Methotrexate

Boxed Warning 3/2021 Indications and Usage ( 1.1 , 1.2 , 1.3 , 1.4 , 1.5 , 1.6 , 1.7 , 1.8 , 1.10 ) 3/2021 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 , 2.10 , 2.11 , 2.12 ) 3/2021 Warnings and Precautions ( 5.1 , 5.3 , 5.5 , 5.6 , 5.7 , 5.9 , 5.13 ) 3/2021

1 INDICATIONS AND USAGE Methotrexate Injection is a folate analog metabolic inhibitor indicated for: The following neoplastic diseases for the: Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen ( 1.1 ) Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia ( 1.2 ) Treatment of adult and pediatric patients with non-Hodgkin lymphoma ( 1.3 ) Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen ( 1.4 ) Treatment of adults with breast cancer as part of a combination chemotherapy regimen ( 1.5 ) Treatment of adults with squamous cell carcinoma of the head and neck as single-agent ( 1.6 ) Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen ( 1.7 ) Treatment of adults with rheumatoid arthritis (RA). ( 1.8 ) Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). ( 1.9 ) Treatment of adults with severe psoriasis. ( 1.10 ) 1.1 Acute Lymphoblastic Leukemia Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. 1.2 Meningeal Leukemia: Prophylaxis and Treatment Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients. 1.3 Non-Hodgkin Lymphoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with Non-Hodgkin lymphoma. 1.4 Osteosarcoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. 1.5 Breast Cancer Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen. 1.6 Squamous Cell Carcinoma of the Head and Neck Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent. 1.7 Gestational Trophoblastic Neoplasia Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen. 1.8 Rheumatoid Arthritis Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA). 1.9 Polyarticular Juvenile Idiopathic Arthritis Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.10 Psoriasis Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. ( 2.1 , 4 , 5.1 ) Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response. Once achieved, reduce to lowest possible dosage. ( 2.12 ) 2.1 Important Dosage and Safety Information Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ]. Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications (4) and Warnings and Precautions (5.1) ]. For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability . 2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions (5) ] : Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose) . Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin Prescribing Information for additional information. For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens. Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase Prescribing Information for additional information) 2.3 Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . Lower doses (e.g., 20 to 30 mg/m 2 /week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. 2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age: less th …

3 DOSAGE FORMS AND STRENGTHS Injection: ( 3 ) Preservative-free (single-dose vials): 50 mg/2 mL (25 mg/mL), 100 mg/4 mL (25 mg/mL), 200 mg/8 mL (25 mg/mL), 250 mg/10 mL (25 mg/mL) Injection: Methotrexate Injection is a clear, yellow solution and is supplied in single-dose vials (preservative-free) in the following strengths: Preservative-free (single-dose vial) 50 mg/2 mL (25 mg/mL) 100 mg/4 mL (25 mg/mL) 200 mg/8 mL (25 mg/mL) 250 mg/10 mL (25 mg/mL)

4 CONTRAINDICATIONS Methotrexate Injection is contraindicated in: Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2) ] . Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . History of severe hypersensitivity to methotrexate. ( 4 ) Pregnancy: in patients with non-neoplastic diseases. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Myelosuppression [see Warnings and Precautions (5.4) ] Serious Infections [see Warnings and Precautions (5.5) ] Renal Toxicity [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Neurotoxicity [see Warnings and Precautions (5.8) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.9) ] Pulmonary Toxicity [see Warnings and Precautions (5.10) ] Dermatologic Reactions [see Warnings and Precautions (5.11) ] 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, and abdominal distress. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n=128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ). Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3000/mm 3 ), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Interstitial pneumonitis. Other less common adverse reactions: Decreased hematocrit, 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 approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%. Psoriasis In two published series of adult psoriasis patients (n=204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%). 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 estim …

7 DRUG INTERACTIONS Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 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. 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: Penicillin or sulfonamide antibiotics Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs) Mercaptopurine Hepatotoxic products 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 (5.12) ]. 7.2 Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. ( 8.4 ) 8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. 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. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . 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, CNS 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/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2 to 58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8 to 29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13 to 22.8). 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 to 5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03 to 9.5]) (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 reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection 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 [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) and Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective co …

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, pJIA, and in psoriasis is unknown.

11 DESCRIPTION Methotrexate is a folate analog metabolic inhibitor with the chemical name of N -[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid and a molecular weight of 454.44. The molecular formula is C 20 H 22 N 8 O 5 and the structural formula is shown below: Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use. Methotrexate Injection, USP, Isotonic Liquid, Preservative Free is available in 25 mg/mL, 2 mL (50 mg), 4 mL (100 mg), 8 mL (200 mg), and 10 mL (250 mg) single-dose vials. Each 25 mg/mL, 2 mL vial contains 50 mg methotrexate, USP equivalent to 54.8 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 9.8 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 2 mL solution contains approximately 0.43 mEq of sodium per vial and is an isotonic solution. Each 25 mg/mL, 4 mL vial contains 100 mg methotrexate, USP equivalent to 109.7 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 19.6 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 4 mL solution contains approximately 0.86 mEq of sodium per vial and is an isotonic solution. Each 25 mg/mL, 8 mL vial contains 200 mg methotrexate, USP equivalent to 219.3 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 39.2 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 8 mL solution contains approximately 1.72 mEq of sodium per vial and is an isotonic solution. Each 25 mg/mL, 10 mL vial contains 250 mg methotrexate, USP equivalent to 274.2 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 49 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 10 mL solution contains approximately 2.15 mEq of sodium per vial and is an isotonic solution. Chemical Structure

10 OVERDOSAGE Manifestations Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.19) ]. Manifestations of 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. Manifestations of intrathecal overdosage include CNS symptoms (e.g., headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, is a clear, yellow, sterile solution and is supplied in a single-dose vial containing 25 mg/mL of methotrexate as the base in the following package strengths: Strength/Fill volume NDC number Package Configuration 50 mg/2 mL (25 mg/mL) 0143-9519-10 Carton containing ten (10) single-dose vials 100 mg/4 mL (25 mg/mL) 0143-9518-01 Carton containing one (1) single-dose vial 200 mg/8 mL (25 mg/mL) 0143-9517-01 Carton containing one (1) single-dose vial 250 mg/10 mL (25 mg/mL) 0143-9516-01 Carton containing one (1) single-dose vial Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 For Product Inquiry call 1-877-845-0689.