Methotrexate Oral Solution

Acute Lymphoblastic Leukemia

XATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

Polyarticular Juvenile Idiopathic Arthritis

XATMEP is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

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 pJIA is unknown; it may affect immune function.

Pharmacodynamics

Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mono-nuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects.

Pharmacokinetics

In pediatric patients with ALL, oral absorption of methotrexate appears to be dose dependent; the absorption of doses greater than 40 mg/m2 is significantly less than that of lower doses. The extent of oral absorption ranges from 23% to 95%, and the time to peak concentration (Tmax) ranges from 0.7 hours to 4 hours after an oral dose of 15 mg/m2 .

In pediatric patients with pJIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours following oral administration of methotrexate at a dose of 6.4 mg/m2/week to 11.2 mg/m2/week.

Effect of Food

The administration of XATMEP with food did not affect the area under the curve (AUC), but decreased the maximal concentrations (Cmax) by 50% and delayed the absorption.

After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight).

Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved.

Methotrexate in serum is approximately 50% protein bound.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally.

In adults, the half-life of methotrexate following administration of low dose methotrexate (less than 30 mg/m2) ranges from 3 hours to 10 hours.

In pediatric patients receiving methotrexate for ALL (6.3 mg/m2 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 hours to 5.8 hours.

In pediatric patients receiving methotrexate for JIA (3.75 mg/m2 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.9 hours to 2.3 hours.

Metabolism

Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. 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. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. The aqueous solubility of 7-hydroxymethotrexate is 3-to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.

Excretion

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in patients at doses between 7.5 mg and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels.

Methotrexate clearance decreases at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. When a patient has delayed drug elimination due to compromised renal function, a third-space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

Clinical Studies

Clinical trials in patients with polyarticular juvenile idiopathic arthritis were performed using other formulations of methotrexate.

In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile idiopathic arthritis (JIA) (mean age, 10.1 years; age range 2.5 to 18 years, mean duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given one time weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JIA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/week methotrexate. The overwhelming majority of the remaining patients had systemic-course JIA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial.

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Bone Marrow Suppression [see WARNINGS AND PRECAUTIONS]
• Serious Infections [see WARNINGS AND PRECAUTIONS]
• Renal Toxicity and Increased Toxicity with Renal Impairment [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Toxicity [see WARNINGS AND PRECAUTIONS]
• Hepatic Toxicity [see WARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
• Secondary Malignancies [see WARNINGS AND PRECAUTIONS]
• Ineffective Immunization and Risks Associated with Live Vaccines [see WARNINGS AND PRECAUTIONS]
• Infertility [see WARNINGS AND PRECAUTIONS]
• Increased Toxicity Due to Third-Space Accumulation [see WARNINGS AND PRECAUTIONS]
• Soft Tissue and Bone Toxicity with Radiation Therapy [see WARNINGS AND PRECAUTIONS]

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.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase methotrexate toxicity.

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of 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%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.

Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia

Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis,decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex.

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis

Read the entire FDA prescribing information for Xatmep (Methotrexate Oral Solution)

• It is used to treat cancer.
• It is used to treat juvenile arthritis.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to methotrexate or any other part of methotrexate oral solution.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Bone marrow disease (like low white blood cell count, low platelet count, or anemia), drinking problem, liver disease, or a weak immune system.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with methotrexate oral solution.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take methotrexate oral solution or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to methotrexate oral solution. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017