Methotrexate is an antimetabolite and antifolate agent with antineoplastic and immunosuppressant activities. Methotrexate binds to and inhibits the enzyme dihydrofolate reductase, resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of DNA and RNA syntheses. Methotrexate also exhibits potent immunosuppressant activity although the mechanism(s) of actions is unclear.
Methotrexate is an antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.
Methotrexate is an antineoplastic antimetabolite with immunosuppressant properties. It is a chemotherapy agent and immune system suppressant.It is used to treat cancer, autoimmune diseases, ectopic pregnancy, and for medical abortions. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, and osteosarcoma.Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn’s disease.It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA .
Mechanism of Action of Methotrexate
Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis
Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine – which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the “S” phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.
Indications of Methotrexate
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Psoriasis
- Active Pauciarticular juvenile rheumatoid arthritis
- Ankylosing Spondylities
- Nonleukemic meningeal cancer
- Severe, active Rheumatoid arthritis
- Acute Lymphocytic Leukemia
- Acute Lymphoblastic Leukemia
- Acute Nonlymphocytic Leukemia
- Advanced Alibert-Bazin syndrome
- Advanced non-Hodgkin lymphoma
- Bladder Cancer
- Brain Tumor
- Breast Cancer
- Bullous Pemphigoid
- Cervical Cancer
- Choriocarcinoma
- Cogan’s Syndrome
- Colorectal Cancer
- Dermatomyositis
- Ectopic Pregnancy
- Eczema
- Esophageal Carcinoma
- Gastric Cancer
- Head and Neck Cancer
- Hodgkin’s Lymphoma
- Juvenile Idiopathic Arthritis
- Lymphoma
- Mantle Cell Lymphoma
- Meningeal Leukemia
- Mycosis Fungoides
- Neoplastic Diseases
- Non-Hodgkin’s Lymphoma
- Non-Small Cell Lung Cancer
- Osteosarcoma
- Ovarian Cancer
- Pancreatic Cancer
- Pemphigoid
- Pemphigus
- Pityriasis rubra pilaris
- Scleroderma
- Small Cell Lung Cancer
- Soft Tissue Sarcoma
- Solid Tumors
- Systemic Sclerosis
- Trophoblastic Disease
- Uveitis
Therapreutic Indications of Methotrexate
- Treatment of alkaptonuria
- Gordimer is indicated for the treatment of active rheumatoid arthritis in adult patients, polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA), when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,
- Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, psoralens, and ultraviolet A (PUVA), and retinoids, and severe psoriatic arthritis in adult patients.
In rheumatological and dermatological diseases
- Active rheumatoid arthritis in adult patients.
- Polyarthritis forms of active, severe juvenile idiopathic arthritis (JIA) in adolescents and children aged 3 years and over when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.
- Severe, treatment refractory, disabling psoriasis which does not respond sufficiently to other forms of treatment such as phototherapy, psoralen and ultraviolet A radiation (PUVA) therapy and retinoids, and severe psoriatic arthritis in adult patients.
In oncology
- Maintenance treatment of acute lymphoblastic leukemia (ALL) in adults, adolescents, and children aged 3 years and over
Therapeutic Uses of Methotrexate
- Methotrexate is indicated for the treatment of breast carcinoma, head and neck cancers (epidermoid), non-small cell lung carcinoma (especially squamous cell types), small cell lung carcinoma, and gestational trophoblastic tumors (gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole).
- Methotrexate is indicated for treatment of cervical carcinoma, ovarian carcinoma, bladder carcinoma, colorectal carcinoma, esophageal carcinoma, gastric carcinoma, pancreatic carcinoma, and penile carcinoma.
- Methotrexate is indicated for treatment of acute lymphocytic leukemia and prophylaxis and treatment of meningeal leukemia.
- Methotrexate is indicated for treatment of acute nonlymphocytic leukemia.
- Methotrexate is indicated for the treatment of non-Hodgkin’s lymphomas, including advanced cases of lymphosarcoma (particularly in children) and Burkitt’s lymphoma.
- Methotrexate is indicated for the treatment of Hodgkin’s disease.
- Methotrexate is indicated in high doses along with leucovorin rescue, in combination with other agents, for treatment of nonmetastatic osteosarcoma in patients who have undergone primary surgical treatment.
- Methotrexate is indicated for the treatment of soft tissue sarcomas.
- Methotrexate is indicated for the treatment of carcinomatous menigitis (intrathecal and intraventricular administration).
- Methotrexate is indicated for treatment of central nervous system (CNS) lymphomas.
- Methotrexate is indicated only for treatment of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy, as confirmed by biopsy and/or dermatologic consultation. It is important to rule out that a psoriasis “flare” is not caused by an undiagnosed disease affecting immune response.
- Methotrexate tablets are indicated for (and the parenteral dosage formes are used) in the treatment of selected cases of severe or active rheumatoid arthritis not adequately responsive to other forms of therapy.
- Methotrexate is being used for treatment of selected cases of active severe psoriatic arthritis.
- Methotrexate is used for treatment of systemic dermatomyositis (polymyositis)
- Methotrexate is indicated in the treatment of severe disabling seronegative arthritides.
Contra Indications of Methotrexate
- Extreme Loss of Body Water
- Condition resulting from a defective immune system
- Decreased Function of Bone Marrow
- Low blood counts due to bone marrow failure
- Defective Growth of Bone Marrow
- Severe anemia
- Severely Decreased Platelets
- Decreased white blood cells
- Alcoholism
- Escape of Fluid into the Lungs
- Interstitial Pneumonitis
- Lung Fibrosis
- Canker Sore
- Ulcer from Stomach Acid
- Ulcerated Colon
- Hardening of the Liver caused by Alcohol
- Hardening of the Liver
- Excess Liver Fibrous Tissue
- Severe liver disease
- Kidney disease with reduction in kidney function
- Diarrhea
- Ascites
- Abnormal liver function tests
- Pregnancy
- A mother who is producing milk and breastfeeding
- Allergies to Folic Acid Antagonist & Methotrexate Analogues
Dosage of Methotrexate
Strengths : 2.5mg ,5mg ,7.5mg ,10mg ,15mg
Rheumatoid Arthritis
- Single dose: 7.5 mg orally or subcutaneously once a week
- Divided dose: 2.5 mg orally every 12 hours for 3 doses once a week
- Maximum weekly dose: 20 mg
Lymphoblastic Leukemia
- Induction: 3.3 mg/m2/day orally or parenterally (in combination with prednisone 60 mg/m2) daily for 4 to 6 weeks
- Maintenance dose during remission: 30 mg/m2 orally or IM 2 times a week
- Alternate maintenance dose during remission: 2.5 mg/kg IV every 14 days
Lymphoma
- Burkitt’s tumor Stages I to II: 10 to 25 mg orally once a day for 4 to 8 days
- Burkitt’s tumor Stage III: Methotrexate is commonly given concomitantly with other antitumor agents
- Duration of therapy: All stages usually require several courses of therapy interposed with 7 to 10 day rest periods
- Lymphosarcoma Stage III: 0.625 to 2.5 mg/kg orally daily as a part of combination chemotherapy
Choriocarcinoma
- 15 to 30 mg orally or IM daily for a 5-day course; courses are usually repeated for 3 to 5 times, with rest periods of one or more weeks between courses, until any manifesting toxic symptoms subside
Psoriasis
- Single Dose: 10 to 25 mg/week orally, IM, IV, or subcutaneously until adequate response is achieved
- Divided Dose: 2.5 mg orally every 12 hours for 3 doses once a week
- Maximum dose: 30 mg/week
Mycosis Fungoides
- Early stage dosing: 5 to 50 mg orally or parenterally once a week; alternatively, 15 to 37.5 mg 2 times a week may be used in patients who have responded poorly to weekly therapy
Breast Cancer
- 40 mg/m² IV; days 1 and 8 every 4 weeks in combination with cyclophosphamide and fluoracil for 6-12 cycles
Head and Neck Cancer
- 40 mg/m² IV; once weekly until disease progression or unacceptable toxicity
Burkitt’s Tumor
- Burkitt’s tumor Stages I to II: 10 to 25 mg orally once a day for 4 to 8 days
- Burkitt’s tumor Stage III: Methotrexate is commonly given concomitantly with other antitumor agents
- Duration of therapy: All stages usually require several courses of therapy interposed with 7 to 10 day rest periods
- Lymphosarcoma Stage III: 0.625 to 2.5 mg/kg orally daily as a part of combination chemotherapy
Osteosarcoma
- Initial Dose: 12 g/m2 IV as a 4-hour infusion (in combination with other chemotherapeutic agents); if this dose is not adequate to achieve a peak serum concentration of 1000 micromolar at the end of the infusion, the dose may be increased to 15 g/m2
- Treatments may occur at 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 weeks after surgery.
Meningeal Leukemia
- 12 mg (maximum 15 mg) intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
Ectopic Pregnancy (Off-label)
Acute Lymphoblastic Leukemia
- Only for Children Pharmaceuticals; 35 bis rue Gay; Lusac, France
Pediatric
Rheumatoid Arthritis
- Initial dose: 10 mg/m2 orally or subcutaneously once a week
- Maximum dose: 20 mg/m2/week (although there is experience with doses up to 30 mg/m2/week in children, there are too few published data to assess how doses over 20 mg/m2/week might affect the risk of serious toxicity in children; experience suggests that children receiving 20 to 30 mg/m2/week
Meningeal Leukemia
- Less than 1 year old: 6 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
- One year old: 8 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
- Two years old: 10 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
- Three years and older: 12 mg intrathecally every 2 to 5 days until the cell count of the CSF returns to normal; at this point, one additional dose is advisable
Acute Lymphoblastic Leukemia
- Induction: 3.3 mg/m2/day orally or parenterally (in combination with prednisone 60 mg/m2) daily for 4 to 6 weeks
- Alternate induction: 20 mg/m2 orally once a week as a component of a multi-agent combination
- Maintenance dose during remission: 30 mg/m2 orally or IM 2 times a week
- Alternate maintenance dose during remission: 2.5 mg/kg IV every 14 day
Side effects of Methotrexate
The most common
- diarrhea
- mouth sores,
- any signs of infection, or a skin rash.
- stomach pain, especially if it comes along with fever and diarrhea or constipation
- yellowing of the skin or eyes
- loss of appetite
- Constipation
- sleepiness or unusual drowsiness
- clumsiness or unsteadiness
- dizziness
- drowsiness
- dry mouth
- false sense of well-being
- increased watering of mouth
- lightheadedness
- constipation;
- vision changes;
- breast swelling (in men or women); or
- decreased sex drive, impotence, or difficulty having an orgasm.
- blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- restless muscle movements in your eyes, tongue, jaw, or neck;
Common
- Drowsiness and lightheadedness the day after taking the medicine.
- Confusion.
- Numbed emotions.
- Visual disturbances such as blurred vision or double vision.
- Shaky movements and unsteady walk (ataxia).
- Loss of memory (amnesia).
- Muscle weakness.
- Dizziness.
- A headache.
- Skin rashes.
- Disturbances of the gut such as diarrhea, constipation, nausea, vomiting or abdominal pain.
- Difficulty in passing urine (urinary retention).
- Changes in sex drive.
- Low blood pressure (hypotension).
- Blood disorders.
- Jaundice.
- Unexpected aggression, restlessness or irritability (tell your doctor if you experience this).
- Nightmares or hallucinations (tell your doctor if you experience this).
Rare
- agitation
- anxiety
- behavioral changes, including aggressiveness, angry outbursts, bizarre behavior, or decreased inhibitions
- confusion
- increased trouble sleeping
- memory problems
- muscle spasms
- shortness of breath
Drug Interactions of Methotrexate
Methotrexate may interact with following drugs, supplements, & may change the efficacy of drugs
- abatacept
- anakinra
- anti-tumour necrosis factor agents (e.g., adalimumab, etanercept, infliximab, )
- azathioprine
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- beta-blockers (e.g., carvedilol, metoprolol, propranolol)
- carbamazepine
- clonidine
- clozapine
- corticosteroids (e.g.dexamethasone, hydrocortisone, prednisone)
- cyclosporine
- diltiazem
- imatinib
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- methotrexate
- methyldopa
- mycophenolate
- phenobarbital
- phenytoin
- rituximab
- tacrolimus
- verapamil
The avobe list is not the sufficient drugs interactions list, please always consult your doctor or pharmacist before taking this drug.
Pregnancy & lactation of Methotrexate
FDA Pregnancy Category X
Methotrexate is contraindicated in pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to a pregnant woman. In women of reproductive potential, methotrexate use is not recommended unless the benefits of therapy are expected to outweigh the considered risks. Advise females of reproductive potential to avoid pregnancy while taking methotrexate; counsel these patients on the fetal risk if pregnancy occurs.
Lactation
Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy with methotrexate. An abstinence period of at least 1 week after chemotherapy doses of methotrexate has been suggested.
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