JYLAMVO

1 INDICATIONS AND USAGE JYLAMVO is a folate analog metabolic 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 JYLAMVO 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 JYLAMVO is indicated for the treatment of adults with rheumatoid arthritis. 1.3 Polyarticular Juvenile Idiopathic Arthritis JYLAMVO is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.4 Psoriasis JYLAMVO is indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential before starting JYLAMVO. ( 2.1, 4, 5.1 ) Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. ( 2.1, 5.9 ) 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 Verify pregnancy status in females of reproductive potential before starting JYLAMVO [see Contraindications (4), Warnings and Precautions (5.1) ]. Instruct patients and caregivers on how to measure and administer the recommended dosage using the copackaged syringe and bottle adaptor as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9) ]. Ensure patients and caregivers understand the instructions provided in the Patient Information on proper dosing of JYLAMVO based on volume (mL) utilizing the copackaged syringe before use. Advise patients and caregivers to only use the copackaged syringe to measure JYLAMVO and that a teaspoon is not an appropriate measuring device. The dosing syringe utilizes mL as the unit of measure; ensure that the correct dose expressed in volume (mL) is prescribed. JYLAMVO contains 2 mg of methotrexate in each mL of solution. JYLAMVO is intended for oral use only. When switching the patient’s dosing regimen from a methotrexate product for oral administration to a methotrexate product for intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary due to potential differences in bioavailability. JYLAMVO is a hazardous drug. Follow applicable special handling and disposal procedures 1 . 2.2 Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of JYLAMVO is 20 mg/m 2 orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating JYLAMVO, 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 JYLAMVO is 25 mg 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 JYLAMVO 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 JYLAMVO 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 occur between 3 and 6 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) ] . 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dose of JYLAMVO is 10 mg/m …

5 WARNINGS AND PRECAUTIONS Serious Infections : Monitor patients for infection during and after treatment with JYLAMVO. Withhold or discontinue methotrexate for serious infections as appropriate. ( 5.11 ) Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue methotrexate as appropriate. ( 5.12 ) Secondary Malignancies : Can occur with methotrexate. ( 5.13 ) Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of JYLAMVO. ( 5.14 ) Immunizations and Risks Associated with Live Vaccines : Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. ( 5.15 ) Infertility : 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 can cause fetal harm, including fetal death, when administered to a pregnant woman. JYLAMVO is contraindicated for use in pregnant women receiving JYLAMVO for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JYLAMVO and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during JYLAMVO treatment and for at least 3 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 JYLAMVO [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 JYLAMVO taking into account the importance of JYLAMVO 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 a greater risk of developing severe gastrointestinal adverse reactions [see Drug Interactions (7.1) ] . Withhold or discontinue JYLAMVO for severe gastrointestinal toxicity taking into account the importance of JYLAMVO 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) ] . 5.5 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6.1) ] . The safety of JYLAMVO 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 a total cumulative dose of 1.5 g or more. Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue JYLAMVO …

4 CONTRAINDICATIONS JYLAMVO is contraindicated in: Pregnant women 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) ] . Pregnant patients with non-neoplastic diseases ( 4 ) History of severe hypersensitivity to methotrexate ( 4 )

7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with JYLAMVO. ( 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 Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Hepatotoxic products Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Probenecid 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) ] .

8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no animal data that meet current standards for nonclinical developmental toxicity studies. In pregnant women with non-malignant disease, JYLAMVO is contraindicated. Consider the benefits and risks of JYLAMVO and risks to the fetus when prescribing JYLAMVO to a pregnant patient with a neoplastic disease. The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

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 Shorla Oncology at 844-9-SHORLA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 ), 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 mg/kg 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 drug exposure.…