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WARNING
EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS and SEVERE ADVERSE REACTIONS
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. The molecular formula is C20H22N8O5 and the molecular weight is 454.4 g/mol. The structural formula is:
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JYLAMVO (methotrexate) oral solution is a clear yellow solution that contains methotrexate, 2 mg/mL. Inactive ingredients include citric acid, ethylparaben, glycerin, methylparaben sodium, orange flavoring powder, polyethylene glycol, purified water, sodium citrate and sucralose. The target pH of the oral solution is 6.8.
JYLAMVO is indicated for the:
JYLAMVO is indicated for the treatment of adults with rheumatoid arthritis.
JYLAMVO is indicated for the treatment of adults with severe psoriasis.
Verify pregnancy status in females of reproductive potential before starting JYLAMVO [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Instruct patients and caregivers on how to measure, dose, and administer the recommended dosage as directed, because medication errors have led to deaths [see WARNINGS AND PRECAUTIONS].
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 cytotoxic drug. Follow applicable special handling and disposal procedures1.
The recommended starting dosage of JYLAMVO is 20 mg/m² 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.
The recommended dosage of JYLAMVO is 25 to 75 mg orally once weekly when administered as a single agent or 10 mg/m² 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.
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].
The recommended dosage of JYLAMVO is 10 to 25 mg orally once weekly until an adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed a dose 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 risk of methotrexate adverse reactions [see WARNINGS AND PRECAUTIONS].
Discontinue JYLAMVO for
Oral solution: clear yellow solution containing methotrexate 2 mg/mL.
JYLAMVO is supplied as a clear yellow oral solution that contains 2 mg of methotrexate per mL. It is packaged in a 75 mL amber type III glass bottle with tamper evident child-resistant closure (polypropylene with expanded polyethylene liner) containing 60 mL of oral solution.
Each pack contains one bottle, a low-density polyethylene (LDPE) bottle adaptor and a 10 mL white polypropylene dosing syringe (with major graduations at every 1 mL and minor graduations at every 0.25 mL) (NDC 55792-020-01).
Store JYLAMVO 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]. In Use storage conditions: Store JYLAMVO at room temperature 20°C to 25°C (68°F to 77°F). Keep the bottle tightly closed. After first opening, discard any unused medicine after 3 months.
JYLAMVO is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
REFERENCES
1. “OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html.
Distributed by: Lukare Medical, LLC 4 Julia Court Scotch Plains, NJ 07076 1-908-834-2206. Revised: Nov 2022
The following clinically significant adverse reactions are described elsewhere in the labeling:
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.
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/mm3)
Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count < 3000/mm3), 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.
The most common adverse reactions reported in patients 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m2 to 20 mg/m2 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.
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: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death
Endocrine: Diabetes
Eye: Optic neuropathy, blurred vision, ocular pain, conjunctivitis, xerophthalmia
Gastrointestinal: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration
Hematology: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia
Hepatobiliary: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis
Immune system: Anaphylaxis, anaphylactoid reactions, vasculitis
Metabolism: Hyperglycemia
Musculoskeletal: Stress fracture, soft tissue and bone necrosis, arthralgia, myalgia, osteoporosis
Nervous system: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, and convulsions.
Renal: Azotemia, hematuria, proteinuria, cystitis
Reproductive: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction
Respiratory: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis
Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis
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:
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.
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].
Included as part of the "PRECAUTIONS" Section
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 nonmalignant 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, Use in Specific Populations].
Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see CONTRAINDICATIONS, ADVERSE REACTIONS].
If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue JYLAMVO [see DOSAGE AND ADMINISTRATION].
Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see ADVERSE REACTIONS].
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].
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]. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions [see DRUG INTERACTIONS]
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].
Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].
Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate [see ADVERSE REACTIONS].
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 [see DOSAGE AND ADMINISTRATION].
Severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate [see ADVERSE REACTIONS].
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 [see DOSAGE AND ADMINISTRATION]. Advise patients to avoid excessive sun exposure and use sun protection measures.
Methotrexate can cause renal toxicity, including irreversible acute renal failure [see ADVERSE REACTIONS].
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 [see DOSAGE AND ADMINISTRATION].
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.
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.
Instruct patients and caregivers on how to measure, dose, and administer the recommended dosage as directed [see DOSAGE AND ADMINISTRATION].
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.
Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis [see DOSAGE AND ADMINISTRATION].
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 [see ADVERSE REACTIONS].
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 [see DOSAGE AND ADMINISTRATION].
Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].
Secondary malignancies can occur with methotrexate [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].
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.
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.
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 [see Use In Specific Populations].
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.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see WARNINGS AND PRECAUTIONS]
Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
For patients who are prescribed a once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as a single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see WARNINGS AND PRECAUTIONS].
Before use, instruct patients and caregivers on how to measure and administer the recommended dosage, utilizing the copackaged syringe and bottle adaptor and that a teaspoon is not an appropriate measuring device. Advise patients and caregivers to only use the copackaged syringe and that a household spoon is not an accurate measuring device [see DOSAGE AND ADMINISTRATION].
Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients on the risk of second primary malignancies during treatment with JYLAMVO [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid receiving vaccines during treatment with JYLAMVO because they may not be effective and live virus vaccines may cause infections [see WARNINGS AND PRECAUTIONS ].
Instruct women not to breastfeed during treatment with JYLAMVO and for 1 week after the final dose [see Use In Specific Populations].
Advise females and males of reproductive potential that methotrexate may impair fertility [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].
Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see DRUG INTERACTIONS].
Advise patients to store JYLAMVO at room temperature (20°C to 25°C/ 68°F to 77°F). Once the bottle has been opened, any remaining medication must be disposed of after 90 days. Inform patients and caregivers of the need for proper disposal of the medication, bottle, and syringe [see REFERENCES]. This medicine should not be disposed of in wastewater or household waste.
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain.
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]. 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.
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.
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.
Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [Use in Specific Populations].
Verify the pregnancy status of females of reproductive potential prior to initiating JYLAMVO [see CONTRAINDICATIONS, Use in Specific Populations].
Females
JYLAMVO can cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with JYLAMVO and for 6 months after the final dose of JYLAMVO.
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.
Females
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.
Males
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.
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 [see INDICATIONS, DOSAGE AND ADMINISTRATION, and ADVERSE REACTIONS].
The safety and effectiveness of JYLAMVO have not been established in pediatric patients for the other indications [see INDICATIONS].
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]. 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 [see WARNINGS AND PRECAUTIONS].
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]. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue JYLAMVO as appropriate [see WARNINGS AND PRECAUTIONS].
REFERENCES
1. “OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html.
Overdosage, including fatal overdosage, has occurred with methotrexate [see WARNINGS AND PRECAUTIONS].
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.
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.
JYLAMVO is contraindicated in:
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.
At doses of 30 mg/m2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized.
Effect of Food
Food has been shown to delay absorption and reduce peak concentration.
Methotrexate in serum is approximately 50% protein bound.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.
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.
The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown.
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 (Cmax 0.11 to 2.3 micromolar after a 20 mg/m2 dose) was 20-fold. The time to peak concentration (Tmax 0.67 to 4 hours after a 15 mg/m2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m2 is significantly less than that of lower doses.
In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m2/week to 11.2 mg/m2/week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at 1 hour, 0.44 micromolar (0.01 to 1.00) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours.
In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m2 to 30 mg/m2) or for JIA (3.75 mg/m2 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively.
The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.
JYLAMVO
(Jye lam voe)
(methotrexate) oral solution
What is the most important information I should know about JYLAMVO?
JYLAMVO can cause serious side effects that may be severe and lead to death, including:
Harm to an unborn baby, including birth defects or death of an unborn baby. Females who can become pregnant:
Males with female partners who are able to become pregnant:
Severe allergic reactions. Severe allergic reactions can happen with JYLAMVO.Signs and symptoms of a severe allergic reaction may include:
Do not take JYLAMVO if you have had a severe allergic reaction to methotrexate in the past.
Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction listed above.
Decreased blood cell counts. JYLAMVO can affect your bone marrow and cause decreases in red blood counts, white blood cell counts, and platelets that can be severe and life-threatening.
Call your healthcare provider right away if you develop any of the following:
Severe stomach and intestine problems (gastrointestinal) problems.
Tell your healthcare provider if you develop new or worsening diarrhea, vomiting, or mouth sores during treatment with JYLAMVO.
Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools.
Liver problems. JYLAMVO can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death.
Tell your healthcare provider if you have any signs or symptoms of liver problems during treatment with JYLAMVO, including:
Lung problems. Lung problems can happen suddenly (acute) with JYLAMVO or they can develop over a long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death. Tell your healthcare provider if you have any new or worsening symptoms including: cough (especially a dry cough), fever, or trouble breathing.
Severe skin reactions. Severe skin reactions can happen with JYLAMVO and can lead to death.
Limit sunlight exposure during treatment with JYLAMVO. Use sunscreen and wear protective clothing when you will be exposed to sunlight during treatment with JYLAMVO.
Tell your healthcare provider right away about any new or worsening skin rash during treatment with JYLAMVO. Kidney problems. Kidney problems can happen with JYLAMVO, including kidney failure which can happen suddenly (acute) and may not go away (irreversible).
Your healthcare provider will check your kidney function before you start and during treatment with JYLAMVO.
Tell your healthcare provider right away if you have any signs or symptoms of kidney problems, including:
See “What are the possible side effects of JYLAMVO” for more information about side effects.
What is JYLAMVO?
JYLAMVO is a prescription medicine used:
It is not known if JYLAMVO is safe and effective in children for the treatment of any medical condition other than ALL as part of a combination regimen used for maintenance therapy of their cancer, and pJIA.
It is not known if JYLAMVO is safe in people with liver problems.
Do not take JYLAMVO if you:
Before taking JYLAMVO tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. JYLAMVO and certain other medicines can affect each other and cause serious side effects. Do not start or change any medicines unless you have talked to your healthcare provider and your healthcare provider has told you it is safe. Know all the medicines that you take and keep a list of them with you at all times to show healthcare providers and pharmacists.
How should I take JYLAMVO?
If you are taking JYLAMVO for treatment of severe psoriasis, rheumatoid arthritis or polyarticular juvenile idiopathic arthritis:
If you are taking JYLAMVO to treat your cancer:
INSTRUCTIONS FOR USEING JYLAMVO
Each pack of JYLAMVO contains a bottle of medicine with a cap, a bottle neck adaptor, and a white dosing syringe. Always use the dosing syringe provided in the pack to take JYLAMVO. A household teaspoon is not an accurate measuring device.
Note: the dosing syringe measures the amount of oral solution in mL and JYLAMVO contains 2 mg of methotrexate in 1 mL of solution.
Read and carefully follow the instructions below:
What are the possible side effects of JYLAMVO?
JYLAMVO can cause serious side effects that may be severe and lead to death including:
The most common side effects of JYLAMVO include:
These are not all the possible side effects of JYLAMVO. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store JYLAMVO?
Keep JYLAMVO and all medicines out of the reach of children.
General information about the safe and effective use of JYLAMVO.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use JYLAMVO for a condition for which it was not prescribed. Do not give JYLAMVO to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about JYLAMVO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about JYLAMVO that is written for health professionals.
What are the ingredients in JYLAMVO?
Active Ingredient: methotrexate
Inactive Ingredients: citric acid, ethylparaben, glycerin, methylparaben sodium, orange flavoring powder, polyethylene glycol, purified water, sodium citrate and sucralose.
Manufactured By: SGS Quay Pharmaceuticals Ltd., Deeside, UK. Revised: October 2024
This Patient Information has been approved by the U.S. Food and Drug Administration
