Shorla Oncology Announces U.S. Food and Drug Administration (FDA) Expanded Approval of JYLAMVO™ (methotrexate), an Oncology and Autoimmune Drug for Pediatric Indications

Shorla Oncology (‘Shorla’), a U.S.-Ireland specialty pharmaceutical company, announced today that the U.S. Food and Drug Administration (FDA) has expanded the approval of JYLAMVO^™ (methotrexate) to include the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) and polyarticular juvenile idiopathic arthritis (pJIA). With this approval, JYLAMVO is currently the only oral liquid methotrexate on the market approved for both adult and pediatric indications.

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“This approval follows JYLAMVO’s successful use in adult patients and represents a critical step forward in addressing the unmet needs of pediatric care in oncology and autoimmune diseases,” said Sharon Cunningham, chief executive officer of Shorla Oncology. “We are pleased to offer a convenient, patient-friendly alternative for both adult and pediatric patients in the U.S. as we continue to develop innovative solutions for those with limited treatment options.”

JYLAMVO was first approved by the FDA as the only oral liquid methotrexate to treat adults with acute lymphoblastic leukemia, mycosis fungoides, relapsed or refractory non-Hodgkin lymphoma, rheumatoid arthritis and severe psoriasis.

JYLAMVO has an orange flavor and comes with a dedicated dosing syringe.

“For patients with chronic conditions including cancer, JYLAMVO offers a convenient, palatable option for patients who may have difficulty swallowing pills,” said Orlaith Ryan, chief technical officer and co-founder of Shorla Oncology. “At Shorla, we are committed to continuity of supply of age-appropriate formulations for patients in need.”

Rayna Herman, chief commercial officer of Shorla Oncology added, “In addition to its palatable formulation, JYLAMVO offers key differences over similar drugs, such as room temperature stability for three months after opening, which eliminates the need for refrigeration before dispensing and adds convenience for patients. We are excited to expand our portfolio of innovative therapies for underserved patient populations.”

About JYLAMVO^™

JYLAMVO is an anti-inflammatory and cancer oral methotrexate solution approved by the U.S. Food and Drug Administration for use in adult and pediatric patients with rheumatological, dermatological and oncological diseases. JYLAMVO is an easy-to-administer, orange flavored solution that eliminates the need for crushing or splitting pills, or compounding into a liquid formulation. JYLAMVO offers advantages because it remains stable at room temperature (68°F to 77°F) for 90 days and does not require cold chain storage pre-dispense.

About Shorla Oncology

Shorla Oncology is a privately- held, U.S. and Ireland- based commercial stage specialty pharmaceutical company established by Sharon Cunningham and Orlaith Ryan. The company has an advanced pipeline of innovative oncology drugs for orphan and pediatric cancers. Shorla is focused on indications where existing treatments are limited, in shortage or the drug applications are inadequate for the target population. The company’s growing portfolio brings accessible, affordable and life-saving treatments to patients, delivering a major contribution to patient care. Shorla currently markets two products, Nelarabine for the treatment of T-cell leukemia and JYLAMVO for the treatment of acute lymphoblastic leukemia and other indications.

For further information, please visit www.shorlaoncology.com.

IMPORTANT SAFETY INFORMATION

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.
• 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 lymphoma as part of a metronomic combination regimen.
• Treatment of adults with rheumatoid arthritis.
• Treatment of adults with severe psoriasis.
• Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA)

CONTRAINDICATION

• JYLAMVO is contraindicated in pregnant women with non-neoplastic disease and patients with a history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate.

WARNINGS AND PRECAUTIONS

• 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.
• Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate. If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue JYLAMVO. Advise patients and their caregivers of the potential risk of hypersensitivity and that JYLAMVO is contraindicated in patients with a history of hypersensitivity reactions to methotrexate. Instruct patients to seek immediate medical attention for signs of a hypersensitivity reaction.
• Myelosuppression: Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia. Obtain blood counts at baseline and 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. Inform patients and their caregivers that JYLAMVO 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.
• 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. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions. 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. 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.
• Hepatotoxicity: Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure. 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 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. Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider.
• Pulmonary Toxicity: Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate. Monitor patients for pulmonary toxicity and withhold 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. Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider.
• Dermatologic Reactions: Severe, including fatal, dermatologic reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme can occur with methotrexate. 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 JYLAMVO for severe dermatologic reactions 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. Advise patients and their caregivers that JYLAMVO 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.
• Renal Toxicity: Methotrexate can cause renal toxicity, including irreversible acute renal failure. Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue JYLAMVO for severe renal 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. Administer glucarpidase in patients with 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. 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.
• Risk of Serious Adverse Reactions with Medication Error: Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed. For patients prescribed a once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death. Before use, instruct patients and caregivers on how to measure, dose, and administer the recommended dosage, utilizing the co-packaged syringe and that a teaspoon is not an appropriate measuring device. Advise patients and caregivers to only use the co-packaged syringe and that a household spoon is not an accurate measuring device.
• 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 and psoriasis.
• 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 B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections. Monitor patients for infection during and after treatment with JYLAMVO. Withhold or discontinue JYLAMVO for serious infections 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. Inform patients and their caregivers that JYLAMVO 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.
• Neurotoxicity: Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal. The risk of leukoencephalopathy is increased in patients who received prior cranial radiation. Monitor patients for neurotoxicity and withhold 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. Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider.
• Secondary Malignancies: Secondary malignancies can occur with methotrexate. 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 JYLAMVO. Advise patients on the risk of second primary malignancies during treatment with JYLAMVO.
• 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 JYLAMVO.
• 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 JYLAMVO. Update immunizations according to immunization guidelines prior to initiating JYLAMVO. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines for patients on immunosuppressive agents.
• 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.
• 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 JYLAMVO administration 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.

ADVERSE REACTIONS

In clinical trials, common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.

DRUG INTERACTIONS

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.

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. 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. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Lactation: 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, including myelosuppression, advise women not to breastfeed during treatment with JYLAMVO and for 1 week after the final dose.

Females and Males of Reproductive Potential: Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses.

Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating JYLAMVO.

Contraception for Females - JYLAMVO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with JYLAMVO and for 6 months after the final dose of JYLAMVO.

Contraception for Males - Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with JYLAMVO and for at least 3 months after the final dose of JYLAMVO.

Female Infertility - Based on published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with JYLAMVO and after the final dose. It is not known if the infertility may be reversed in all affected females.

Male Infertility - Based on published reports of male infertility after treatment with methotrexate, advise males of reproductive potential that methotrexate can cause oligospermia or infertility during treatment with JYLAMVO and after the final dose. It is not known if the infertility may be reversed in all affected males.

Pediatric Use: The safety and effectiveness of JYLAMVO in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA. No new safety signals have been observed in pediatric patients in these clinical studies.

The safety and efficacy of JYLAMVO have not been established for pediatric patients in other indications.

Renal Impairment: Methotrexate elimination is reduced in patients with renal impairment. 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 JYLAMVO as appropriate.

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. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue JYLAMVO as appropriate.

To report suspected adverse reactions, contact Shorla Oncology at 844-9-SHORLA (844-974-6752) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here for full Prescribing Information, including Boxed Warning regarding embryo-fetal toxicity, hypersensitivity reactions, and severe adverse reactions.

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