Antimetabolite

antimetabolite /an·ti·me·tab·o·lite/ (an?te-) (an?ti-me-tab´o-lit) a substance bearing a close structural resemblance to one required for normal physiological functioning, and exerting its effect by interfering with the utilization of the essential metabolite.

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an·ti·me·tab·o·lite (nt-m-tb-lt, nt-)

n.

A substance that closely resembles an essential metabolite and competes with, interferes with, or replaces the metabolite in physiological reactions.

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Antimetabolite

A drug that interferes with a cell's growth or ability to multiply.

Mentioned in: Chemotherapy

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antimetabolite

a substance bearing a close structural resemblance to one required for normal physiological functioning, and exerting its effect by interfering with the utilization of the essential metabolite.

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methotrexate sodium Warning - Hazardous drug!

Pharmacologic class: Antimetabolite, folic acid antagonist

Therapeutic class: Antineoplastic

Pregnancy risk category X

FDA Boxed Warning

• Give drug under supervision of physician experienced in antimetabolite use.
• Use drug only in life-threatening neoplastic diseases or in patients with severe, recalcitrant, disabling psoriasis that responds inadequately to other therapies.
• Deaths have occurred when drug was used to treat cancer and psoriasis.
• Monitor patient closely for bone marrow, liver, lung, and kidney toxicities. Explain risks involved, and stress importance of adequate follow-up.
• Use caution when giving high-dose regimen for osteosarcoma. (High-dose regimens for other cancers are investigational.)
• Don't use preserved forms and diluents containing preservatives for intrathecal or high-dose therapy.
• Don't give to pregnant women or women with childbearing potential unless medical evidence suggests benefits may outweigh risks. Drug has caused fetal death and congenital anomalies.
• Drug elimination is reduced in patients with renal impairment, ascites, or pleural effusions. Monitor them carefully for toxicity; dosage may need to be reduced or drug may need to be stopped.
• Unexpectedly severe (sometimes fatal) bone marrow suppression and GI toxicity have occurred in patients receiving drug (usually in high doses) concurrently with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Drug causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acute liver enzyme elevations are common but usually transient and asymptomatic. Perform periodic liver biopsies in psoriasis patients receiving long-term therapy.
• Potentially dangerous lung disease may arise acutely at any time during therapy. Not always fully reversible, it has occurred at dosages as low as 7.5 mg/week.
• Interrupt therapy for diarrhea and ulcerative stomatitis; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
• Malignant lymphomas may occur at low dosages and may not require cytotoxic treatment. Discontinue drug first; if lymphoma doesn't regress, begin appropriate treatment.
• Drug may induce tumor lysis syndrome in patients with rapidly growing tumors.
• Severe and occasionally fatal skin reactions have occurred within days of single or multiple P.O., I.M., I.V., or intrathecal doses. Drug withdrawal has led to recovery.
• Potentially fatal opportunistic infections may occur.
• When given concomitantly with radiation therapy, drug may increase risk of soft-tissue necrosis and osteonecrosis.

Action

Binds to dihydrofolate reductase, interfering with folic acid metabolism and inhibiting DNA synthesis and cellular replication

Availability

Injection: 20-mg, 25-mg, 50-mg, 100-mg, 250-mg, and 1,000-mg vials (lyophilized powder, preservative-free) Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg

⊘Indications and dosages

➣ Acute lymphoblastic leukemia

Adults and children: 3.3 mg/m² P.O. or I.M. daily for 4 to 6 weeks, then 20 to 30 mg/m² P.O. or I.M. weekly in two divided doses; given with corticosteroid. Alternatively, 2.5 mg/kg I.V. q 14 days.

➣ Meningeal leukemia

Adult and children: 12 mg/m² (maximum of 15 mg) intrathecally at intervals of 2 to 5 days, repeated until cerebrospinal fluid cell count is normal

➣ Burkitt's lymphoma

Adults: In stages I and II, 10 to 25 mg P.O. daily for 4 to 8 days; in stage III, combined with other neoplastic drugs. Patients in all stages usually require several courses of therapy, with 7- to 10-day rest periods between courses.

➣ Mycosis fungoides

Adults: 2.5 to 10 mg/day P.O. or 50 mg I.M. q week or 25 mg I.M. twice weekly

➣ Osteosarcoma

Adults: As part of adjunctive regimen with other antineoplastics, initially 12 g/m² I.V. as 4-hour infusion, then 12 to 15 g/m² I.V. in subsequent 4-hour infusions given at weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 until peak blood level reaches 1,000 micromoles. Leucovorin rescue must start 24 hours after methotrexate infusion begins; if patient can't tolerate oral leucovorin, dose must be given I.M. or I.V. on same schedule.

➣ Trophoblastic tumors (choriocarcinoma, hydatidiform mole)

Adults: 15 to 30 mg P.O. or I.M. daily for 5 days. Repeat course three to five times as required, with rest periods of at least 1 week between courses, until toxic symptoms subside.

➣ Lymphosarcoma (stage III)

Adults: 0.625 to 2.5 mg/kg/day P.O., I.M., or I.V.

➣ Psoriasis

Adults: After test dose, 2.5 mg P.O. at 12-hour intervals for three doses weekly, to a maximum of 30 mg weekly. Alternatively, 10 to 25 mg P.O., I.M., or I.V. as a single weekly dose, to a maximum of 30 mg weekly; decrease dosage when adequate response occurs.

➣ Rheumatoid arthritis

Adults: 7.5 mg P.O. weekly as a single dose or divided as 2.5 mg q 12 hours for three doses weekly. May gradually increase, if needed, up to 20 mg/week; decrease when adequate response occurs.

Dosage adjustment

• Renal or hepatic impairment
• Elderly patients

Off-label uses

• Relapsing-remitting multiple sclerosis
• Refractory Crohn's disease

Contraindications

• Hypersensitivity to drug
• Psoriasis or rheumatoid arthritis in pregnant patients
• Breastfeeding

Precautions

Use cautiously in:
• severe myocardial, hepatic, or renal disease; decreased bone marrow reserve; active infection; hypotension; coma
• elderly patients
• patients with childbearing potential
• young children.

Administration

☞ Be aware that methotrexate is a high-alert drug.
☞ Know that patient must be adequately hydrated before therapy and urine must be alkalized using sodium bicarbonate.
• Follow facility policy for handling, preparing, and administering carcinogenic, mutagenic, and teratogenic drugs.
• Be aware that oral administration is preferred. Give oral dose 1 hour before or 2 hours after meals. (Food decreases absorption of tablets and reduces peak blood level.)
• Reconstitute powder for injection with preservative-free solution, such as 5% dextrose solution or 0.9% sodium chloride injection. Reconstitute 20-mg and 50-mg vials to yield a concentration no greater than 25 mg/ml. Reconstitute 1-g vial with 19.4 ml to yield a concentration of 50 mg/ml.
• For high-dose I.V. infusion, dilute in 5% dextrose solution. Administer each 10 mg over 1 minute or by infusion over 30 minutes to 4 hours as directed.
• For intrathecal use, reconstitute immediately before administration, using preservative-free solution (such as 0.9% sodium chloride for injection), to a concentration of 1 mg/ml.
☞ For intrathecal or high-dose therapy, use preservative-free injection form.
• Avoid I.M. injections if platelet count is below 50,000/mm³.
☞ For osteosarcoma, make sure leucovorin rescue is used appropriately in patients receiving high methotrexate doses. Rescue usually starts 24 hours after methotrexate infusion begins.

Route	Onset	Peak	Duration
P.O.	Unknown	1-2 hr	Unknown
I.V.	Immediate	Immediate	Unknown
I.M.	Unknown	0.5-1 hr	Unknown
Intrathecal	Unknown	Unknown	Unknown

Adverse reactions

CNS: malaise, fatigue, drowsiness, dizziness, headache, aphasia, hemiparesis, demyelination, seizures , leukoencephalopathy , chemical arachnoiditis (with intrathecal use)

EENT: blurred vision, pharyngitis

GI: nausea, vomiting, stomatitis, hematemesis, melena, GI ulcers, enteritis, gingivitis, pharyngitis, anorexia, GI bleeding

GU: hematuria, cystitis, infertility, menstrual dysfunction, defective spermatogenesis, abortion, tubular necrosis, severe nephropathy , renal failure

Hematologic: anemia, leukopenia, thrombocytopenia, severe bone marrow depression

Hepatic: hepatotoxicity

Metabolic: hyperuricemia, diabetes mellitus

Musculoskeletal: joint pain, myalgia, osteonecrosis, osteoporosis (with long-term use in children)

Respiratory: dry nonproductive cough, pneumonitis, pulmonary fibrosis, pulmonary interstitial infiltrates

Skin: pruritus, rash, urticaria, alopecia, painful plaque erosions, photosensitivity

Other: chills, fever, increased susceptibility to infection, septicemia, anaphylaxis , sudden death

Interactions

Drug-drug. Activated charcoal: decreased blood level of oral or I.V. methotrexate

Folic acid derivatives: antagonism of methotrexate effects

Fosphenytoin, phenytoin: decreased blood levels of these drugs

Hepatotoxic drugs: increased risk of hepatotoxicity

NSAIDs, phenylbutazone, probenecid, salicylates, sulfonamides: increased methotrexate toxicity

Oral antibiotics: decreased methotrexate absorption

Penicillin, sulfonamide: increased methotrexate blood level

Procarbazine: increased nephrotoxicity

Theophylline: increased theophylline level

Vaccines: vaccine inefficacy

Drug-diagnostic tests. Hemoglobin, platelets, red blood cells, white blood cells: decreased values

Pregnancy tests: false-positive result

Protein-bound iodine, transaminases, uric acid: increased levels

Drug-food. Any food: delayed methotrexate absorption and decreased peak blood level

Drug-herbs. Astragalus, echinacea, melatonin: interference with methotrexate-induced immunosuppression

Drug-behaviors. Alcohol use: increased hepatotoxicity

Sun exposure: photosensitivity

Patient monitoring

• Watch for vomiting, diarrhea, or stomatitis, which may cause dehydration.
☞ Know that high-dose therapy may cause nephrotoxicity. Monitor renal function, hydration status, urine alkalization (for pH above 6.5), and methotrexate blood level.
☞ Assess for fever, sore throat, bleeding, increased bruising, and other signs and symptoms of hematologic compromise or infection.
• With high-dose or intrathecal therapy, watch for CNS toxicity.
☞ Monitor creatinine and methotrexate blood levels 24 hours after therapy starts and then daily. Adjust leucovorin dosage as prescribed.
• Check hematologic studies at least monthly; blood or platelet transfusions may be necessary.
• Monitor liver and kidney function studies every 1 to 3 months. Evaluate uric acid levels.
☞ Watch for signs and symptoms of pulmonary toxicity, such as fever, dry nonproductive cough, dyspnea, hypoxemia, and infiltrates on chest X-ray.
• Know that methotrexate exits slowly from third-space compartments (ascites, pleural effusions). Before therapy starts, fluid should be evacuated; during therapy, monitor drug blood level.

Patient teaching

☞ Review dosing instructions carefully with patient to avoid toxicity. Tell patient with rheumatoid arthritis or psoriasis to take doses weekly.
• Advise patient to take oral doses 1 hour before or 2 hours after meals.
• Instruct patient to report diarrhea, abdominal pain, clay-colored or black tarry stools, fever, chills, sore throat, unusual bleeding or bruising, sores in or around mouth, cough or shortness of breath, yellowing of skin or eyes, dark or bloody urine, swelling of feet or legs, or joint pain.
• Tell patient to take temperature daily and to report fever or other signs or symptoms of infection.
• Instruct patient to drink 2 to 3 L of fluid each day.
• Advise male patients to use reliable contraception during and for at least 3 months after therapy. Advise female patients to use reliable contraception during and for one ovulatory cycle after therapy; also caution them not to breastfeed.
• Advise patient to avoid sun exposure and to use sunscreen and protective clothing (especially if he has psoriasis).
• Instruct patient to avoid alcohol.
• Tell patient he'll need to undergo blood tests during therapy.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, herbs, and behaviors mentioned above.

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antimetabolite Antimetabolic agent Pharmacology Any agent–eg, MTX, 6-mercaptopurine, thioguanine, 5-FU, gemcitabine that is a structural analogue of a native cell metabolite, which either inhibits the enzymes of a particular metabolic pathway or is incorporated during synthesis to produce defective product or prevents replication; anti-metabolites are used as chemotherapeutics, antivirals and as immunosuppressants, and include analogues of purines–eg azathioprine, pyrimidines, folic acid–eg aminopterin, MTX See Azathioprine, Methotrexate.