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Methotrexate. Pharm D student: Noha Alaa El Dine Alexandria University Hospitals Supervised by: Prof. Nashaat Lotfy Professor of Oncology Faculty of Medicine. Mechanism of action. MTX is an antifolate belonging to the antimetabolite class of antineoplastic agents.

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Methotrexate

Methotrexate

Pharm D student: Noha Alaa El Dine

Alexandria University Hospitals

Supervised by: Prof. Nashaat Lotfy

Professor of Oncology Faculty of Medicine


Mechanism of action
Mechanism of action

MTX 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 acid

Dihydrofolate reductase

Tetrahydrofolic

acid

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

Indications


Protocols
Protocols

Trophoblastic 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 andmercaptopurine or methotrexate, dactinomycin, and chlorambucil have also been used.


Protocols

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.


Administration
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
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

Platelets > 75,000/mm3

Neutrophils > 200/mm3

s.bilirubin<1.2mg/dl

SGPT (ALT)<450 U

Normal s. Cr.

Creatinine clearance>60ml/min

Previous mucositis should be healed

& pleural effusions should be drained prior to MTX administration


Hydration urine alkalinization leucoverin rescue
Hydration, Urine alkalinization & Leucoverin rescue high-dose methotrexate (HDMTX)

  • Administer 1 L/m2 of IV fluids over 6 hrsprior to initiation of MTX infusion. Continue hydration at 125ml/m2/hr(3 L/m2 daily) during the MTX infusion & for 2 daysafter 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/m2every 6 hours for 12 doses was begun at the end of the MTX infusion


Iv administration
IV Administration high-dose methotrexate (HDMTX)

Reconstitution. 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
Stability high-dose methotrexate (HDMTX)

  • 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
Intrathecal Administration high-dose methotrexate (HDMTX)

  • 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
Adverse drug reactions high-dose methotrexate (HDMTX)

Dermatologic and Sensitivity Reactions.

Severe, occasionally fatal cutaneous or sensitivity reactions e.g.,

  • Toxic epidermal necrolysis

  • Stevens-Johnson syndrome

  • Exfoliative dermatitis

  • Skin necrosis

  • Erythema multiforme

    reported 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
Hematologic Effects high-dose methotrexate (HDMTX)

Monitoring

Suppressed hematopoiesis:

  • Anemia

  • Aplastic anemia

  • Pancytopenia

  • Leukopenia

  • Neutropenia

  • Thrombocytopenia.

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

Management

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.


Nephrotoxicity
Nephrotoxicity high-dose methotrexate (HDMTX)

Prevention

Monitoring

  • 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.

  • Careful attention to renal function including:

  • Adequate hydration

  • Urine alkalinization

  • Measurement of methotrexate and Scr concentrations is essential.

  • Scr 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).

  • 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.

Management


Dose adjustment in renal impairment
Dose adjustment in renal impairment high-dose methotrexate (HDMTX)


Hepatotoxicity

Monitoring high-dose methotrexate (HDMTX)

Hepatotoxicity

  • 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).

Management

  • If 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
Dose adjustment in hepatic impairment high-dose methotrexate (HDMTX)


Pulmonary toxicity

Monitoring high-dose methotrexate (HDMTX)

Pulmonary toxicity

  • 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.

  • 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.

Management

  • Management is mainly supportive and may include mechanical ventilation.


Gi effects
GI Effects. high-dose methotrexate (HDMTX)

  • Vomiting

  • Diarrhea

  • Ulcerative Stomatitis

Management

  • Discontinue drug until recovery otherwise intestinal perforation may lead to hemorrhagic enteritis & death.

  • Previous mucositis should be healed

  • Use with extreme caution in presence of peptic ulcer disease or ulcerative colitis.


Drug Interactions high-dose methotrexate (HDMTX)


Pharmacodynamic Interactions high-dose methotrexate (HDMTX)

Additive Adverse Drug effect:

  • Hepatotoxic Agents (retinoids, azathioprine, sulfasalazine)

  • Increase in adverse hepatic effects expected.

  • Nephrotoxic Drugs

  • Possible altered renal elimination of methotrexate.

Action required:

Close monitoring of

LFTs & renal function


Pharmacokinetic Interactions high-dose methotrexate (HDMTX)

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.


Pharmacokinetic Interactions high-dose methotrexate (HDMTX)

MTX may decrease clearance of theophylline

Monitor

theophylline

level

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).

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:

NSAIDs should be avoided in patients receiving HD -MTX

Action required:

Close monitoring


Resistance to methotrexate
Resistance to methotrexate high-dose methotrexate (HDMTX)

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
References high-dose methotrexate (HDMTX)

  • AHFS detailed monograph 2009

  • AHFS drug information, Dosing Companion 2004

  • Epocrates 2008

  • Clinical pharmacology 2001

  • Trissel’s™ 2 Clinical Pharmaceutics Database 2009