your healthcare provider right away if you have any signs or symptoms of kidney problems, including:oa big change (either increase or decrease) in the amount of urine you produceoswelling in your legs, ankles or feetoshortness of breathotirednessoweight gainSee What are the possible side effects of methotrexate tablets for more information about side effects.What are methotrexate tabletsMethotrexate tablets are prescription medicine used: oin combination with other chemotherapy medicines in adults and children, for maintenance treatment of acute lymphoblastic leukemia (ALL) oto treat adults with mycosis fungoides (cutaneous T-cell lymphoma) oin combination with other therapies to treat adults with non-Hodgkin lymphoma that has come back (relapsed) or did not respond to previous treatment (refractory) oto treat adults with rheumatoid arthritis oto treat children with polyarticular juvenile idiopathic arthritis (pJIA) oto treat adults with severe psoriasis It is not known if methotrexate tablets are safe and effective in treating children with any disease other than ALL as part of combination regimen used for maintenance therapy of their cancer, and for the treatment of pJIA. It is not known if methotrexate tablets are safe in people with liver problems.Do not take methotrexate tablets if you: oare pregnant and are being treated or will be treated with methotrexate tablets for rheumatoid arthritis, pJIA, or severe psoriasis or for any disease other than cancer). Methotrexate tablets can cause harm to an unborn baby, including birth defects or death of an unborn baby. See What is the most important information should know about methotrexate tablets ohave or had severe allergic reaction to methotrexate in the past. See What is the most important information should know about methotrexate tablets See the end of this leaflet for complete list of ingredients in methotrexate tablets.Before taking methotrexate tablets tell your healthcare provider about all of your medical conditions, including if you: ohave problems swallowing tablets ohave kidney problems or are receiving dialysis treatments ohave liver problems odrink alcohol-containing beverages and, during treatment with methotrexate tablets, if there are any changes in the amount of alcoholic beverages you drink ohave fluid in your stomach-area (ascites) ohave lung problems or fluid in your lungs (pleural effusion)oplan to have any surgeries with general anesthesia, including dental surgery ohave stomach ulcers (peptic ulcer disease) ohave ulcerative colitis ohave recently received or are scheduled to receive vaccine. You should not receive live vaccines during treatment with methotrexate tablets. oare breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for week after your last dose of methotrexate tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Methotrexate tablets and certain other medicines can affect each other and cause serious side effects. Do not start or change any medicines unless you have talked to your doctor and your doctor has told you it is safe. Know all the medicines that you take and keep list of them with you at all times to show doctors and pharmacists.How should take methotrexate tablets oTake methotrexate tablets exactly as prescribed by your healthcare provider. Your dose of methotrexate tablets and when you take them will depend on the condition that is being treated. oDo not take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to. oTaking more methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death. oIf you take too many methotrexate tablets call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive medicine as soon as possible to help reduce side effects that could be severe and could cause death. oIf you miss taking dose of methotrexate tablets, call your healthcare provider for instructions about when to take your next dose of methotrexate tablets. If you are taking methotrexate tablets for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis: oTake your methotrexate tablets dose time each week, not every day. Severe side effects and death have happened in people who mistakenly have taken methotrexate tablets every day instead of time each week. oTake folic acid or folinic acid supplement every day during treatment with methotrexate tablets, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores. If you are taking methotrexate tablets to treat your cancer: oFollow your healthcare providers instructions about how many methotrexate tablets to take and when to take them. oDo not take folic acid or folinic acid during treatment with methotrexate tablets unless your healthcare provider tells you to. Taking folic acid or folinic acid with methotrexate tablets may make your methotrexate tablet treatment less effective.What are the possible side effects of methotrexate tabletsMethotrexate tablets can cause serious side effects that may be severe and lead to death including: oSee What is the most important information should know about methotrexate tabletsoSerious infections. People who take methotrexate tablets have an increased risk of developing infections that can be life-threatening or cause death. These infections may include: bacterial, fungal, or viral infections, including Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis infection that comes back (reactivation), tuberculosis infection that may be new or reactivation, and Herpes zoster or cytomegalovirus (CMV) that spreads throughout the body (disseminated). Tell your healthcare provider right away if you develop new fever or if you have any symptoms of infection during treatment with methotrexate tablets. oBrain and spinal cord (nervous system) problems. Methotrexate tablets can cause nervous system problems that can be severe and last for short time or last for long time. These nervous system problems can get progressively worse, may not get better (irreversible), and can cause death. The risk for certain nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head (cranial radiation) in the past. Tell your healthcare provider about any new nervous system symptoms that you develop during treatment with methotrexate tablets. oSecondary cancers. Secondary (new) cancers can happen in people who take methotrexate tablets. oIn people with psoriasis, the risk of new skin cancers is increased with methotrexate tablets and further increased if you take the medicine cyclosporine after receiving treatment with methotrexate tablets. oCertain blood cancers can happen during treatment with methotrexate tablets. In some cases, these blood cancers may completely go away (regress completely) after methotrexate tablets are stopped. oTumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving methotrexate tablets as cancer treatment. oPossible fertility problems (infertility) in males and females. Methotrexate tablets can cause fertility problems in males and females, and can cause sperm production to stop in males, and menstrual problems in females. Males may not be able to father child. Females may not be able to become pregnant. It is not known if your fertility may return. Talk with your healthcare provider about your risk for infertility if this is concern for you.The most common side effects of methotrexate tablets include:omouth sores olow white blood cells. See What is the most important information should know about methotrexate tabletsonausea, upset stomach These are not all the side effects of methotrexate tablets Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.How should store methotrexate tablets oStore methotrexate tablets at 20 to 25C (68 to 77F). oKeep methotrexate tablets away from light. Keep methotrexate tablets and all medicines out of the reach of children.General information about the safe and effective use of methotrexate tablets. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use methotrexate tablets for condition for which they were not prescribed. Do not give methotrexate tablets to other people, even if they have the same symptoms that you have. They may harm them. This leaflet summarizes the most important information about methotrexate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about methotrexate tablets that is written for healthcare professionals.What are the ingredients in methotrexate tablets Active Ingredient: methotrexateInactive Ingredients: colloidal silicon dioxide, FD&C Red No. 40 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium carbonate (monohydrate), sodium lauryl sulfate and sodium starch glycolate (potato). Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.For additional information contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Patient Information has been approved by the U.S. Food and Drug Administration.Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 6/2021MTX:R21pt/PL:MTX:R4pt. oYour healthcare provider should do pregnancy test before you start taking methotrexate tablets to see if you are pregnant.oIf you are being treated for medical condition other than cancer, do not take methotrexate tablets if you are pregnant. See Who should not take methotrexate tabletsoIf you are taking methotrexate tablets to treat your cancer, you and your healthcare provider will decide if you will take methotrexate tablets if you are pregnant.oUse effective birth control (contraception) during treatment and for months after your final dose of methotrexate tablets. Ask your healthcare provider what forms of birth control you can use during this time.. oIf you are being treated for medical condition other than cancer, do not take methotrexate tablets if you are pregnant. See Who should not take methotrexate tablets. oIf you are taking methotrexate tablets to treat your cancer, you and your healthcare provider will decide if you will take methotrexate tablets if you are pregnant.. oUse effective birth control (contraception) during treatment and for months after your final dose of methotrexate tablets. Ask your healthcare provider what forms of birth control you can use during this time.. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with methotrexate tablets. oUse effective birth control during treatment and for months after your final dose of methotrexate tablets. Tell your healthcare provider right away if your female partner becomes pregnant during treatment with methotrexate tablets. . oskin rash, itching and hives. oswelling of the face, lips, tongue, or throat. odizziness. otrouble breathing. owheezing. ofast heart rate. ofeeling faint. ostomach-area pain. ovomiting or diarrhea. oYour healthcare provider will check your blood cell counts when you start and during treatment with methotrexate tablets.. oa new fever. osymptoms of infection. oEasy bruising or bleeding that will not stop (persistent bleeding). oDiarrhea, vomiting, nausea, and mouth sores can happen in people who take methotrexate tablets.. oInflammation of the intestine with severe bleeding and tear in the intestinal wall (perforation) have happened with methotrexate tablets and cause death.. oPeople who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have greater risk of developing severe stomach or intestine problems with methotrexate tablets.. oIn people with psoriasis who take methotrexate tablets, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases as with the amount of methotrexate tablets that you take over time. oYour healthcare provider will do tests to monitor your liver function before you start and during treatment with methotrexate tablets.. otiredness. oeasy bleeding or bruising. oloss of appetite. onausea. odifficulty thinking clearly. oswelling in your legs, feet or ankles. oweight loss. oitchy skin. oyellowing of your skin or the white part of your eyes. oweakness. oIn people with psoriasis: Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light. oMethotrexate tablets can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall dermatitis) and cause sunburn to come back (photodermatitis).. oa big change (either increase or decrease) in the amount of urine you produce. oswelling in your legs, ankles or feet. oshortness of breath. otiredness. oweight gain. oin combination with other chemotherapy medicines in adults and children, for maintenance treatment of acute lymphoblastic leukemia (ALL) oto treat adults with mycosis fungoides (cutaneous T-cell lymphoma) oin combination with other therapies to treat adults with non-Hodgkin lymphoma that has come back (relapsed) or did not respond to previous treatment (refractory) oto treat adults with rheumatoid arthritis oto treat children with polyarticular juvenile idiopathic arthritis (pJIA) oto treat adults with severe psoriasis oare pregnant and are being treated or will be treated with methotrexate tablets for rheumatoid arthritis, pJIA, or severe psoriasis or for any disease other than cancer). Methotrexate tablets can cause harm to an unborn baby, including birth defects or death of an unborn baby. See What is the most important information should know about methotrexate tablets ohave or had severe allergic reaction to methotrexate in the past. See What is the most important information should know about methotrexate tablets See the end of this leaflet for complete list of ingredients in methotrexate tablets.. ohave problems swallowing tablets ohave kidney problems or are receiving dialysis treatments ohave liver problems odrink alcohol-containing beverages and, during treatment with methotrexate tablets, if there are any changes in the amount of alcoholic beverages you drink ohave fluid in your stomach-area (ascites) ohave lung problems or fluid in your lungs (pleural effusion). oplan to have any surgeries with general anesthesia, including dental surgery ohave stomach ulcers (peptic ulcer disease) ohave ulcerative colitis ohave recently received or are scheduled to receive vaccine. You should not receive live vaccines during treatment with methotrexate tablets. oare breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for week after your last dose of methotrexate tablets.. oTake methotrexate tablets exactly as prescribed by your healthcare provider. Your dose of methotrexate tablets and when you take them will depend on the condition that is being treated. oDo not take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to. oTaking more methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death. oIf you take too many methotrexate tablets call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive medicine as soon as possible to help reduce side effects that could be severe and could cause death. oIf you miss taking dose of methotrexate tablets, call your healthcare provider for instructions about when to take your next dose of methotrexate tablets. oDo not take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to. oTaking more methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death. oIf you take too many methotrexate tablets call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive medicine as soon as possible to help reduce side effects that could be severe and could cause death. oIf you miss taking dose of methotrexate tablets, call your healthcare provider for instructions about when to take your next dose of methotrexate tablets. oTake your methotrexate tablets dose time each week, not every day. Severe side effects and death have happened in people who mistakenly have taken methotrexate tablets every day instead of time each week. oTake folic acid or folinic acid supplement every day during treatment with methotrexate tablets, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores. oFollow your healthcare providers instructions about how many methotrexate tablets to take and when to take them. oDo not take folic acid or folinic acid during treatment with methotrexate tablets unless your healthcare provider tells you to. Taking folic acid or folinic acid with methotrexate tablets may make your methotrexate tablet treatment less effective.. oSee What is the most important information should know about methotrexate tablets. oSerious infections. People who take methotrexate tablets have an increased risk of developing infections that can be life-threatening or cause death. These infections may include: bacterial, fungal, or viral infections, including Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis infection that comes back (reactivation), tuberculosis infection that may be new or reactivation, and Herpes zoster or cytomegalovirus (CMV) that spreads throughout the body (disseminated). Tell your healthcare provider right away if you develop new fever or if you have any symptoms of infection during treatment with methotrexate tablets. oBrain and spinal cord (nervous system) problems. Methotrexate tablets can cause nervous system problems that can be severe and last for short time or last for long time. These nervous system problems can get progressively worse, may not get better (irreversible), and can cause death. The risk for certain nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head (cranial radiation) in the past. Tell your healthcare provider about any new nervous system symptoms that you develop during treatment with methotrexate tablets. oSecondary cancers. Secondary (new) cancers can happen in people who take methotrexate tablets. oIn people with psoriasis, the risk of new skin cancers is increased with methotrexate tablets and further increased if you take the medicine cyclosporine after receiving treatment with methotrexate tablets. oCertain blood cancers can happen during treatment with methotrexate tablets. In some cases, these blood cancers may completely go away (regress completely) after methotrexate tablets are stopped. oIn people with psoriasis, the risk of new skin cancers is increased with methotrexate tablets and further increased if you take the medicine cyclosporine after receiving treatment with methotrexate tablets. oCertain blood cancers can happen during treatment with methotrexate tablets. In some cases, these blood cancers may completely go away (regress completely) after methotrexate tablets are stopped.. oTumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving methotrexate tablets as cancer treatment. oPossible fertility problems (infertility) in males and females. Methotrexate tablets can cause fertility problems in males and females, and can cause sperm production to stop in males, and menstrual problems in females. Males may not be able to father child. Females may not be able to become pregnant. It is not known if your fertility may return. Talk with your healthcare provider about your risk for infertility if this is concern for you.. omouth sores olow white blood cells. See What is the most important information should know about methotrexate tablets. onausea, upset stomach oStore methotrexate tablets at 20 to 25C (68 to 77F). oKeep methotrexate tablets away from light.

SPL UNCLASSIFIED SECTION.


1.1Neoplastic Diseases Methotrexate tablets are indicated for the:otreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen.otreatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as single agent or as part of combination chemotherapy regimen.otreatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of metronomic combination chemotherapy regimen.. otreatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of combination chemotherapy maintenance regimen.. otreatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as single agent or as part of combination chemotherapy regimen.. otreatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of metronomic combination chemotherapy regimen.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Lactation: Instruct not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary. Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)], methotrexate can cause embryo-fetal toxicity and fetal death when administered to pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. 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 methotrexate is widely distributed and persists in the body for prolonged period, there is potential risk to the fetus from preconception methotrexate exposure.A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmune disease (17%; 95% CI: 13, 23). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI: 0.6, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%). Major birth defects associated with pregnancies exposed to 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 methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for week after the final dose. 8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1)]. Pregnancy Testing. Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate tablets [see Contraindications (4), Use in Specific Populations (8.1)]. Contraception. Females Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose.. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose.. Infertility. Females Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected females.. Males Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use The safety and effectiveness of methotrexate tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1), Dosage and Administration (2)]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)]. The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1)]. 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.. 8.6 Renal Impairment Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk for methotrexate adverse reactions. Closely monitor patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, Cockcroft-Gault] for adverse reactions. Reduce the dosage or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.8)]. 8.7 Hepatic Impairment The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reactions based on the elimination characteristics of methotrexate [see Clinical Pharmacology (12.3)]. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.5) ].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oSerious Infections: Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections as appropriate. (5.11) oNeurotoxicity: Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets as appropriate. (5.12)oSecondary Malignancies: Can occur with methotrexate. (5.13) oTumor Lysis Syndrome: Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets. (5.14) oImmunizations and Risk Live Vaccines: Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. (5.15) oInfertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction. (5.16, 8.3) oSerious Infections: Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections as appropriate. (5.11) oNeurotoxicity: Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets as appropriate. (5.12). oSecondary Malignancies: Can occur with methotrexate. (5.13) oTumor Lysis Syndrome: Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets. (5.14) oImmunizations and Risk Live Vaccines: Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. (5.15) oInfertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction. (5.16, 8.3) 5.1 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate tablets can cause fetal harm, including fetal death, when administered to pregnant woman. Methotrexate tablets are contraindicated for use in pregnant women receiving methotrexate tablets for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for months after the final dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3)]. 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Contraindications (4), Adverse Reactions (6.1)].If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets [see Dosage and Administration (2.6)]. 5.3 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6.1)].Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.4 Gastrointestinal Toxicity Diarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported [see Adverse Reactions (6.1, 6.2)]. Patients with peptic ulcer disease or ulcerative colitis are at greater risk of developing severe gastrointestinal adverse reactions [see Drug Interactions (7.1)].Withhold or discontinue methotrexate tablets for severe gastrointestinal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.5Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6.1)]. The safety of methotrexate tablets in patients with hepatic disease is unknown.The risk of hepatotoxicity is increased with heavy alcohol consumption. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of total cumulative dose of 1.5 or more.Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.6Pulmonary Toxicity Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate [see Adverse Reactions (6.1, 6.2)].Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.7 Dermatologic Reactions Severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate [see Adverse Reactions (6.1, 6.2)].Exposure to ultraviolet radiation while taking methotrexate may aggravate psoriasis.Methotrexate can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.Monitor patients for dermatologic toxicity and withhold or permanently discontinue methotrexate tablets for severe dermatologic reactions taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. Advise patients to avoid excessive sun exposure and use sun protection measures.. 5.8 Renal Toxicity Methotrexate can cause renal toxicity, including irreversible acute renal failure [see Adverse Reactions (6.2)].Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets for severe renal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)].Administer glucarpidase in patients with toxic plasma methotrexate concentrations (> micromole per liter) and delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information.. 5.9 Risk of Serious Adverse Reactions with Medication Error Deaths occurred in patients as result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when weekly dosing regimen was prescribed.For patients prescribed once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death.. 5.10 Folic Acid Supplementation Neoplastic Diseases. Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Therefore, instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider.. Non-neoplastic Diseases. Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration (2.3, 2.4, 2.5)]. 5.11 Serious Infections Patients treated with methotrexate 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 reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections [see Adverse Reactions (6.2)].Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.12 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see Adverse Reactions (6.2)]. The risk of leukoencephalopathy is increased in patients who received prior cranial radiation.Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6)]. 5.13 Secondary Malignancies Secondary malignancies can occur with methotrexate [see Adverse Reactions (6.2)]. The risk of cutaneous malignancies is further increased when cyclosporine is administered to patients with psoriasis who received prior methotrexate.In some cases, lymphoproliferative disease occurring during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue methotrexate tablets [see Dosage and Administration (2.6)]. 5.14 Tumor Lysis Syndrome Methotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets.. 5.15 Immunization and Risks Associated with Live Vaccines Disseminated infections following administration of live vaccines have been reported. Immunization with live vaccines is not recommended during treatment. Follow current vaccination practice guidelines for administration of immunizations in patients receiving methotrexate tablets.Update immunizations according to immunization guidelines prior to initiating methotrexate tablets. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines regarding immunosuppressive agents.. 5.16 Infertility Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible. Discuss the risk of infertility with females and males of reproductive potential [see Use in Specific Populations (8.3)]. 5.17 Increased Risk of Adverse Reactions Due to Third-Space Accumulation Methotrexate accumulates in third-spaces (e.g., pleural effusions or ascites), which results in prolonged elimination and increases the risk of adverse reactions. Evacuate significant third-space accumulations prior to methotrexate tablets administration taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy.