Methotrexate

Methotrexate is an Immunosuppressant belonging to Antineoplastic agent.

Methotrexate is an antineoplastic agent used the treatment of a wide variety of cancers as well as severe psoriasis, severe rheumatoid arthritis, and juvenile rheumatoid arthritis.

Methotrexate rapidly absorbed from the gastrointestinal tract and rapidly and completely absorbed after IM doses. Bioavailability is found to be ~60% (low dose). Time to peak plasma concentrations is about 0.75-6 hours (oral); 30-60 minutes (IM). Methotrexate distributes to tissues and extracellular fluids; penetrates ascitic fluid and effusions. It crosses placenta and enters into breast milk. Volume of distribution of IV dose: 0.18 L/kg (initial); 0.4-0.8 L/kg (steady state). The plasma protein binding is approximately 50%. Methotrexate partly metabolized in the intestinal flora by carboxypeptidase to DAMPA; undergoes hepatic metabolism by aldehyde oxidase to form 7-hydroxy methotrexate; and intracellular metabolism into polyglutamates, which may also be converted by hydrolase enzymes back to methotrexate. Methotrexate mainly via urine (80-90% as unchanged drug; 5-7% as 7-hydroxy methotrexate); faeces (<10%). The elimination half-life is approximately 3-10 hours (low-dose treatment); 8-15 hours (high-dose treatment).

Methotrexate shows side effects like Dizziness, drowsiness, Headache, swollen, tender gums, decreased appetite, reddened eyes, hair loss.

Methotrexate is available in the form of Oral solution, Oral Tablet, and Injectable solution.

Methotrexate is available in India, US, Singapore, Canada, Spain, France, Italy, Malaysia, China, Japan, and Australia.

Methotrexate belongs to the Antineoplastic agent acts as an Immunosuppressant.

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 is unknown; it may affect immune function.

The onset and duration of action of Methotrexate is not clinically established.

The Tmax of Methotrexate is approximately 1-2 hours (oral route) and 30-60min (intramuscular route).

Methotrexate is used in the treatment of life-threatening conditions like rheumatoid arthritis, psoriasis, and few cancers. It should be used under the supervision of a qualified professional. It may cause severe liver, kidney and lung injury if taken in more quantities.

Methotrexate is approved for use in the following clinical indications

Adult indication

• Acute lymphoblastic leukemia
• Acute promyelocytic leukemia maintenance phase
• Bladder cancer
• Breast cancer
• Gestational trophoblastic neoplasia
• Graft-vs-host disease, acute, prophylaxis
• Head and neck cancer
• Large granular lymphocyte leukemia, symptomatic
• Mycosis fungoides
• Non-Hodgkin lymphoma
• Nonleukemic meningeal cancer
• Osteosarcoma
• Primary CNS lymphoma, newly diagnosed
• Primary cutaneous anaplastic large cell lymphoma
• Soft tissue sarcoma

Pediatric indication

• Acute lymphoblastic leukemia of infancy
• Acute lymphoblastic leukemia/lymphoma, immature B-cell
• Acute lymphoblastic leukemia/lymphoma, immature T-cell
• CNS tumors, malignant
• Crohn disease
• Dermatomyositis
• Graft-versus-host disease, acute prophylaxis
• Juvenile idiopathic arthritis; polyarticular
• Meningeal leukemia, prophylaxis or treatment
• Non-Hodgkin lymphoma, mature B-cell
• Non-Hodgkin lymphoma, mature T-cell
• Osteosarcoma
• Psoriasis, severe; recalcitrant to topical therapy
• Scleroderma, localized
• Uveitis, recalcitrant

Adult Dose

• Acute lymphoblastic leukemia

Meningeal leukemia prophylaxis or treatment: Intrathecal: 12 to 15 mg (maximum 15 mg/dose) every 2 to 7 days; continue for 1 dose beyond cerebrospinal fluid (CSF) cell count normalization.

CALGB 8811 regimen (as a component of combination chemotherapy)

Early intensification: Intrathecal: 15 mg on day 1 of early intensification phase, repeat in 4 weeks.

CNS prophylaxis/interim maintenance phase: Intrathecal: 15 mg on days 1, 8, 15, 22, and 29. Oral: 20 mg/m² on days 36, 43, 50, 57, and 64.

Prolonged maintenance: Oral: 20 mg/m² on days 1, 8, 15, and 22 every 4 weeks for 24 months from diagnosis.

Protocol 8787 regimen (as part of a multiphase, multiagent regimen): Patients <60 years of age

CNS prophylaxis: Intrathecal: 12 mg at the start of induction, then 12 mg with first postremission chemotherapy, then 12 mg once weekly for 4 more doses, for a total of 6 doses (patients with CNS disease at diagnosis required a total of 10 doses).

Consolidation phases (1C, 2C, and 3C): IV: 220 mg/m² bolus, followed by 60 mg/m²/hour for 36 hours beginning on days 1 and 15 (followed by leucovorin rescue) of each 28-day consolidation cycle (in combination with mercaptopurine).

Maintenance: Oral: 20 mg/m² on days 1, 8, 15, and 22 every 4 weeks (in combination with mercaptopurine) until in complete remission for 30 months.

• Acute promyelocytic leukemia maintenance phase (off-label)

Oral: 15 mg/m² once weekly for 2 years or 20 mg/m² once weekly for 1 year.

IM: 15 mg/m² once weekly for 2 years.

• Bladder cancer (off-label)

Locally advanced or metastatic disease

Dose-dense MVAC regimen: IV: 30 mg/m² on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and growth factor support) until disease progression or unacceptable toxicity.

MVAC regimen: IV: 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for up to 6 cycles (Ref) or 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) until disease progression or unacceptable toxicity (Ref) or 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, cisplatin, and filgrastim) for up to 6 cycles or until loss of clinical benefit.

Neoadjuvant treatment

Dose-dense MVAC regimen: IV: 30 mg/m² on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and pegfilgrastim) for 3 or 4 cycles.

MVAC regimen: IV: 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for 3 cycles.

CMV regimen: IV: 30 mg/m² on days 1 and 8 every 21 days (in combination with cisplatin, vinblastine, and leucovorin) for 3 cycles.

• Breast cancer

CMF regimen: IV: 40 mg/m² days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for 6 to 12 cycles.

• Gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia, low-risk disease (off-label dosing)

8-day regimen: IM: 1 mg/kg every 48 hours (on days 1, 3, 5, and 7) for 4 doses (with leucovorin 30 hours after each methotrexate dose), repeat cycle every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy.

5-day regimen: IV/IM: 0.4 mg/kg (maximum dose: 25 mg) once daily for 5 days, repeat every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy.

Gestational trophoblastic neoplasia, high-risk metastatic disease (off-label dosing)

EMA-CO regimen: IV: 100 mg/m² IV push followed by 200 mg/m² over 12 hours on day 1 (with leucovorin 24 hours after the start of methotrexate; in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide) every 14 days and continuing for at least 2 cycles after hCG level is normal.

• Graft-vs-host disease, acute, prophylaxis (off-label)

IV: 15 mg/m² on day 1 and 10 mg/m² on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) or 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) or 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine, followed by leucovorin); may omit day 11 methotrexate for ≥ grade 2 toxicity.

• Head and neck cancer

IV: 40 mg/m² once weekly until disease progression or unacceptable toxicity.

• Large granular lymphocyte leukemia, symptomatic (off-label)

Oral: Initial: 5 to 7.5 mg once weekly (with or without prednisone), escalate up to 15 to 20 mg once weekly or 10 mg/m²/week over 1 to 3 months; methotrexate was administered in split doses in the morning and evening on one day per week or 10 mg/m²/week (administered in divided doses in the morning and evening on one day per week), in combination with prednisone, followed by a prednisone taper after 30 days or 10 mg/m²/week (administered in divided doses in the morning and evening on one day per week), with or without prednisone; discontinue treatment if no response after 4 months or 7.5 mg/m² once weekly.

• Mycosis fungoides

Oral or IM: 25 to 75 mg orally once weekly (as a single agent) or 10 mg/m² orally twice weekly (as part of a combination regimen) or 5 to 50 mg IM once weekly (for early stage) or 15 to 37.5 mg IM twice weekly (if poor response to weekly therapy) (manufacturer's labeling) or 25 mg orally once weekly, may increase to 50 mg orally once weekly.

• Non-Hodgkin lymphoma

Burkitt lymphoma

Modified CODOX-M/IVAC regimen ± rituximab: Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC).

Adults ≤65 years of age: IV: 300 mg/m² over 1 hour on day 10 followed by 2,700 mg/m² over 23 hours (with leucovorin rescue).

Adults >65 years of age: IV: 100 mg/m² over 1 hour on day 10 followed by 900 mg/m² over 23 hours (with leucovorin rescue).

High-dose methotrexate/cytarabine alternating with Hyper-CVAD: IV: 1,000 mg/m² over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue).

9251 regimens: IV: 150 mg/m² over 30 minutes followed by 1,350 mg/m² over 23.5 hours (with leucovorin rescue) on day 1 of cycles 2 through 7 (in combination with cyclophosphamide, prednisone, ifosfamide, mesna, vincristine, cytarabine, etoposide, dexamethasone, doxorubicin, and CNS prophylaxis).

Mantle cell lymphoma: High-dose methotrexate/cytarabine alternating with Hyper-CVAD (± rituximab)

IV: 200 mg/m² bolus on day 1 or day 2 followed by 800 mg/m² over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue).

• Nonleukemic meningeal cancer (off-label)

Intrathecal: 12 mg/dose twice weekly for 4 weeks, then weekly for 4 doses, then monthly for 4 doses or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months or 10 to 15 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month.

• Osteosarcoma

Adults ≤30 years of age: MAP regimen: IV: 12 g/m² (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 4, 5, 9, and 10, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 24, 25, 28, and 29 (in combination with doxorubicin and cisplatin); other combinations, intervals, age ranges, and doses (8 to 14 g/m²/dose) have been described (with leucovorin rescue), refer to specific reference for details.

• Primary CNS lymphoma, newly diagnosed (off-label)

IV: 8 g/m² over 4 hours (followed by leucovorin rescue) every 14 days until complete response or a maximum of 8 cycles; if complete response, follow with 2 consolidation cycles at the same dose every 14 days (with leucovorin rescue), followed by 11 maintenance cycles of 8 g/m² every 28 days (with leucovorin rescue) or R-MPV regimen: 3.5 g/m² over 2 hours on day 2 every 2 weeks (in combination with rituximab, vincristine, procarbazine, and leucovorin [with intra-Ommaya methotrexate 12 mg between days 5 and 12 of each cycle if positive CSF cytology]) for 5 to 7 induction cycles followed by reduced-dose whole brain radiotherapy and then cytarabine or autologous stem cell transplant or R-MP regimen (patients ≥65 years of age): 3 g/m² over 4 hours on days 2, 16, and 30 of a 42-day cycle (in combination with rituximab, procarbazine, and leucovorin) for 3 cycles or MT-R regimen: 8 g/m² once every 2 weeks (adjusted for creatinine clearance [refer to protocol for details] and in combination with leucovorin, temozolomide, and rituximab) for 7 doses, then followed by high-dose consolidation chemotherapy or 3.5 g/m² on weeks 1, 3, 5, 7, and 9 (in combination with leucovorin, temozolomide, and rituximab), followed by whole-brain radiotherapy and then post-radiation temozolomide.

• Primary cutaneous anaplastic large cell lymphoma (off-label)

Oral: 15 to 25 mg once weekly (range: 10 to 60 mg once weekly); based on response, may increase dosing interval up to once every 2 weeks after the weekly dose has been optimized or 5 to 50 mg once weekly (median dose: 20 to 25 mg once weekly) for up to 48 weeks or until disease progression or unacceptable toxicity.

• Soft tissue sarcoma (off-label)

IV: 30 mg/m² every 7 to 10 days (dose usually rounded to 50 mg) in combination with vinblastine for 1 year.

Pediatric Dose

• Acute lymphoblastic leukemia of infancy

Intensification and Consolidation: Infant (<1 year of age) at diagnosis: IV: 4,000 to 5,000 mg/m² over 24 hours every 7 days for 2 doses; specific days depend on protocol phase.

• Acute lymphoblastic leukemia/lymphoma, immature B-cell

Interim maintenance

High-dose methotrexate: Children and Adolescents: IV: 500 mg/m² over 30 minutes followed by 4,500 mg/m² over 23.5 hours to complete a total dose of 5,000 mg/m² over 24 hours on days 1, 15, 29, and 43 (with leucovorin rescue) in combination with vincristine, mercaptopurine, and intrathecal methotrexate.

Escalating-dose methotrexate: Children and Adolescents: IV: Initial dose: 100 mg/m² then escalate dose by 50 mg/m² every 10 days for 5 doses total in combination with vincristine, pegaspargase, and intrathecal methotrexate.

Maintenance: Children and Adolescents: Oral: 20 mg/m² once weekly in combination with vincristine, prednisone, mercaptopurine, and intrathecal methotrexate. On weeks intrathecal methotrexate is administered, consider holding the oral methotrexate for that week; refer to specific protocol.

CNS prophylaxis intrathecal therapy: Infants, Children, and Adolescents: Intrathecal: Age-based dosing: Days of administration vary based on risk status and protocol; refer to institutional protocols or reference for details

<1 year: 6 mg.

1 to <2 years: 8 mg.

2 to <3 years: 10 mg.

3 to ≤8 years: 12 mg.

>8 years: 15 mg.

• Acute lymphoblastic leukemia/lymphoma, immature T-cell

Interim maintenance

Escalating-dose methotrexate: Children and Adolescents: IV: Initial dose: 100 mg/m² then escalate dose by 50 mg/m² every 10 days for 5 doses total in combination with vincristine and pegaspargase.

CNS prophylaxis intrathecal therapy: Children and Adolescents: Intrathecal: Age-adjusted dosing: Days of administration vary based on risk status and protocol; refer to protocol for details.

1 to <2 years: 8 mg.

2 to <3 years: 10 mg.

3 to <9 years: 12 mg.

≥9 years: 15 mg.

• CNS tumors, malignant

Children <10 years: IV: 400 mg/kg on day 4 with leucovorin rescue until level less than 0.1 micromolar (µM); administer methotrexate every 21 days for 5 cycles (in combination with cisplatin, vincristine, etoposide, and cyclophosphamide; then followed by an autotransplant).

• Crohn disease

BSA-directed dosing: 15 mg/m² once weekly; maximum dose: 25 mg/dose.

Fixed dosing:

20 to 29 kg: 10 mg once weekly.

30 to 39 kg: 15 mg once weekly.

40 to 49 kg: 20 mg once weekly.

≥50 kg: 25 mg once weekly.

• Dermatomyositis

Children and Adolescents

IM or Subcutaneous (preferred): Initial: 15 to 20 mg/m² or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg/dose; used in combination with corticosteroids and with either folic acid or folinic acid supplementation.

Oral (not preferred): Initial: 15 mg/m² or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg/dose; used in combination with corticosteroids.

• Graft-versus-host disease, acute prophylaxis

Standard dose: Children and Adolescents: IV: 15 mg/m²/dose on day 1 and 10 mg/m²/dose on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) or 15 mg/m²/dose on day 1 and 10 mg/m²/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine). Leucovorin rescue may be administered according to protocol.

Mini-dose: Children and Adolescents: IV: 5 mg/m²/dose; frequency of dosing reported is variable; following haploidentical stem cell transplant, doses were administered on days 5, 7, 10, and 15 in combination with posttransplant cyclophosphamide and cyclosporine and leucovorin rescue administered 24 hours after methotrexate dose; following cord blood transplant, doses were administered on days 1, 3, and 6 in combination with tacrolimus.

• Juvenile idiopathic arthritis; polyarticular

BSA-directed dosing: Children and Adolescents: Oral, IM, Subcutaneous: Initial: 10 to 15 mg/m² once weekly; adjust gradually up to 20 to 30 mg/m² once weekly; maximum dose: 25 mg/dose. To reduce GI side effects and improve bioavailability and efficacy, consider parenteral administration (IM, Subcutaneous) of doses >10 mg/m².

Weight-directed dosing: Children and Adolescents: Oral, Subcutaneous: Initial: 0.5 mg/kg once weekly; maximum initial dose: 15 mg/dose; if symptoms worsen or are unchanged after 4 weeks, may increase to Subcutaneous: 1 mg/kg; maximum dose: 25 mg/dose.

• Meningeal leukemia, prophylaxis or treatment

Infants, Children, and Adolescents: Intrathecal.

<1 year: 6 mg/dose.

1 to <2 years: 8 mg/dose.

2 to <3 years: 10 mg/dose.

3 to <9 years: 12 mg/dose.

≥9 years: 15 mg/dose.

• Non-Hodgkin lymphoma, mature B-cell

Intermediate risk:

Induction 1 and 2 (COPADM regimen) and Consolidation 1 and 2 (CYM regimen): Children and Adolescents: IV: 3,000 mg/m² over 3 hours with leucovorin rescue; combination chemotherapy varied with protocol phase.

High risk:

Infants ≥6 months, Children, and Adolescents: IV: 8,000 mg/m² over 4 hours once followed by leucovorin rescue; specific day of therapy and combination chemotherapy depend on protocol phase and clinical factors (eg, CNS positive).

• Non-Hodgkin lymphoma, mature T-cell

Infants, Children, and Adolescents: IV: 3,000 mg/m² over 3 hours with leucovorin rescue (in combination with multi-agent chemotherapy, depending on cycle) for a total of 6 cycles.

• Osteosarcoma

High-dose methotrexate: Children and Adolescents: IV: 12 g/m² (maximum dose: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 3, 4, 8, and 9, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 25, 26, 30, and 31 (in combination with doxorubicin and cisplatin); reported frequencies and durations have varied.

• Psoriasis, severe; recalcitrant to topical therapy

Children and Adolescents: Oral, Subcutaneous: Usual reported range: 0.2 to 0.4 mg/kg once weekly; maximum reported dose: 25 mg/dose; reported treatment duration is highly variable: 6 to 178 weeks.

• Scleroderma, localized

Infants, Children, and Adolescents: Oral, Subcutaneous (preferred): 1 mg/kg once weekly; maximum dose: 25 mg/dose; alone or in combination with corticosteroids; duration of therapy: 12 months.

• Uveitis, recalcitrant

Children and Adolescents:

BSA-directed dosing: Oral, Subcutaneous: Most frequently reported: 15 mg/m² once weekly, usual range: 10 to 25 mg/m²; the Subcutaneous route may be preferred for patients with GI symptoms, poor bioavailability, or doses >15 mg/m²; a maximum dose of 25 mg/dose was reported in other pediatric uveitis trials.

Weight-directed dosing: Subcutaneous: 0.5 to 1 mg/kg once weekly; maximum dose: 25 mg/dose.

Methotrexate is available in various strengths as 2.5 mg; 25 mg/mL; 1 g; 20 mg; 50 mg; 5 mg; 7.5 mg; 10 mg; 15 mg; 2.5 mg/mL; 10 mg/0.4 mL; 12.5 mg/0.4 mL; 15 mg/0.4 mL; 17.5 mg/0.4 mL; 20 mg/0.4 mL; 22.5 mg/0.4 mL; 25 mg/0.4 mL; 7.5 mg/0.4 mL; 7.5 mg/0.15 mL; 10 mg/0.2 mL; 12.5 mg/0.25 mL; 15 mg/0.3 mL; 17.5 mg/0.35 mL; 22.5 mg/0.45 mL; 25 mg/0.5 mL; 27.5 mg/0.55 mL; 30 mg/0.6 mL; 7.5 mg/0.3 mL; 12.5 mg/0.5 mL; 15 mg/0.6 mL; 17.5 mg/0.7 mL; 20 mg/0.8 mL; 22.5 mg/0.9 mL.

Methotrexate is available in the form of Oral solution, Oral Tablet, and Injectable solution.

• Dosage Adjustment in Kidney Patient

There are no specific dosage recommendations provided.

• Dosage Adjustment in Hepatic impairment Patient

Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.

Bilirubin >5 mg/dL: Avoid use.

• Avoid milk and dairy products. Milk and dairy products reduce absorption.
• Caution should be taken with St. John's Wort.
• Limit caffeine intake. Caffeine may reduce the effectiveness of methotrexate.

Methotrexate is contraindicated in patients with

• Pregnancy Methotrexate can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
• Alcoholism or Liver Disease Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
• Immunodeficiency Syndromes Patients who have overt or laboratory evidence of immunodeficiency syndromes.
• Preexisting Blood Dyscrasias Patients who have pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
• Hypersensitivity Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.

• Nonsteroidal anti-inflammatory drugs: Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) prior to or during high dose methotrexate therapy; may increase and prolong serum methotrexate levels. Doses used for psoriasis may still lead to unexpected toxicities; use with caution when administering NSAIDs or salicylates with lower doses of methotrexate for rheumatoid arthritis (RA).
• Proton pump inhibitors: Concomitant use of proton pump inhibitors with methotrexate (primarily high-dose methotrexate) may elevate and prolong serum methotrexate levels and metabolite (hydroxy methotrexate) levels (based on case reports and pharmacokinetic studies). May lead to toxicities; use with caution.
• Vaccines: Immunization may be ineffective during methotrexate treatment. Immunization with live vaccines is not recommended; cases of disseminated vaccinia infections due to live vaccines have been reported.
• Vitamins: Vitamins containing folate may decrease response to systemic methotrexate (in patients with neoplastic diseases); folate deficiency may increase methotrexate toxicity. Folic acid supplementation may be indicated in patients receiving methotrexate for non-neoplastic conditions.

Consumption of alcohol is not recommended due to the risk of liver injury.

Limited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during Methotrexate therapy and for one week after final dose.

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

• Avoid milk and dairy products. Milk and dairy products reduce absorption.
• Caution should be taken with St. John's Wort.
• Limit caffeine intake. Caffeine may reduce the effectiveness of methotrexate.

Common

● Diarrhea, nausea, oral mucosal ulcer, vomiting, Hepatic cirrhosis, hepatotoxicity, increased liver enzymes, Dizziness, fatigue, headache, Cough.

Rare

● Pericardial effusion, Dermal ulcer, erythema multiforme, palmar-plantar erythrodysesthesia, papular rash, photodermatitis, skin abnormalities related to radiation recall , Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, Endocrine & metabolic: Decreased libido, Abdominal distress, mesenteric ischemia, Crystalluria Aplastic anemia, febrile neutropenia, lymphoproliferative disorder (including intestinal follicular lymphoma, large B-cell lymphoma, and T-cell lymphoma [follicular]) skin carcinoma, Exacerbation of hepatitis B, Anaphylaxis, angioedema, hypersensitivity angiitis, severe hypersensitivity reaction (including hyperpigmentation, pustular rash, and severe stomatitis), Herpes zoster infection, histoplasmosis , infection, septicemia, Hypersensitivity at injection site (including fixed drug eruption at injection site), Cerebrovascular accident, encephalopathy seizure , severe neurotoxicity, Myelopathy (intrathecal; subacute), Dry eye syndrome, eye irritation, optic neuropathy, Acute kidney injury, Acute respiratory distress , pleural effusion, pleuritic chest pain, pneumonia due to Pneumocystis jirovecii, tuberculosis.

• Nitrous Oxide

Co-administration 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.

• Folic Acid

Co-administration 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.

The common side effect of Methotrexate includes the following

Common

● Dizziness, drowsiness, Headache, swollen, tender gums, decreased appetite, reddened eyes, hair loss.

Rare

● Blurred vision or sudden loss of vision, seizures, confusion, weakness or difficulty moving one or both sides of the body, loss of consciousness.

• Pregnancy

Pregnancy Category X

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. In pregnant women with non-malignant disease, Methotrexate is contraindicated. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated 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 2-4% and 15-20%, respectively.

• Nursing Mothers

Limited published literature reports the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during Methotrexate therapy and for one week after final dose.

• Pediatric Use

The safety and effectiveness of methotrexate, including Methotrexate, have not been established in pediatric patients with psoriasis. The safety and effectiveness of Methotrexate have not been established in pediatric patients with neoplastic diseases. The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. Methotrexate does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2).

• Geriatric Use

Clinical studies of methotrexate did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease, or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may overestimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.

Symptoms: Haematological (e.g. leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression) and gastrointestinal (e.g. mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulcer and bleeding) reactions; Chronic overdose: Sepsis or septic shock, renal failure, aplastic anaemia; Intrathecal: Headache, nausea, vomiting, seizure or convulsion, acute toxic encephalopathy; cerebellar herniation associated with increased intracranial pressure, death.

Management: Initiate parenteral Ca folinate therapy within 1 hour after methotrexate administration, at a dose equal to the methotrexate dose received by the patient. Administer leucovorin as antidote within 1 hour at a dose equal to or greater than the methotrexate dose. Renal dialysis, blood transfusions and reverse barrier nursing may also be necessary. Hydration and urinary alkalisation may be necessary in case of large overdose. Acute intermittent haemodialysis using a high flux dialysator may be considered for effective clearance of methotrexate. Administer glucarpidase in patients with delayed methotrexate clearance due to impaired kidney function. Avoid concomitant administration of leucovorin within 2 hours or after a dose of glucarpidase.

Pharmacodynamic

Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily.

Pharmacokinetics

• Absorption

Methotrexate rapidly absorbed from the gastrointestinal tract and rapidly and completely absorbed after IM doses. Bioavailability is found to be ~60% (low dose). Time to peak plasma concentrations is about 0.75-6 hours (oral); 30-60 minutes (IM).

• Distribution

Methotrexate distributes to tissues and extracellular fluids; penetrates ascitic fluid and effusions. It crosses placenta and enters into breast milk. Volume of distribution of IV dose: 0.18 L/kg (initial); 0.4-0.8 L/kg (steady state). The plasma protein binding is approximately 50%.

• Metabolism and Excretion

Methotrexate partly metabolized in the intestinal flora by carboxypeptidase to DAMPA (4-deoxy-4-amino-N10-methylpteroic acid); undergoes hepatic metabolism by aldehyde oxidase to form 7-hydroxy methotrexate; and intracellular metabolism into polyglutamates, which may also be converted by hydrolase enzymes back to methotrexate. Methotrexate mainly via urine (80-90% as unchanged drug; 5-7% as 7-hydroxy methotrexate); faeces (<10%). The elimination half-life is approximately 3-10 hours (low-dose treatment); 8-15 hours (high-dose treatment).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210737s000lbl.pdf
• https://www.rxlist.com/trexall-drug.htm#indications
• https://reference.medscape.com/drug/trexall-otrexup-methotrexate-343201
• https://www.mims.com/india/drug/info/methotrexate?type=full&mtype=generic
• https://medlineplus.gov/druginfo/meds/a682019.html#side-effects
• https://www.practo.com/medicine-info/methotrexate-177-api
• https://go.drugbank.com/drugs/DB00563
• https://www.drugs.com/dosage/methotrexate.html
• https://www.uptodate.com/contents/methotrexate-drug-information#F194531