Methotrexate interferes with DNA synthesis, repair, and cellular replication by irreversibly inhibiting the enzyme dihydrofolate reductase resulting in the inhibition of purine and thymidylate synthesis.

Methotrexate Uses (Indications):

• Oncology uses:

  • For the maintenance treatment of Acute lymphoblastic leukemia. 

  • Prophylaxis and treatment of Acute lymphoblastic leukemia with meningeal involvement.

  • Treatment of trophoblastic neoplasms:

    • Gestational choriocarcinoma
    • Chorioadenoma destruens
    • Hydatidiform mole

  • Breast cancer

  • Head and neck epidermal cancer

  • Cutaneous T-Cell Lymphoma (advanced mycosis fungicides’)

  • Lung cancer (squamous cell and small cell carcinoma)

  • Advanced non-Hodgkin lymphomas

  • Osteosarcoma.

• No oncology uses:

  • Treatment of severe, disabling, and recalcitrant psoriasis

  • Active rheumatoid arthritis

  • Active poly particular juvenile idiopathic arthritis

• Off Label Use of Methotrexate in Adults include:

  • For the prophylaxis of acute graft-versus-host disease

  • Maintenance treatment of Acute promyelocytic leukemia

  • Bladder cancer

  • Central nervous system lymphoma

  • For the maintenance of remission or corticosteroid-dependent Crohn disease

  • Dermatomyositis and polymyositis

  • Multiple sclerosis

  • Nonleukemic meningeal cancer

  • Advanced soft tissue sarcoma including desmoid tumors and aggressive fibromatosis

  • Moderate to severe systemic lupus erythematosus

  • Refractory or relapsing Takayasu arteritis

  • Termination of intrauterine pregnancy

  • Tubal ectopic pregnancy

  • Uveitis

Methotrexate Dose in Adults

Note:

• Doses of greater than 100 - 500 mg//m² may require the administration of leucovorin to prevent toxicity.
• Doses greater than 250 mg/m² is associated with vomiting and prophylactic antiemetics should be used.

  ---

Methotrexate Dose in the treatment of Acute lymphoblastic leukemia:

• Treatment or prophylaxis of Meningeal leukemia:

  • Manufacturer’s labeling:
    • 12 mg to a maximum of 15 mg/dose intrathecal every 2 - 7 days
    • Continue for one dose after the normalization of CSF cell counts.

Note: Since CSF volume correlates with age, the optimal dosing of methotrexate as intrathecal chemotherapy should be based on age rather than on body surface area.

• CALGB 8811 combination regimen [Ref]:

  • Early intensification:
    • 15 mg intrathecal on day 1 of early intensification phase
    • Repeat in four weeks

• CNS prophylaxis/ interim maintenance phase:

  • 15 mg intrathecal on day 1, 8, 15, 22, and 29
  • 20 mg/m² orally on days 36, 43, 50, 57, and 64
  • Prolonged maintenance:
    • 20 mg/m² orally on days 1, 8, 15, and 22, followed by every 4 weeks for 24 months from diagnosis

• Dose-intensive regimen:

  • 200 mg/m² intravenous over two hours, followed by 800 mg/m² over 24 hours beginning on day 1 of even-numbered cycles in combination with cytarabine alternates with Hyper-CVAD, followed by leucovorin rescue therapy.

  • CNS prophylaxis:

    • 12 mg intrathecal on day 2 of each cycle
    • Maintenance:
      • 10 mg/m² /day intravenous for five days every month for two years in combination with prednisone, vincristine, and mercaptopurine.

---

Methotrexate Dose in the treatment of Breast cancer:

• CMF regimen:

  • 40 mg/m² intravenous on days 1 and 8 every four weeks in combination with cyclophosphamide and fluorouracil for 6 - 12 cycles

---

Methotrexate Dose in the treatment of Chorioadenoma, choriocarcinoma, and gestational trophoblastic diseases:

• 15 - 30 mg oral or intramuscular once a day for 5 days.
• The dose may be repeated for 3 - 5 courses as per the manufacturer’s labeling or
• 100 mg/m² intravenous over 30 minutes followed by 200 mg/m² intravenous over 12 hours with folinic acid (leucovorin) 24 hours after the start of methotrexate.
• If the hCG levels plateau for three consecutive weeks, administer a second course or
• 100 mg/m² intravenous push followed by 200 mg/m² intravenous over 12 hours on day 1 with leucovorin 24 hours after the start of methotrexate in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide [EMA-CO regimen]) every two weeks. Continue treatment for at least 2 cycles after hCG levels are normal.

---

Methotrexate Dose in the treatment of advanced head and neck cancer:

• 40 mg/m² intravenous once a week until toxicity or disease progression.

---

Methotrexate Dose in the patients with Non-Hodgkin Lymphoma: 

• CODOX-M/IVAC regimen:

  • Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC)

  • Adults 65 years of age or less:

    • 300 mg/m² intravenous over one hour (on day 10) followed by 2,700 mg/m² over 23 hours with leucovorin.

  • Adults older than 65 years:

    • 100 mg/m² intravenous over one hour on day 10 followed by 900 mg/m² over 23 hours with leucovorin

• Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen:

  • 1,000 mg/m² intravenous over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles or
  • 200 mg/m² intravenous bolus on day 1 followed by 800 mg/m² over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles with leucovorin.

---

Methotrexate Dose in the treatment of cutaneous T-cell lymphoma (Mycosis fungoides):

• 5 - 50 mg orally once a week or 15 - 37.5 mg two times a week orally or intramuscular for early stages as per manufacturer’s labeling or
• 25 mg orally once a week, the dose may be increased to 50 mg once a week.

---

Methotrexate Dose in the treatment of Osteosarcoma:

• Adults 30 years of age or less:

  • MAP regimen:

    • 12 gms/m² intravenous to a maximum dose of 20 gms/dose over four hours followed by leucovorin rescue for 4 doses during induction prior to 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.

---

Methotrexate Dose in the treatment of Psoriasis:

• 2.5 - 5 mg/dose orally twice daily three times a week or
• 10 - 25 mg given once week oral, intramuscular, intravenous, or subcutaneous.
• The dose may be adjusted gradually to optimal response (doses above 20 mg once a week are associated with an increased incidence of toxicity).
• The dose should not exceed 30 mg per week.

Note: Patients at risk of hematologic toxicity or renal impairment should be initiated with a lower dose i.e. 2.5 - 5 mg per week.

---

Methotrexate Dose in the treatment of Rheumatoid arthritis:

• 10 - 15 mg orally once a week.
• Increase the dose by 5 mg every 2 - 4 weeks to a maximum of 20 - 30 mg once a week.
• Patients with inadequate response or intolerance to oral therapy may be advised parenteral methotrexate.

---

Methotrexate Dose in the maintenance phase of Acute promyelocytic leukemia:

• 15 mg/m² orally once a week for 2 years or 20 mg/m² once a week for one year.
• 15 mg/m² intramuscular once a week for 2 years.

  ---

Methotrexate Dose as off-label use in the treatment of Bladder cancer: 

• Dose-dense MVAC regimen:

  • 30 mg/m² intravenous on day 1 every 14 days in combination with vinblastine, doxorubicin, and cisplatin.

• CMV regimen:

  • 30 mg/m² intravenous on days 1 and 8 every 21days for 3 cycles in combination with cisplatin, vinblastine, and leucovorin.

    ---

Methotrexate Dose as off-label use in the treatment of CNS lymphoma:

• 8,000 mg/m² intravenous over four hours followed by leucovorin rescue every 2 weeks until complete response or a maximum of 8 cycles.
• This should be followed with 2 consolidation cycles at the same dose every 2 weeks with leucovorin rescue, followed by 11 maintenance cycles of 8,000 mg/m² every 4 weeks with leucovorin rescue in patients with a complete response or
• 2,500 mg/m² intravenous over 2 - 3 hours every 14 days for 5 doses in combination with vincristine, procarbazine, intrathecal methotrexate, leucovorin, dexamethasone, and cytarabine or
• 3,500 mg/m² intravenous over two hours on day 2 every 14 days in combination with rituximab, vincristine, procarbazine, and leucovorin with intrathecal methotrexate 12 mg between days 5 and 12 of each cycle in patients with positive CSF cytology for 5 to 7 induction cycles.

  ---

Methotrexate Dose as off-label use in the treatment or remission maintenance of corticosteroid dependent Crohn disease:

• 25 mg subcutaneous or intramuscular once a week.
• The dose may be reduced to 15 mg once a week if steroid-free remission maintained for 4 months.

  ---

Methotrexate Dose as off-label use in the treatment of Dermatomyositis and polymyositis:

• 5 - 15 mg orally once a week as an adjunct with prednisone.
• The dose may be increased to 25 mg once a week in increments of 2.5 mg per week.

Note: The maximum dose should not exceed 50 mg per week. Doses greater than 25 mg per week should be administered parenterally.

---

Methotrexate Dose in the prophylaxis of acute Graft-versus-host disease:

• 15 mg/m² /dose intravenous 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 intravenous on day 1 and 10 mg/m² /dose on days 3, 6, and 11 after allogeneic transplant in combination with cyclosporine or
• 15 mg/m² /dose intravenous on day 1 and 10 mg/m² /dose on days 3, 6, and 11 after an allogeneic transplant in combination with cyclosporine, followed by leucovorin.
• Omit day-11 methotrexate for grade 2 or higher toxicity.

  ---

Methotrexate Dose as off-label use in the treatment of Multiple sclerosis:

 

• 7.5 or 20 mg orally once a week either alone or as add-on therapy to interferon beta-1a.

---

Methotrexate Dose as off-label use in the treatment of Nonleukemic meningeal cancer:

• 12 mg/dose two times a week intrathecal for 4 weeks, then once a week for 4 doses, then once a month for 4 doses or
• 10 mg two times a week for 4 weeks, then once a week for 1 month, then every 2 weeks for 2 months or
• 10 - 15 mg two times a week for 4 weeks, then once a week for 4 weeks, then a maintenance regimen of once a month.

  ---

Methotrexate Dose as off-label use in the treatment of advanced Soft tissue sarcomas like desmoid tumors and aggressive fibromatosis:

• 30 mg/m² intravenous every 7 - 10 days in combination with vinblastine for one year.

---

Methotrexate Dose as off-label use in the treatment of moderate-to-severe Systemic lupus erythematosus:

• 7.5 mg orally once a week initially to a maximum dose of 20 mg once a week in combination with prednisone.
• Increase the dose in increments of 2.5 mg at weekly intervals.

  ---

Methotrexate Dose as off-label use in the treatment of refractory or relapsing Takayasu arteritis:

• 0.3 mg/kg/week orally initially to a maximum dose of 15 mg per week in combination with a steroid.
• The dose should be increased in increments of 2.5 mg per week until the maximum dose is reached.

  ---

Methotrexate Dose as off-label use in the treatment of Termination of intrauterine pregnancy:

• 50 mg/m² intramuscular followed by vaginal misoprostol 3 - 7 days later in pregnancies that are less than 49 days' gestation.

---

Methotrexate Dose as off-label use in the treatment of tubal ectopic pregnancy:

• Single-dose regimen:

  • 50 mg/m² intramuscular on day 1.
  • Measure serum hCG levels on days 4 and 7.
  • If the hCG levels decrease by less than 15%, repeat the dose on day 7.

• Two-dose regimen:

  • 50 mg/m² intramuscular on day 1.
  • Measure serum hCG levels on days 4 and administer a second dose of methotrexate 50 mg/m² intramuscular.
  • Measure serum hCG levels on day 7.
  • If the hCG levels decrease by less than 15%, administer the third dose and repeat hCG levels on day 11.
  • If the hCG levels decrease by less than 15%, administer the fourth dose and repeat hCG levels on day 14.

• Multidose regimen in combination with leucovorin:

  • 1 mg/kg intramuscular on days 1, 3, 5, and 7 alternating with leucovorin calcium on days 2, 4, 6, and 8.
  • On each day of methotrexate administration, measure serum hCG levels.
  • If the serum hCG decreases by more than 15% from the previous measurement, discontinue methotrexate.
  • If serum hCG decreases by less than 15% from the previous measurement, administer methotrexate to a maximum of 4 doses.

    ---

Methotrexate Dose as off label use in the treatment of Uveitis:

• 7.5 - 20 mg orally once a week either alone or in conjunction with steroids and immunosuppressants.

Methotrexate Dose in Childrens

Note:

Methotrexate doses between 100 - 500 mg/m² may require leucovorin calcium rescue.

Methotrexate doses greater than 500 mg/m² require leucovorin calcium rescue.

Methotrexate Dose in the treatment of Acute lymphoblastic leukemia of infancy: 

• Intensification and Consolidation:

  • Infant less than one year of age at diagnosis:
    • 4,000 - 5,000 mg/m² intravenous over 24 hours every week for 2 doses.

---

Methotrexate Dose in the treatment of Acute lymphoblastic leukemia:

Interim maintenance:

• High-dose methotrexate in children and adolescents:

  • 500 mg/m² intravenous over half an hour 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.

• Escalating-dose methotrexate in children and adolescents:

  • 100 mg/m² intravenous then escalate the dose by 50 mg/m² every 10 days for a total of 5 doses.

• Maintenance in children and adolescents:

  • 20 mg/m² orally once a week.

• Intrathecal therapy for CNS prophylaxis:

  • Intrathecal:
    • Less than 1 year: 6 mg
    • 1 to less than 2 years: 8 mg
    • 2 to less than 3 years: 10 mg
    • 3 to 8 years or less: 12 mg
    • more than 8 years: 15 mg

---

Methotrexate Dose in the treatment of malignant CNS tumors (medulloblastoma, PNET, ependymoma, and brainstem glioma):

• Head Start II Protocol:

  • Children less than 10 years:
    • 400 mg/kg intravenous on Day 4 with leucovorin rescue until the level is less than 0.1 micromolar (μM) every three weeks for 5 cycles in combination with cisplatin, vincristine, etoposide, and cyclophosphamide followed by an auto-transplant.

---

Methotrexate Dose in the treatment of Crohn disease: 

• BSA-directed dosing:

  • 15 mg/m² once a week subcutaneous to a maximum dose of 25 mg per week.

• Fixed-dosing:

  • 20 - 29 kg: 10 mg once a week
  • 30 - 39 kg: 15 mg once a week
  • 40 - 49 kg: 20 mg once a week
  • 50 kgs or more: 25 mg once a week

---

Methotrexate Dose in the treatment of Dermatomyositis: 

• Children and Adolescents:

  • 15 to 20 mg/m² intramuscular or subcutaneous once a week in combination with corticosteroids and with either folic acid or folinic acid supplementation

    • Intramuscular or SubQ (preferred):

      • 15 to 20 mg/m² or 1 mg/kg (whichever is less) IM or subQ (preferred) once a week to a maximum dose of 40 mg in combination with corticosteroids or

    • Oral:

      • 15 mg/m² or 1 mg/kg (whichever is less) once a week orally to a maximum dose of 40 mg in combination with corticosteroids.

        ---

Methotrexate Dose in the prophylaxis of acute Graft-versus-host disease:

• Children and Adolescents:
  • 15 mg/m² /dose intravenous 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 intravenous on day 1 and 10 mg/m² /dose on days 3, 6, and 11 after allogeneic transplant in combination with cyclosporine.

    ---

Methotrexate Dose in the treatment of polyarticular juvenile idiopathic arthritis:

• BSA-directed dosing:

  • Children and Adolescents 2 - 16 years:
    • 10 mg/m² once a week orally, intramuscular, or subQ initially.
    • The dose should be adjusted gradually up to 20 - 30 mg/m² once a week to the usual maximum dose of 25 mg.
    • Parenteral administration may reduce the gastrointestinal side effects.

• Weight-directed dosing:

  • Children and Adolescents:
    • 0.5 mg/kg once a week orally or subQ to the maximum initial dose of 15 mg.
    • The dose may be increased by 1 mg/kg to the maximum dose of 30 mg after 4 weeks if the symptoms do not improve or worsen.

---

Methotrexate Dose in the prophylaxis or treatment of Meningeal leukemia:

• Since CSF volume correlates with the age of the patient, intrathecal dose administration should be based on age rather than the body surface area.
  • Less than 1 year: 6 mg/dose
  • 1 to less than 2 years: 8 mg/dose
  • 2 to less than 3 years: 10 mg/dose
  • 3 to less than 9 years: 12 mg/dose
  • 9 years of age or older: 15 mg/dose

---

Methotrexate Dose in the treatment of B-cell Non-Hodgkin Lymphoma:

• Intermediate risk:

  • Induction 1 and 2 (COPADM regimen) and Consolidation 1 and 2 (CYM regimen):
    • 3,000 mg/m² intravenous over 3 hours with leucovorin rescue

• High risk: 

  • 8,000 mg/m² intravenous over 4 hours once followed by leucovorin rescue.

    ---

Methotrexate Dose in the treatment of T-cell Anaplastic Large Cell Lymphoma:

NHL-BFM90 protocol:

• Course B:

  • 500 mg/m² intravenous over 24 hours.
  • Administer 10% of the dose over the first 30 minutes and the remaining 90% of dose over 23.5 hours on Day 1 in combination with dexamethasone, cyclophosphamide, doxorubicin, and triple intrathecal therapy.
  • Administer intrathecal on day one 2 hours after the start of the methotrexate intravenous infusion
    • Less than 1 year: 6 mg/dose
    • 1 to less than 2 years: 8 mg/dose
    • 2 - 3 years: 10 mg/dose
    • 3 years or more: 12 mg/dose

  • Course BB:

    • 5,000 mg/m² intravenous over 24 hours.
    • Administer 10% of the dose over the first 30 minutes and the remaining 90% of dose over 23.5 hours on Day 1 in combination with dexamethasone, cyclophosphamide, vincristine, doxorubicin, and triple intrathecal therapy.
    • Administer 2 hours intrathecal on day one and on day 5 after the start of the methotrexate intravenous infusion.

Note: The dose may be reduced by 50% in patients with overt CNS disease and an implantable intraventricular device.

• Less than 1 year: 3 mg/dose
• 1 to less than 2 years: 4 mg/dose
• 2 to less than 3 years: 5 mg/dose
• 3 years or more: 6 mg

---

Methotrexate Dose in the treatment of Osteosarcoma:

• High-dose methotrexate in children and adolescents:

  • 12 g/m² to a maximum dose of 20 g/dose intravenous over 4 hours followed by leucovorin rescue)
    • for four doses during induction (before surgery) at weeks 3, 4, 8, and 9
    • for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 25, 26, 30, and 31 in combination with doxorubicin and cisplatin.

---

Methotrexate Dose in the treatment of severe Psoriasis that is recalcitrant to topical therapy: 

• 0.2 - 0.4 mg/kg orally or subcutaneously once a week for 6 - 178 weeks.

---

Methotrexate Dose in the treatment of localized juvenile Scleroderma:

• 1 mg/kg once a week orally or subQ (preferred) to a maximum dose of 25 mg as monotherapy or in combinations with corticosteroids for 12 months.

---

Methotrexate Dose in the treatment of recalcitrant Uveitis: 

• BSA-directed dosing:

  • 15 mg/m² once a week orally or subQ to the usual dose of 10 - 25 mg/m².

• Weight-directed dosing:

  • 0.5 - 1 mg/kg subQ once a week to the maximum dose of 25 mg

    ---

• Dosing adjustment for toxicity:

  • Non-hematologic toxicity:

    • Discontinue until recovery of diarrhea, stomatitis, or vomiting

  • Hematologic toxicity:

    • Discontinue immediately if significant cytopenias occur

  • Oncologic uses:

    • Patients with profound granulocytopenia and fever should be evaluated and treated immediately with broad-spectrum parenteral antimicrobial agents.

Pregnancy Risk Factor X

• Methotrexate crosses over the placental boundary. It is not recommended for pregnant women.
• [US Boxed Warning] Methotrexate can cause severe congenital abnormalities and fetal death
• Methotrexate administration during the first trimester may increase the risk for skull anomalies, facial dysfunction, CNS abnormalities, and limb abnormalities.
• If administered in the second or third trimester, it can also cause intrauterine growth restriction or functional abnormalities.
• [US Boxed Warning]: When prescribing, consider the risks and benefits to the fetusMethotrexate for pregnant women with neoplastic diseases
• Methotrexate has been approved for treatment of gestational cancer, chorioadenoma and hydatidiform mole.
• It is used to medically manage ectopic pregnancies in carefully selected patients. Also, it can be used to medically terminate an intrauterine pregnancy at a gestational age of up to 49 days.
• [US Boxed Warning] Methotrexate contraindicated in psoriasis and polyarticular juvenile Idiopathic.Treatment of RA in pregnant women with arthritis
• Before starting treatment, pregnant women with reproductive potential should have their pregnancy tested.
• It should be stopped 3 to 6 months before a planned pregnancy.
• [US Boxed Warning] Effective contraception should always be recommended to both males and women of reproductive potential before and after methotrexate administration.
• Females who are receiving methotrexate for treatment should use effective contraception. This is for at least six months, or for one cycle of ovulatory stimulation after the last dose.
• Males should use effective contraception during therapy, and at least three months after receiving their last dose of methotrexate.
• It can cause infertility, menstrual irregularities, or oligospermia. This condition is not reversible by treatment discontinuation.

Methotrexate use during breastfeeding:

• Methotrexate and 7-hydroxymethotrexate are excreted in breast milk.
• Low maternal doses can be associated with low neonatal risks, but most guidelines recommend that methotrexate is not used during breastfeeding.

Methotrexate Dose in Kidney disease:

The manufacturer has not recommended any dose adjustment in patients with renal disease. The following dose adjustment may be used:

• CrCl 10 - 50 mL/minute:

  • Administer 50% of the dose

• CrCl less than 10 mL/minute:

  • Avoid its use

• Intermittent hemodialysis:

  • Administer 50% of the dose after dialysis.

• Continuous renal replacement therapy:

  • Administer 50% of the dose.

• Hemodialysis patients with cancer:

  • Administer 25% of the dose after hemodialysis.
  • Monitor the patient closely for toxicity

• High-dose methotrexate (dose-intensive regimen for ALL (200 mg/m² over 2 hours, followed by 800 mg/m² over 24 hours with leucovorin rescue):

  • Serum creatinine of less than 1.5 mg/dL:

    • Adjustment in the dose is not necessary

  • Serum creatinine 1.5 - 2 mg/dL:

    • Administer 75% of the dose

  • Serum creatinine of more than 2 mg/dL:

    • Administer 50% of the dose

Methotrexate dose in liver disease:

The manufacturer has not recommended any dose adjustment, however, the following guidelines may be followed:

• Bilirubin 3.1 - 5 mg/dL or transaminases more than 3 times the upper limits of normal:

  • Administer 75% of the dose

• Bilirubin greater than 5 mg/dL:

  • Avoid its use

Side effects of Methotrexate:

• Cardiovascular:

  • Arterial Thrombosis
  • Cerebral Thrombosis
  • Chest Pain
  • Deep Vein Thrombosis
  • Hypotension
  • Pericardial Effusion
  • Pericarditis
  • Plaque Erosion
  • Pulmonary Embolism
  • Retinal Thrombosis
  • Thrombophlebitis
  • Vasculitis

• Central Nervous System:

  • Dizziness
  • Headache
  • Abnormal Cranial Sensation
  • Brain Disease
  • Chemical Arachnoiditis
  • Chills
  • Cognitive Dysfunction
  • Drowsiness
  • Fatigue
  • Leukoencephalopathy
  • Malaise
  • Mood Changes
  • Neurological Signs And Symptoms
  • Severe Neurotoxicity
  • Speech Disturbance

• Dermatologic:

  • Alopecia
  • Burning Sensation Of Skin
  • Skin Photosensitivity
  • Skin Rash
  • Dermatitis
  • Pruritus
  • Acne Vulgaris
  • Dermal Ulcer
  • Diaphoresis
  • Ecchymoses
  • Erythema Multiforme
  • Erythematous Rash
  • Exfoliative Dermatitis
  • Furunculosis
  • Hyperpigmentation
  • Hypopigmentation
  • Skin Abnormalities Related To Radiation Recall
  • Skin Necrosis
  • Stevens-Johnson Syndrome
  • Telangiectasia
  • Toxic Epidermal Necrolysis
  • Urticaria

• Endocrine & Metabolic:

  • Decreased Libido
  • Decreased Serum Albumin
  • Diabetes Mellitus
  • Gynecomastia
  • Menstrual Disease

• Gastrointestinal:

  • Diarrhea
  • Nausea And Vomiting
  • Stomatitis
  • Abdominal Distress
  • Anorexia
  • Aphthous Stomatitis
  • Enteritis
  • Gastrointestinal Hemorrhage
  • Gingivitis
  • Hematemesis
  • Intestinal Perforation
  • Melena
  • Pancreatitis

• Genitourinary:

  • Azotemia
  • Cystitis
  • Defective Oogenesis
  • Defective Spermatogenesis
  • Dysuria
  • Hematuria
  • Impotence
  • Infertility
  • Oligospermia
  • Proteinuria
  • Severe Renal Disease
  • Vaginal Discharge

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Leukopenia
  • Pancytopenia
  • Agranulocytosis
  • Anemia
  • Aplastic Anemia
  • Bone Marrow Depression
  • Decreased Hematocrit
  • Eosinophilia
  • Gastric Ulcer
  • Hypogammaglobulinemia
  • Lymphadenopathy
  • Lymphoma
  • Lymphoproliferative Disorder
  • Neutropenia
  • Non-Hodgkin’s Lymphoma
  • Tumor Lysis Syndrome

• Hepatic:

  • Increased Liver Enzymes
  • Cirrhosis
  • Hepatic Failure
  • Hepatic Fibrosis
  • Hepatitis
  • Hepatotoxicity

• Hypersensitivity:

  • Anaphylactoid Reaction

• Infection:

  • Cryptococcosis
  • Cytomegalovirus Disease
  • Herpes Simplex Infection
  • Herpes Zoster
  • Histoplasmosis
  • Infection
  • Vaccinia

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia
  • Myelopathy
  • Osteonecrosis
  • Osteoporosis

• Ophthalmic:

  • Blurred Vision
  • Conjunctivitis
  • Eye Pain
  • Visual Disturbance

• Otic:

  • Tinnitus

• Renal:

  • Renal Failure

• Respiratory:

  • Interstitial Pneumonitis
  • Chronic Obstructive Pulmonary Disease
  • Cough
  • Epistaxis
  • Pharyngitis
  • Pneumonia
  • Pulmonary Alveolitis
  • Pulmonary Disease
  • Pulmonary Fibrosis
  • Respiratory Failure
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Fever
  • Nodule
  • Tissue Necrosis

Contraindications to Methotrexate Include:

• Allergy reactions to methotrexate and any component of the formulation
• Breastfeeding
• Pregnancy
• Alcoholism, alcoholic or other chronic liver diseases
• Immunodeficiency syndromes
• Pre-existing blood disorders like bone marrow dysplasia, leukopenia and thrombocytopenia as well as significant anemia are all possible.
• Grave renal impairment
• Use nitrous oxide anesthesia in conjunction.

Warnings and Precautions

• Acute renal failure:

  • It can cause kidney damage that could lead to acute renal failure.
  • High-dose patients on methotrexate are at greater risk for developing renal dysfunction.
  • Monitoring of renal functions and levels of methotrexate should be closely done.
  • It is important to hydrate and do a urine alkalinization.

• Suppression of bone marrow [US Boxed Warning]

  • It has been associated with severe bone marrow suppression, including anemia, especially when taken in high doses.
  • It is important to monitor blood counts regularly.
  • Patients who have a history of marrow suppression or other preexisting conditions should be cautious about taking the drug.
  • Cytopenias should be treated immediately.

• CNS effects

  • Patients who received intravenous methotrexate and cranial radiation have been known to suffer neurotoxicity, including leukoencephalopathy.
  • Chronic leukoencephalopathy can be seen even in the absence of cranial radiation. This is due to patients who have received high doses of intrathecal metotrexate. This condition can be fatal, progressive, and not reversible.
  • With high and intermediate doses of methotrexate, there have been reports of generalized and focal seizures as well as a stroke-like condition manifesting in confusion, hemiparesis and transient blindness.
  • Intrathecal administration of methotrexate may cause chemical arachnoiditis, which manifests as headaches, back pain, nuchal rigidity and fever.

• Dermatologic toxicities:

  • It can cause severe and even fatal skin reactions.
  • Skin reactions can occur as soon as the medication is administered.
  • There have been reports of severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis. This usually requires that methotrexate be stopped.

• Gastrointestinal toxicity: [US Boxed Warning]

  • High doses of NSAIDs may cause gastrointestinal toxicities.
  • This can manifest as diarrhea or ulcerative stomatitis, which may need to be treated immediately.
  • Death from intestinal perforation or hemorhagic enteritis may also occur.
  • Patients with ulcerative colitis and peptic ulcer disease are at greater risk of developing gastrointestinal adverse reactions.
  • High doses of medication may require the use of antiemetics.

• Hepatotoxicity: [US Boxed Warning]

  • Methotrexate prolonged use can cause liver damage, fibrosis and cirrhosis.
  • It is recommended to have periodic liver biopsies as elevated liver enzymes may not precede liver injury.
  • A cumulative dose of 1.5g or more, and prolonged exposure are all risk factors.
  • It is important to monitor your liver function, including the levels of albumin, regularly.
  • Patients with rheumatoid arthritis may have abnormal liver functions that could indicate liver injury. However, this is not the case for patients with psoriasis.
  • Patients with severe or moderate liver biopsy changes may need to stop taking Methotrexate.
  • It should be used with caution in patients with preexisting liver disease and those on concomitant hepatotoxic agents like sulfasalazine, retinoids, and azathioprine.
  • Patients at high risk for liver injury also include:
    • People with a history of moderate to high ethanol consumption
    • An abnormal liver chemistries
    • Histories of chronic liver disease, including hepatitis B and C
    • A family history of inheritable liver disease
    • Diabetes
    • Obesity
    • Hyperlipidemia
    • Methotrexate therapy is not complete without folate supplementation
    • Cumulative methotrexate dose exceeding 1.5 gms
    • Continuous daily methotrexate dosing
    • Significant history of exposure to hepatotoxic drug
    • Senior age

• Hypersensitivity

  • Anaphylactic reactions, including severe allergic reactions, may occur and may need to be treated with an interruption of treatment or alternate agents.

• Infections [US Boxed Warning]

  • Possibilities of fatal opportunistic infections, such as Pneumocystis pneumonia jirovecii, may arise.
  • It can also increase the risk of developing other infections. These include:
    • Bacterial infections that can cause death or serious illness are life-threatening.
    • Fungal infections
    • Viral infections
    • Hepatitis B reactivation
    • Tuberculosis
    • Disseminated herpes zoster infection
    • Cytomegalovirus infection.
  • Patients with active infections should use it with caution. It is also contraindicated for patients with immunodeficiency disorders.
  • It is important to monitor patients for signs and symptoms of infection, and get them treated immediately.

• Pneumonitis: [US Boxed Warning]

  • Treatment interruption may not be possible for acute or chronic interstitial pneumonia.
  • You may experience a dry cough, fever, hypoxemia, dyspnea, or pulmonary infiltrates.

• Secondary malignancy [US Boxed Warning]

  • Chronic low-dose methotrexate use has been linked to malignant lymphomas. These may regress after withdrawal and may not require cytotoxic therapy.

• Tumor lysis syndrome [US Boxed Warning]​​​​​​​

  • Patients with high tumor burdens may develop tumor lysis syndrome, which should be treated and prevented.

• Ascites/pleural effusions: [US Boxed Warning]

  • Patients with third-spacing such as ascites or pleural effusion have a higher half-life.
  • These patients are at high risk for developing toxicities and need to be closely monitored.

• Hepatic impairment

  • Preexisting liver disease patients should be cautious when taking the drug.

• Peptic ulcer disease:

  • Patients suffering from peptic ulcer disease, diarrhea, or stomatitis need to be advised of the dangers.

• Renal impairment [US Boxed Warning]

  • Patients with impaired renal function may need to be given a lower dose.
  • In advanced cases, it is best to stop treating.

Methotrexate: Drug Interaction

Risk Factor C (Monitor therapy)
Alitretinoin (Systemic)	May enhance the hepatotoxic effect of Methotrexate.
Bile Acid Sequestrants	May decrease the absorption of Methotrexate.
Cephalothin	May diminish the therapeutic effect of Methotrexate.
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Ciprofloxacin (Systemic)	May increase the serum concentration of Methotrexate.
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Diethylamine Salicylate	May increase the serum concentration of Methotrexate.
Eltrombopag	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Fosphenytoin-Phenytoin	Methotrexate may decrease the serum concentration of FosphenytoinPhenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug.
Gemfibrozil	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions.
Ibrutinib	May increase the serum concentration of Methotrexate.
Leflunomide	Methotrexate may enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity.
LevETIRAcetam	May increase the serum concentration of Methotrexate.
Lumacaftor	May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Mipomersen	May enhance the hepatotoxic effect of Methotrexate.
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Penicillins	May increase the serum concentration of Methotrexate.
P-glycoprotein/ABCB1 Inducers	May decrease the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Proton Pump Inhibitors	May increase the serum concentration of Methotrexate.
Pyrimethamine	May enhance the adverse/toxic effect of Methotrexate.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Sapropterin	Methotrexate may decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin.
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
SulfaSALAzine	May enhance the hepatotoxic effect of Methotrexate.
Tegafur	Methotrexate may enhance the adverse/toxic effect of Tegafur.
Teriflunomide	May increase the serum concentration of OAT3 Substrates.
Teriflunomide	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Theophylline Derivatives	Methotrexate may increase the serum concentration of Theophylline Derivatives.
Tofacitinib	Methotrexate may enhance the immunosuppressive effect of Tofacitinib. Management: Avoid the use of tofacinib in combination with potent immunosuppressive methotrexate-containing regimens.
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Alcohol (Ethyl)	May enhance the hepatotoxic effect of Methotrexate. Management: Limit alcohol consumption in patients taking methotrexate. The use of methotrexate for the treatment of psoriasis or rheumatoid arthritis is contraindicated in patients with alcoholism or alcoholic liver disease.
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
CycloSPORINE (Systemic)	May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity.
Dexketoprofen	May increase the serum concentration of Methotrexate. Management: Concurrent use of dexketoprofen with methotrexate doses of 15 mg/week or more is inadvisable. Use with lower methotrexate doses should only be performed with caution and increased monitoring.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Lenograstim	Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Loop Diuretics	Methotrexate may diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Nonsteroidal Anti-Inflammatory Agents	May increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate.
Palifermin	May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.
Probenecid	May increase the serum concentration of Methotrexate. Management: Avoid concomitant use of probenecid and methotrexate if possible. If used together, consider lower methotrexate doses and monitor for evidence of methotrexate toxicity.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Salicylates	May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern.
Sulfonamide Antibiotics	May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and therapeutic doses of sulfonamides (eg, trimethoprim/sulfamethoxazole). Patients receiving prophylactic doses of trimethoprim/sulfamethoxazole and methotrexate should be carefully monitored.
Tolvaptan	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Tolvaptan	May increase the serum concentration of OAT3 Substrates.
Trimethoprim	May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression).
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Vaccines (Live)	Methotrexate may enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided.
Risk Factor X (Avoid combination)
Acitretin	May enhance the hepatotoxic effect of Methotrexate.
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.
Dipyrone	May enhance the adverse/toxic effect of Methotrexate. Methotrexate may enhance the adverse/toxic effect of Dipyrone. Specifically, the risk for agranulocytosis and pancytopenia may be increased.
Foscarnet	May enhance the nephrotoxic effect of Methotrexate.
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Nitrous Oxide	May enhance the adverse/toxic effect of Methotrexate.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.

Monitroing Pararmeters:

Monitoring parameters when used as a chemotherapeutic agent:

• Monitor at baseline and frequently during the therapy, the following parameters:
  • CBC with differential and platelets
  • Serum creatinine and BUN
  • Liver function tests
  • Methotrexate levels
  • Urine pH (with high-dose methotrexate)
  • Fluid and electrolyte status in patients with impaired elimination of methotrexate
  • Chest x-ray
  • Pulmonary function test.
  • Monitor for toxicities especially in patients with ascites, pleural effusion, decreased folate stores, renal disease, and hepatic impairment.

    ---

Monitoring parameters when used for the treatment of Psoriasis:

• CBC with differential and platelets at baseline, one to two weeks after initiating therapy or dosage increase, every 2 - 4 weeks for first few months, and then every 1 - 3 months)
• Patients at risk of hematologic toxicity (e.g. elderly patients, patients with hypoalbuminemia, and patients with kidney disease) should be monitored more closely
• BUN, serum creatinine, and eGFR at baseline and every 2 - 3 months
• Consider PPD (Montoux test) for latent TB screening at baseline
• Liver function tests at baseline, monthly for the first 6 months, and then every 1 - 2 months. (patients at a high risk of hepatotoxicity should have liver function tests monitored five days after the last dose.
• Pregnancy test in females of reproductive potential
• Chest x-ray at baseline in patients with underlying lung disease.
• Pulmonary function test in patients suspected of having methotrexate-induced lung toxicity.

Liver biopsy in patients with risk factors for hepatotoxicity:

• At baseline or after 2 - 6 months of therapy and with each 1 - 1.5 gms of cumulative dose interval.

Liver biopsy for patients without risk factors for hepatotoxicity:

• Patients with persistent elevations (5 out of 9 AST levels) during a 12-month period or a decline of serum albumin levels below the normal range in patients with normal nutritional status.
• Consider liver biopsy after a cumulative dose of 3.5 - 4 gms and after each additional 1.5 gm.

  ---

Monitoring Parameters when used for the treatment of Rheumatoid arthritis:

• Monitor CBC with differential and platelets, serum creatinine, and liver function tests at baseline, two to four weeks for 3 months after initiating therapy or dosage increase, every 8 - 12 weeks for the first 3 - 6 months, followed by every 12 weeks.
• Hepatitis B and C serology at baseline.
• PPD (Montoux test) at baseline and annually who are at risk.
• Pregnancy test in females of reproductive potential
• Chest x-ray prior to initiation of therapy (within one year prior to initiation)
• Liver biopsy:
  • At baseline in patients with persistently abnormal LFTs, history of alcohol intake, or patients with chronic hepatitis B and C infection or
  • During the treatment, if the patient has persistently elevated liver enzymes (6 out of 12 abnormal tests over one year or 5 out of 9 abnormal reports if the LFTs are performed at 6-weeks intervals).

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Monitoring parameters when used to treat Polyarticular-course juvenile idiopathic arthritis:

• CBC with differential and platelets at baseline and at least monthly.
• BUN, serum creatinine, and eGFR at baseline and every 1 - 2 months
• Consider PPD (Montoux test) for latent TB screening at baseline
• Liver function tests at baseline and every 1 - 2 months
• Pregnancy test in females of reproductive potential
• Pulmonary function test in patients suspected of having methotrexate-induced lung toxicity.

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Monitoring parameters when used to treat patients with Crohn disease:

• CBC with differential and platelets at baseline and periodically thereafter.
• Liver function tests at baseline and every 1 - 2 months
• Liver biopsy at baseline in patients with chronic liver disease and those with abnormal baseline liver function tests.
• Liver biopsy at one year in patients with persistently elevated AST and reduced albumin.
• Chest X-ray at baseline.

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Monitoring parameters when used to treat patients with Tubal ectopic pregnancy:

• Before starting the treatment, serial hCG levels should be measured 2 - 7 days apart to exclude the presence of a viable intrauterine pregnancy.
• Monitor CBC with differential counts, liver function tests, and serum creatinine
• Assess for any contraindications to methotrexate.

Single-dose regimen:

• Monitor serum hCG levels after treatment on days 4 and 7, if the levels decrease by more than 15%, continue monitoring serum hCG once a week until non-pregnant levels are reached.
• If the serum hCG levels do not decline to the pre-pregnancy levels after 2 doses, consider alternative treatment options.

Two-dose regimen:

• Monitor serum hCG levels after treatment on days 4 and 7, if the levels decrease by more than 15%, continue monitoring serum hCG once a week until non-pregnant levels are reached.
• If the serum hCG levels do not decline to the pre-pregnancy levels after 4 doses, consider alternative treatment options.

Multidose regimen in combination with leucovorin:

• Measure serum hCG levels on the days of methotrexate administration.
• When hCG decrease by more than 15%, monitor hCG weekly until non-pregnant levels are achieved.

How to administer Methotrexate?

• Antiemetics may be given to patients who are administered methotrexate at doses greater than 250 mg/m² intravenously.
• It can be administered orally, intramuscular, intravenous, intrathecally, or Subcutaneously.
• Intravenous administration should be given as a slow push at a rate of 10 mg/minute when given as an intravenous bolus infusion or may be administered in the form of 24-hour continuous infusion.
• For high dose methotrexate or intrathecal administration, a preservative-free formulation should be used.
• To prevent methotrexate toxicity in patients administered high doses of methotrexate, leucovorin (calcium folinate) should follow methotrexate administration.
• The oral solution should be administered using a calibrated oral syringe or a dosing cup. Do not use a tablespoon or a household teaspoon to measure the dose.
• Patients may use Otrexup and Rasuvo (autoinjectors) for once-weekly self-administration subcutaneously in the abdomen or thigh after appropriate training.

Mechanism of action of Methotrexate:

• Methotrexate acts as an antimetabolite and inhibits DNA repair, synthesis, and cell replication.
• It causes DNA damage, repair, and cell replication. Methotrexate is very harmful to cells that are actively growing.
• It blocks cell proliferation in the S phase. It targets the rapidly growing epithelial cells in the skin. 
• It is unknown what mechanism it works in Crohn's colitis, juvenile idiopathic and rheumatoid joint disease. 
• Its anti-inflammatory and immunomodulatory actions are likely to be the most probable mechanisms.

It has an onset of action of 3 to 6 weeks when used as an anti-rheumatic drug. Absorption of the drug is highly variable and dose-dependent (absorption decreases at higher doses). It is completely absorbed following intramuscular injection. It slows downPermeatesThe drug is absorbed into the pleural effusions, ascites, and then exits slowly from these areas. The liver and kidneys retain the drug in high concentrations.

50% of the drug isprotein-bound. It is converted intracellularly to polyglutamates, which are as potent and as potent than methotrexate.

ThebioavailabilityChildren are more likely to have a high degree of variability after oral administration (23%-95%) 

The bioavailability in adults is approximately 60%, and it is dose-dependent.

It has been ahalf-life eliminationAdults have a half-life of between 3-10 hours with low doses and 8-15 hours with high doses. 

The half-life elimination in children varies from 0.7 to 5.8 hours.

TheTime to achieve peak serum concentrationOral administration in children takes 0.7 to 4 hours, and adults take 0.75 to 6 hours. After intramuscular injection, it takes between 30 and 60 minutes for the peak serum concentration to be reached.

The drug can be excreted.Route dependent and ose dependent The drug is eliminated unchanged from the urine after intravenous administration.  

International Brands of Methotrexate:

• JAMP-Methotrexate
• Metoject
• PMS-Methotrexate
• RATIO-Methotrexate Sodium
• Abitrexate
• Alltrex
• Artrait
• Atrexel
• Bertanel
• Biotrexate
• Brimexate
• Canceren
• Cytotrex
• Ebetrex
• Ebetrexat
• Emthexat
• Emthexate
• Emthrxate
• Hytas
• Imutrex
• Jylamvo
• Lantarel
• Maxtrex
• Medsatrexate
• Meisusheng
• Merox-50
• Metex
• Methoblastin
• Methocip
• Methofill
• Methotrexat
• Methotrexat
• Bigmar
• Methotrexat Ebewe
• Methotrexat Farmos
• Methotrexat Lachema
• Methotrexat Teva
• Methotrexate
• Methotrexate Pharmacia
• Methotrexate Wyeth Lederle
• Methotrexate
• Methotrexato
• Methox
• Metodik
• Metoject
• Metotreksat
• Metotressato Teva
• Metotrexato DBL
• Metrex
• Mexat
• Midu
• Mtrex
• MTX
• MTX Hexal
• Neotrexate
• Novatrex
• Onkomet
• Otaxem
• P&U Methotrexate
• Pterin
• Quinux
• Reumatrex
• Sanotrexat
• Texate
• Trexan
• Trexject
• Trexol
• Trexonate
• Trexxol
• Trixilem
• Xantromid
• Zexate

Methotrexate brand names in Pakistan:

Methotrexate Injection 1 G
Methotrexate	Bio Pharma
Unitrexate	Al-Habib Pharmaceuticals.

Methotrexate Injection 5 Mg
Emthexate Pf	Turner Grahams Of Pakistan (Pvt) Ltd.
Methotrexate	Umair Associates

Methotrexate Injection 25 Mg
Mtx	Highnoon Laboratories Ltd.

Methotrexate Injection 50 Mg
Emthexate Pf	Turner Grahams Of Pakistan (Pvt) Ltd.
Methotrexate	Umair Associates
Methotrexate	Pfizer Laboratories Ltd.
Methotrexate	Bio Pharma
Methotrexate	Atco Laboratories Limited
Pharmatrexate	Pharmedic (Pvt) Ltd.
Unitrexate	Al-Habib Pharmaceuticals.

Methotrexate Inj 500 Mg
Methotrexate	Umair Associates
Unitrexate	Al-Habib Pharmaceuticals.

Methotrexate Tablets 10 Mg
Cytotrexate	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Emthexate	Turner Grahams Of Pakistan (Pvt) Ltd.
Methotrexate	Umair Associates
Methotrexate	Werrick Pharmaceuticals

Methotrexate Tablets 2.5 Mg
Cytotrexate	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Dmard	Wilshire Laboratories (Pvt) Ltd.
Emthexate	Turner Grahams Of Pakistan (Pvt) Ltd.
Methotrexate	Umair Associates
Methotrexate	Werrick Pharmaceuticals
Mtx	Highnoon Laboratories Ltd.
Pharmatrexate	Pharmedic (Pvt) Ltd.
Unitrexate	Al-Habib Pharmaceuticals.