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Methotrexate; Uses, Dosage, Side Effects, Interactions, Pregnancy

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.

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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

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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/m&sup2 IV; days 1 and 8 every 4 weeks in combination with cyclophosphamide and fluoracil for 6-12 cycles

Head and Neck Cancer

40 mg/m&sup2 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)

50 mg/m² IM; measure serum hCG levels on days 4 and 7; may repeat dose on day 7 if necessary
If hCG levels decrease <15% between days 4 and 7, administer methotrexate 50 mg/m² IM; if hCG ≥15% between days 4 and 7, discontinue treatment and measure hCG weekly until reaching nonpregnant levels

Acute Lymphoblastic Leukemia

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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;

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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, c onstipation, 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

Pregnancy

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.