Methotrexate: Package Insert and Label Information (Page 3 of 5)

8.2 Lactation

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 0.08:1. 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, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final dose.

8.3 Females and Males of Reproductive Potential

Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [ Use in Specific Populations (8.1)] .

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate tablets [see Contraindications (4), Use in Specific Populations (8.1)] .

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose.

Males

Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose.

Infertility

Females

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

8.4 Pediatric Use

The safety and effectiveness of methotrexate tablets 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 and Usage (1), Dosage and Administration (2)] . No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)] .

The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1)] .

8.5 Geriatric Use

Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal Impairment

Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology (12.3)] . 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 methotrexate tablets as appropriate [see Warnings and Precautions (5.8)] .

8.7 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 [see Clinical Pharmacology (12.3)] . Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.5)] .

10 OVERDOSAGE

Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.9)] .

Manifestations

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.

Management

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.

11 DESCRIPTION

Methotrexate, USP is dihydrofolate reductase inhibitor with the chemical name of N-[4-[[(2,4 diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L glutamic acid. The molecular formula is C ₂₀ H ₂₂ N ₈ O ₅ and the molecular weight is 454.4 g/mol. The structural formula is:

Methotrexate tablets, USP for oral use are available in bottles of 36 and 100 tablets. Each methotrexate tablet, USP contains 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium and the following inactive ingredients: lactose monohydrate, magnesium stearate and maize starch.

12 CLINICAL PHARMACOLOGY

12.1 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 rheumatoid arthritis and in psoriasis is unknown.

12.3 Pharmacokinetics

Absorption

At doses of 30 mg/m ² 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.

Distribution

Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.

Elimination

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.

Specific Populations

The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown.

Pediatric Patients

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 (C _max 0.11 to 2.3 micromolar after a 20 mg/m ² dose) was 20-fold. The time to peak concentration (T _max 0.67 to 4 hours after a 15 mg/m ² dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m ² 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/m ² /week to 11.2 mg/m ² /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/m ² to 30 mg/m ²) or for JIA (3.75 mg/m ² to 26.2 mg/m ²), 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.

Patients with Renal impairment

The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

15 REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

Methotrexate Tablets USP, 2.5 mg , are supplied as round, biconvex, yellow tablets, scored in half on one side, engraved with “A” above the score and “1” below. They are available as follows:

Bottles of 100: NDC 42291-505-01

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Methotrexate tablets, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. ¹

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Embryo-Fetal Toxicity

• Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1)] .
• Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose [see Use in Specific Populations (8.3)] .
• Advise males of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose [see Use in Specific Populations (8.3)] .

Hypersensitivity Reactions

Advise patients and their caregivers of the potential risk of hypersensitivity and that methotrexate tablets are 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 (5.2)] .

Myelosuppression and Serious Infections

Inform patients and their caregivers that methotrexate tablets 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 (5.3, 5.11)] .

Gastrointestinal Toxicity

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 (5.4)] .

Hepatotoxicity

Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.5)] .

Pulmonary Toxicity

Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see Warnings and Precautions (5.6)] .

Dermatologic Reactions

Advise patients and their caregivers that methotrexate tablets 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 (5.7)] .

Renal Toxicity

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 (5.8)] .

Risk of Serious Adverse Reactions with Medication Error

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 (5.9)] .

Neurotoxicity

Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions (5.12)] .

Secondary Malignancies

Advise patients on the risk of second primary malignancies during treatment with methotrexate tablets [see Warnings and Precautions (5.13)] .

Lactation

Instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final dose [see Use in Specific Populations (8.2)] .

Infertility

Advise females and males of reproductive potential that methotrexate may impair fertility [see Warnings and Precautions (5.16), Use in Specific Populations (8.3)] .

Drug Interactions

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 (7)] .

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 05-2020-02

AV 09/20 (P)