Methotrexate

RECENT MAJOR CHANGES Boxed Warning 5/2020 Indications and Usage ( 1 ) 5/2020 Dosage and Administration ( 2 ) 5/2020 Contraindications ( 4 ) 5/2020 Warnings and Precautions ( 5 ) 5/2020

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

2 DOSAGE AND ADMINISTRATION • Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. ( 2.1 , 5.9 ) • Verify pregnancy status in females of reproductive potential before starting Methotrexate Tablets ( 4 , 5.1 ). • ALL: The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen. ( 2.2 ) • Mycosis fungoides: The recommended dosage is 25 mg to 75 mg orally once weekly as monotherapy; 10 mg/m 2 orally twice weekly as part of combination chemotherapy. ( 2.2 ) • Relapsed 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 ) • Rheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response ( 2.3 ) • pJIA: The recommended starting dosage is 10 mg/m 2 orally once weekly; adjust dose to achieve an optimal response ( 2.4 ) • Psoriasis: The recommended dosage is 10 mg to 25 mg orally once weekly until adequate response is achieved. ( 2.5 ) 2.1 Important Dosage and Safety Information in females of reproductive potential before starting Methotrexate Tablets 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 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.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 a tablet.Do not administer to patients who are unable to swallow a tablet. Methotrexate Tablets is a cytotoxic drug. Follow applicable special handling and disposal procedures. Methotrexate Tablets is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 2.2 Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of Methotrexate Tablets is 20 mg/m 2 orally once weekly, as part of a 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 a 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 a single agent or 10 mg/m 2 orally twice weekly as part of a combination chemotherapy regimen. Relapsed or Refractory Non-Hodgkin Lymphomas The recommended dosage of Methotrexate Tablets is 2.5 mg orally 2 to 4 times per week (maximum 10 mg per week) as part of a 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 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.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 maj …

3 DOSAGE FORMS AND STRENGTHS 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 M 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 )

4 CONTRAINDICATIONS is contraindicated in: Methotrexate Tablets is contraindicated in: • Pregnant 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 )]. • 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 )

6 ADVERSE REACTIONS 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 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 ), pancytopenia, dizziness 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 to 20 mg/m 2 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 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. 6.2 Postmarketing Experience 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 dru …

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: • Oral antibiotics (including neomycin) • Oral or intravenous penicillin or sulfonamide antibiotics • Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) • Probenecid • Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulphonamides) • Aspirin and other nonsteroidal anti-inflammatory drugs • Hepatotoxic products • Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) • Proton pump inhibitors • Weak acids (e.g., 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 ( 5.10 )] .

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 a 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 a 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 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]) (2.9%). 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 a breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 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 [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 fe …

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 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.

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 C 20 H 22 N 8 O 5 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

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 (> 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Methotrexate Tablets, USP are supplied as follows: 2.5 mg: Yellow, oval-shaped, film-coated, scored, biconvex tablet. Debossed with b/572 on the scored side. NDC: 71335-0782-1: 30 Tablets in a BOTTLE NDC: 71335-0782-2: 12 Tablets in a BOTTLE NDC: 71335-0782-3: 20 Tablets in a BOTTLE NDC: 71335-0782-4: 100 Tablets in a BOTTLE NDC: 71335-0782-5: 36 Tablets in a BOTTLE NDC: 71335-0782-6: 24 Tablets in a BOTTLE NDC: 71335-0782-7: 90 Tablets in a BOTTLE NDC: 71335-0782-8: 4 Tablets in a BOTTLE Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Keep this and all medications out of the reach of children. Methotrexate Tablets is a cytotoxic drug. Follow applicable special handling and disposal procedures. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504