Methotrexate Pharm D student: Noha Alaa El Dine Alexandria University Hospitals Supervised by: Prof. Nashaat Lotfy Professor of Oncology Faculty of Medicine.

Methotrexate

Pharm D student: Noha Alaa El DineAlexandria University Hospitals

Supervised by: Prof. Nashaat LotfyProfessor of Oncology Faculty of Medicine

Mechanism of actionMTX is an antifolate belonging to the antimetabolite class of antineoplastic agents.

MTX is a cell cycle specific chemotherapeutic agents that acts on S-phase & thus inhibit DNA synthesis

Folic acidTetrahydrofolic

acid

Dihydrofolate reductase

THF included at two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil)

Indications All Labeled Uses: 

Acute Lymphoid Leukemia Breast Carcinoma Burkitt's Lymphoma Diffuse Large B-Cell Lymphoma Gestational Trophoblastic

Neoplasm Juvenile Rheumatoid Arthritis Locally Advanced Breast

Carcinoma Lung Carcinoma Malignant Tumor of Head and

Neck Metastatic Breast Carcinoma Mycosis Fungoides Psoriasis Rheumatoid Arthritis Small Cell Lung Carcinoma

Unlabeled Uses:  Acute Myeloid Leukemia Acute Promyelocytic Leukemia Colorectal Cancer Ectopic Pregnancy Malignant Tumor of Cervix Malignant Tumor of Urinary

Bladder Metastatic Colorectal Cancer Polymyositis Psoriatic Arthritis Systemic Dermatomyositis Systemic Lupus Erythematosus Vasculitis Wegener's Granulomatosis

ProtocolsTrophoblastic Neoplasms The usual dosage of methotrexate is 15–30 mg daily, administered

orally or IM for 5 days. A repeat course may be given after a period of one or more weeks

provided all signs of residual toxicity have disappeared. Three to five courses of therapy are usually employed. Therapy is usually evaluated by 24-hour quantitative analysis of

urinary chorionic gonadotropin which should return to normal or less than 50 IU/24 hours, usually after the third or fourth course.

Complete resolution of measurable lesions usually occurs 4–6 weeks later.

One or two courses of methotrexate therapy are usually given after normalization of urinary chorionic gonadotropin hormone concentrations is achieved.

In the treatment of trophoblastic disease in women, regimens alternating courses of methotrexate therapy and dactinomycin therapy or combining administration of methotrexate and mercaptopurine or methotrexate, dactinomycin, and chlorambucil have also been used.

Lymphomas The usual dosage of methotrexate for the treatment of stages I or II of Burkitt’s

lymphoma is 10–25 mg/day orally for 4–8 days. Methotrexate is commonly given concomitantly with other antineoplastic agents

in the treatment of stage III Burkitt’s lymphoma and lymphosarcomas. In all stages, several courses of drug therapy are usually administered

interposed with 7- to 10-day rest periods. Stage III lymphosarcomas may respond to combined drug therapy with methotrexate given in doses of 0.625–2.5 mg/kg daily.

Mycosis Fungoides Clinical response occurs in up to 50% of patients receiving single-agent therapy

with methotrexate for mycosis fungoides (cutaneous T-cell lymphoma). In early stages of the disease, the usual dosage is 5–50 mg orally once weekly.

The need for dosage reduction or discontinuance of therapy is determined by response to therapy and hematologic monitoring.

Methotrexate also has been administered twice weekly in doses of 15–37.5 mg in patients with disease that has responded poorly to once-weekly dosing.

In patients with advanced stages of mycosis fungoides, combination chemotherapy regimens that include IV methotrexate in higher doses followed by leucovorin rescue have been used.

Protocols

Breast Cancer One commonly employed regimen (CMF) for the treatment of

early breast cancer includes a methotrexate dosage of 40 mg/m2 (administered IV) on days 1 and 8 of each cycle combined with cyclophosphamide 100 mg/m2 on days 1 through 14 of each cycle and fluorouracil 600 mg/m2 on days 1 and 8 of each cycle.

Cycles generally were repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6–12 cycles.

Dosage was reduced In patients older than 60 years of age & if myelosuppression developed.

There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with early breast cancer and more than 3 positive axillary lymph nodes.

Protocols

Administration

Great care should be taken to prevent inhaling particles of the chemical and exposing the skin to it.

Methotrexate formulations or diluents containing preservatives (benzyl alcohol) must not be used for intrathecal administration or high-dose methotrexate therapy.

Guidelines for parenteral administration of intermediate- or high-dose methotrexate (HDMTX)

500mg/m2 over <4hrs or 1gm/m2 over >4hrs Prior to MTX administration the following laboratory

parameters should be confirmed:

WBCs > 1500/mm3 Neutrophils > 200/mm3 Platelets > 75,000/mm3

Previous mucositis should be healed& pleural effusions should be drained prior to MTX administration

Normal s. Cr.Creatinine clearance>60ml/min

s.bilirubin<1.2mg/dlSGPT (ALT)<450 U

Hydration, Urine alkalinization & Leucoverin rescue

Administer 1 L/m2 of IV fluids over 6 hrs prior to initiation of MTX infusion. Continue hydration at 125ml/m2/hr (3 L/m2 daily) during the MTX infusion & for 2 days after the infusion has been completed.

Urine should be alkalinized using sodium bicarbonate. Alkalinize urine to maintain the urine pH >7 during the MTX infusion & leucoverin therapy. Alkalinization may be either orally or by incorporating sodium bicarbonate in the IV fluids

Leucovorin rescue required for MTX doses >500mg/m2, & considered for MTX doses 100-500mg/m2 for ALL, Breast CA, head/neck CA lung CA, osteosarcoma, non hodgkin’s lymphoma, others

Leucoverin dose 15 mg/m2 every 6 hours for 12 doses was begun at the end of the MTX infusion

IV AdministrationReconstitution. Reconstitute lyophilized powder for

injection immediately before use with a sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection)

Reconstitute 20 mg vial to a concentration ≤25 mg/mL Reconstitute 1 g vial with 19.4 mL of appropriate solution to yield a concentration of 50 mg/mL.

Dilution. When high doses are administered by IV infusion, dilute total dose of reconstituted solution in 5% dextrose injection.

May further dilute commercially available solution for IV injection containing preservatives with a compatible solution (e.g., 0.9% sodium chloride injection).

Preservative-free solutions may be diluted immediately prior to use with an appropriate sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection)

Stability Methotrexate sodium injection and powder for injection

should be protected from light and stored at 15–30°C. Compatible with:

Dextrose 5% in water Sodium chloride 0.9%

Maximum reported stability periods: In D5W- 10 days at room temperature and 30 days refrigerated

protected from light. In NS- 7 days at room temperature and 105 days refrigerated

protected from light. Storage of solutions containing preservatives after

further dilution for 24 hours at 21–25°C results in a product within 90% of label potency.

Use preservative-free solution immediately after further dilution

Intrathecal Administration

Reconstitution. For intrathecal injection, reconstitute lyophilized powder to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).

Dilution. For intrathecal injection, dilute methotrexate preservative-free solution for injection to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).

Adverse drug reactions

Dermatologic and Sensitivity Reactions.

Severe, occasionally fatal cutaneous or sensitivity reactions e.g., Toxic epidermal necrolysis Stevens-Johnson syndrome Exfoliative dermatitis Skin necrosis Erythema multiformereported in pediatric and adult patients within days of receiving drug at various

dosages, by various routes, and for various conditions.

Erythematous rashes, pruritus, dermatitis, urticaria, folliculitis, photosensitivity, depigmentation, hyperpigmentation, petechiae, ecchymoses, telangiectasia, acne, furunculosis, and skin ulceration also reported.

Hematologic Effects

Suppressed hematopoiesis: Anemia Aplastic anemia Pancytopenia Leukopenia Neutropenia Thrombocytopenia.

Monitoring

Perform CBCs, including differential and platelet counts, at least weekly in patients with neoplastic disease

If profound leukopenia and fever occur, observe patient closely and initiate broad-spectrum antibiotic therapy if there are signs of infection.

Blood or platelet transfusions may be necessary in patients with severe myelosuppression.

Management

If renal impairment develops during methotrexate therapy, dosage should be reduced or the drug discontinued until renal function is improved or restored.

Institute appropriate corrective measures (e.g., use of leucovorin calcium, acute intermittent hemodialysis with a high-flux dialyzer).

In addition, tumor lysis syndrome associated with other cytotoxic drugs (e.g., fludarabine, cladribine) also has been reported in patients with rapidly growing tumors who were receiving methotrexate.

Nephrotoxicity MonitoringScr must be normal and Clcr >60 ml/min before therapy initiation. Repeat Scr and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate concentration is <0.023 mcg/mL (0.05 mcM).

•May cause renal damage that may lead to acute renal failure.•Nephrotoxicity is due principally to precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules.

Prevention

Careful attention to renal function including: Adequate hydration Urine alkalinization Measurement of methotrexate and Scr concentrations is essential.

Management

Dose adjustment in renal impairment

Cr Cl 60-80 ml/min Decrease dose 25%

Cr Cl 50-60 ml/min Decrease dose 33%

Cr Cl 10-50 ml/min Decrease dose 50-70%

Cr Cl < 10 ml/min Avoid use

HD Give 50% dose as supplement

CAPD No supplement

Hepatotoxicity Monitoring

Liver function tests at baseline. Abnormal liver function test results frequently occur 1–2 days following a dose of methotrexate, and it is recommended that liver function tests be performed at least 1 week after the last dose of the drug. Because these tests generally return to normal within a few days. Liver biopsy is currently the only reliable measure of hepatotoxicity.

Possible hepatotoxicity; may be acute (increased serum aminotransferase concentrations) or chronic (fibrosis and cirrhosis).

ManagementIf substantial abnormal liver function test results develop and persist, methotrexate therapy should be withheld for 1–2 weeks and liver function tests repeated. However, if substantial abnormal liver function test results persist, a liver biopsy is recommended.

Dose adjustment in hepatic impairment

s.bilirubin 4-5mg/dl Decrease dose 25%

s.bilirubin >5mg/dl Omit

ALT <180 Decrease dose 25%

ALT>450 U/L Omit

Pulmonary toxicity

Monitoring

Frequently Chest radiographs should be performed If manifestations (e.g., fever, cough [especially dry and nonproductive), dyspnea, chest pain, hypoxemia [possibly severe], radiographic evidence of pulmonary infiltrates [usually diffuse and/or alveolar]) occur, discontinue and carefully evaluate, including exclusion of possible infectious causes.

Potentially fatal pulmonary toxicity; can progress rapidly and may not be fully reversible. Adverse pulmonary effects (i.e., acute or chronic interstitial pneumonitis, pulmonary fibrosis) may occur at any dosage at any time during therapy.

ManagementManagement is mainly supportive and may include mechanical ventilation.

Vomiting Diarrhea Ulcerative Stomatitis

GI Effects.

Management

Discontinue drug until recovery otherwise intestinal perforation may lead to hemorrhagic enteritis & death.Previous mucositis should be healedUse with extreme caution in presence of peptic ulcer disease or ulcerative colitis.

Additive Adverse Drug effect:Hepatotoxic Agents (retinoids, azathioprine, sulfasalazine)Increase in adverse hepatic effects expected.

Nephrotoxic DrugsPossible altered renal elimination of methotrexate.

Action required:Close monitoring of LFTs & renal function

MTX cause damage of GIT

Reduce absorption of Verapamil & Phenytoin by 20-35% and so loss of therapeutic effect.

MTX is also displaced from protein binding sites by:

Salicylates Co-trimoxazole(sulfonamides) Sulfonylureas, phenytoin, phenylbutazone, tetracyclines, chloramphenicol, and aminobenzoic acid resulting in increased free methotrexate concentrations.

Salicylates & NSAIDs can cause severe, possibly fatal MTX toxicity

including hematologic and GI toxicity ( HD-MTX) either by competition with MTX for active tubular secretion & delay of

elimination or by decreasing renal perfusion (due to inhibition of PG

synthesis (PD interaction).

Action required:

NSAIDs should be avoided in patients receiving HD -MTX

Concomitant use of penicillins (e.g., amoxicillin, carbenicillin) may decrease renal clearance of methotrexate, presumably

by inhibiting renal tubular secretion of the drug & thus

increase serum concentrations of methotrexate, resulting in GI

or hematologic toxicity

Action required:Close monitoring

MTX may decrease

clearance of theophylline

Monitortheophyllin

elevel

Resistance to methotrexate

Due to: Decreased cellular uptake of the drug Increased dihydrofolate reductase activity (associated

with increased synthesis of the enzyme) Decreased binding of methotrexate to dihydrofolate

reductase (because of mutated dihydrofolate reductase protein)

Decreased intracellular concentrations of polyglutamylated metabolites of methotrexate

However, the precise mechanism of this resistance development has not been established.

References

AHFS detailed monograph 2009 AHFS drug information, Dosing

Companion 2004 Epocrates 2008 Clinical pharmacology 2001 Trissel’s™ 2 Clinical Pharmaceutics

Database 2009