METHOTREXATE- methotrexate_injection, solution

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. Distribution 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 L/kg 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 intravenously. Elimination Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 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. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate and accumulation may become significant at the high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous 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 at doses between 7. 5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving high-dose methotrexate for ALL (5,000 mg/m 2 Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.

Methotrexate Injection is a dihydrofolate reductase inhibitor indicated for the treatment of: adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen ( 1. 1 adults with relapsed or refractory non-Hodgkin lymphoma as part of a combination chemotherapy regimen ( 1. 2 adults and pediatric patients with Burkitt lymphoma as part of a combination chemotherapy regimen ( 1. 3 adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen ( 1. 4 Limitations of Use: 1. 5 Methotrexate Injection is indicated for the treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults and pediatric patients with Burkitt lymphoma as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. Methotrexate Injection is not indicated for non-oncology diseases.

For intravenous use only 2. 1 See full prescribing information about monitoring and concomitant therapies for intermediate- and high-dose regimens ( 2. 2 Acute Lymphoblastic Leukemia 2 2 2. 3 Non-Hodgkin Lymphoma and Burkitt Lymphoma 2 2 2. 4 Osteosarcoma grams 2 grams 2. 5 For intravenous use only. Methotrexate Injection is available as a preservative-free solution at a concentration of 100 mg/mL. Verify the concentration prior to preparation and administration to avoid overdosage. Consider leucovorin rescue for patients who will receive Methotrexate Injection doses between 100 mg/m 2 2 2 Consider the following for patients who will receive Methotrexate Injection doses between 100 mg/m 2 2 2 [see Warnings and Precautions (5. 3) The recommended dosage of Methotrexate Injection varies from 30 mg/m 2 2 The recommended dosage of Methotrexate Injection varies from 1,000 mg/m 2 2 The recommended dosage of Methotrexate Injection varies from 1,000 mg/m 2 2 The recommended dosage of Methotrexate Injection is typically 12 grams 2 grams [see Dosage and Administration (2. 2) Discontinue Methotrexate Injection for Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5. 1) Lymphoproliferative disease [see Warnings and Precautions (5. 11) Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for: Myelosuppression [see Warnings and Precautions (5. 5) Withhold or discontinue Methotrexate Injection as appropriate for: Neurotoxicity [see Warnings and Precautions (5. 2) Severe renal toxicity [see Warnings and Precautions (5. 3) Hepatotoxicity [see Warnings and Precautions (5. 4) Severe gastrointestinal toxicity [see Warnings and Precautions (5. 6) Pulmonary toxicity [see Warnings and Precautions (5. 7) Severe dermatologic reactions [see Warnings and Precautions (5. 8) Serious infections [see Warnings and Precautions (5. 9) Methotrexate Injection is available as a solution at a concentration of a 100 mg/mL. Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 Methotrexate Injection may be further diluted immediately before use with an appropriate sterile, preservative-free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The following clinically significant adverse reactions are described in elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5. 1) Neurotoxicity [see Warnings and Precautions (5. 2) Renal Toxicity [see Warnings and Precautions (5. 3) Hepatotoxicity [see Warnings and Precautions (5. 4) Myelosuppression [see Warnings and Precautions (5. 5) Gastrointestinal Toxicity [see Warnings and Precautions (5. 6) Pulmonary toxicity [see Warnings and Precautions (5. 7) Dermatologic Toxicity [see Warnings and Precautions (5. 8) Serious infections [see Warnings and Precautions (5. 9) Secondary Malignancies [see Warnings and Precautions (5. 11) Tumor Lysis Syndrome [see Warnings and Precautions (5. 12) The following adverse reactions associated with the use of methotrexate were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions were: infection, malaise, fatigue, chills, fever, and dizziness. Blood and lymphatic system disorders: Cardiac disorders: Endocrine disorders: Eye disorders: Gastrointestinal disorders: Hepatobiliary disorders: Immune system disorders: Metabolism and nutrition disorders: Nervous system disorders: Renal and urinary disorders: Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous disorders: Common adverse reactions are: ulcerative stomatitis, leukopenia, nausea and abdominal distress ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate. Reactions have included anaphylaxis [see Warnings and Precautions (5. 1) History of severe hypersensitivity to methotrexate ( 4.

Lactation: (8. 2) Renal Impairment: (8. 6) Hepatic Impairment: (8. 7) Risk Summary Based on published reports and its mechanism of action [see Clinical Pharmacology (12. 1) In the U. 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 cases, 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. Methotrexate exposure during the second and third trimesters of pregnancy is associated with 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 per week after conception. The rate of 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 non-autoimmune 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]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. Risk Summary 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. There are no data on the effects of methotrexate or its metabolites on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Methotrexate Injection 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 [see Use in Specific Populations (8. 1) Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Use in Specific Populations (8. 1) Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Methotrexate Injection and for 6 months after the final dose. Males Methotrexate Injection can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with Methotrexate Injection and for 3 months after the final dose. Infertility Females Based on published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. 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 Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. The safety and effectiveness of Methotrexate Injection have been established in pediatric patients for the treatment of ALL, Burkitt lymphoma and osteosarcoma [see Indications and Usage (1) Dosage and Administration (2) [see Adverse Reactions (6) Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with ALL who received methotrexate at intravenous doses of 1,000 mg/m 2 [see Warnings and Precautions (5. 2) The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for non-Hodgkin lymphoma. Clinical studies of methotrexate did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology (12. 3) Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration (2. 2) 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 (12.

Refer to the full prescribing information for information about drug interactions with methotrexate (7) Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of severe methotrexate 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, closely monitor for methotrexate adverse reactions when coadministered with: Penicillin or sulfonamide antibiotics Highly protein-bound drugs (e. , oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Weak acids (e. , salicylates) Nephrotoxic products Probenecid Antifolate drugs (e. , dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Hepatotoxic 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 Injection. Consider alternative therapies in patients who have recently received nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. 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.

OVERDOSAGE
Manifestations Overdosage, including fatal overdosage, has occurred with methotrexate. Manifestations of overdosage include adverse reactions reported at recommended dosages, 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. Sepsis or septic shock, renal failure, and aplastic anemia were also reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentration closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely, because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high flux dialyzer.
NONCLINICAL TOXICOLOGY
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.
REFERENCES
“OSHA Hazardous Drugs.” OSHA

Accord Healthcare Inc.

METHOTREXATE- methotrexate_injection, solution Product manual source documgent