METHOTREXATE- methotrexate_tablet

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 DNA 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. Absorption At doses of 30 mg/m 2 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 3 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 (C max 2 max 2 2 In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6. 4 mg/m 2 2 In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6. 3 mg/m 2 2 2 2 Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

Methotrexate tablets are a dihydrofolate reductase inhibitor indicated for the: Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen ( 1. 1 Treatment of adults with mycosis fungoides ( 1. 1 Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen ( 1. 1 Treatment of adults with rheumatoid arthritis ( 1. 2 Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) ( 1. 3 Treatment of adults with severe psoriasis ( 1. 4 Methotrexate tablets areindicated for the: treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) aspart of a combination chemotherapy maintenance regimen treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent oras part of a combination chemotherapy regimen. treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part ofa metronomic combination chemotherapy regimen Methotrexate tablets are indicated for the treatment ofadults with rheumatoid arthritis. Methotrexate tablets are indicated for the treatment ofpediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). Methotrexate tablets are indicated forthe treatment of adults with severe psoriasis.

Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. 9 Verify pregnancy status in females of reproductive potential before starting methotrexate tablets ( 4 5. 2 Mycosis fungoides 2 2. 2 Relapsed or refractory non-Hodgkin lymphoma 2. 2 Rheumatoid Arthritis 2. 4 Psoriasis 2. 5 Verify pregnancy status in females ofreproductive potential before starting methotrexate tablets [see Contraindications (4) Warnings and Precautions (5. 1) Instruct patients and caregivers totake 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 administrationtointravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary. Do not administer to patients who are unabletoswallow a tablet. Methotrexate tabletisa cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Acute LymphoblasticLeukemia The recommended starting dosage ofmethotrexate tablets is 20 mg/m 2 MycosisFungoides The recommended dosage of methotrexate tablets is 25 mgto75 mg orally once weekly when administered as a single agent or 10 mg/m 2 Relapsed or RefractoryNon-Hodgkin Lymphomas The recommended dosage of methotrexate tablets is 2. 5 mg orally 2to4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen. 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 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acidorfolinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5. 10) The recommended starting dosage of methotrexate tablets is 10 mg/m 2 2 Administer folic acidorfolinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5. 10) The recommended dosage of methotrexate tablets is 10 mg to 25 mg orally once weekly until an adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceedadose 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 riskofmethotrexate adverse reactions [see Warnings and Precautions (5. 10) Discontinue methotrexate tablets for: Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5. 2) Lymphoproliferative disease [see Warnings and Precautions (5. 13) Withhold, dose reduce or discontinue methotrexate tablets as appropriate for: Myelosuppression [see Warnings and Precautions (5. 3) Withhold or discontinue methotrexate tablets as appropriate for: Severe gastrointestinaltoxicity [see Warnings and Precautions (5. 4) Hepatotoxicity [see Warnings and Precautions (5. 5) Pulmonarytoxicity [see Warnings and Precautions (5. 6) Severedermatologicreactions [see Warnings and Precautions (5. 7) Severerenaltoxicity [see Warnings and Precautions (5. 8) Seriousinfections [see Warnings and Precautions (5. 11) Neurotoxicity [see Warnings and Precautions (5.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5. 2) Myelosuppression [see Warnings and Precautions (5. 3) Gastrointestinal Toxicity [see Warnings and Precautions (5. 4) Hepatotoxicity [see Warnings and Precautions (5. 5) Pulmonary Toxicity [see Warnings and Precautions (5. 6) Dermatologic Reactions [see Warnings and Precautions (5. 7) Renal Toxicity [see Warnings and Precautions (5. 8) Serious Infections [see Warnings and Precautions (5. 11) Neurotoxicity [see Warnings and Precautions (5. 12) Secondary Malignancies [see Warnings and Precautions (5. 13) Tumor Lysis Syndrome [see Warnings and Precautions (5. 14) Increased 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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 www. gov/medwatch. Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 mg 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/mm 3 Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count < 3000/mm 3 Two 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 pneumonitis Other 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 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m 2 2 Psoriasis In two published series of adults with psoriasis (n=204, 248) who received methotrexate up to 25 mg per week for up to 4 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. The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Cardiovascular: Endocrine: Eye: Gastrointestinal: Hematology: Hepatobiliary: Immune system: Metabolism: Musculoskeletal: Nervous system: Renal: Reproductive: Respiratory: Skin:.

Methotrexate tabletsarecontraindicated in: Pregnant women receiving methotrexate tablets for treatmentofnon-neoplastic diseases [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 3) Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate. [see Warnings and Precautions (5. 2) In pregnancy for non-neoplastic diseases ( 4 History of severe hypersensitivity to methotrexate ( 4.

Lactation 8. 2 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) In the U. 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 a prolonged period, there is a 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. Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 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. 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 a breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final dose. Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [ 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 6 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 3 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. 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) [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) Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology (12. 3) [see Warnings and Precautions (5. 8) 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.

Refer to the full prescribing information for drug interactions with methotrexate. ( 7 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: Oral antibiotics (including neomycin) Oral or intravenous penicillin or sulfonamide antibiotics Highly protein-bound drugs (e. , oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Probenecid Antifolate drugs (e. , dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Hepatotoxic products Proton pump inhibitors Weak acids (e. , salicylates) Nephrotoxic 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.

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 (>1 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 a high-flux dialyzer.
NONCLINICAL TOXICOLOGY
Methotrexate has been evaluated in a 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.
REFERENCES
1. “OSHA Hazardous Drugs.” OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html

NuCare Pharmaceuticals, Inc.

METHOTREXATE- methotrexate_tablet Product manual source documgent