Methotrexate (Page 6 of 8)

11 DESCRIPTION

Methotrexate, USP is dihydrofolate reductase inhibitor with the chemical name of L-glutamic acid, N -[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]. The molecular formula is C20 H22 N8 O5 and the molecular weight is 454.45 g/mol. The structural formula is:

22
(click image for full-size original)

Methotrexate tablets, USP for oral use are available in bottles of 36 and 100 tablets. Each tablet contains 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium.

Inactive Ingredients: Anhydrous lactose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized corn starch, propylene glycol, sodium carbonate monohydrate, and talc.

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/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.

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 (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.

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 are supplied as follows:

2.5 mg: Yellow, oval-shaped, scored tablet debossed with stylized b/572 on one side. Available in bottles of 36 tablets (NDC 0555-0572-35) and 100 tablets (NDC 0555-0572-02).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from light.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Methotrexate Tablets 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 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 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 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 (5.2)].

Myelosuppression and Serious Infections

Inform patients and their caregivers that methotrexate 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 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 [see Warnings and Precautions (5.13)].

Lactation

Instruct women not to breastfeed during treatment with methotrexate 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 In Czech Republic By:
Teva Czech Industries, s.r.o.
Opava-Komarov, Czech Republic

Manufactured For:
Teva Pharmaceuticals USA, Inc.
Parsippany, NJ 07054

Rev. D 9/2020

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