Usual Adult Dose for Acute Lymphoblastic Leukemia

Note: A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in anti-leukemic therapy.

• 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

Comments:

• When relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regimen.
• Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Use: Acute lymphoblastic leukemia (ALL)

Usual Adult Dose for 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

Comments:

• The effectiveness of therapy is evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.
• One to two courses of therapy after normalization of hCG is usually recommended.
• Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with this drug has been recommended.
• Chorioadenoma destruens is an invasive form of hydatidiform mole. This drug is administered in these disease states in doses like those recommended for choriocarcinoma.

Use: Gestational trophoblastic disease (GTD) including gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole

Usual Adult Dose for Trophoblastic Disease

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

Comments:

• The effectiveness of therapy is evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.
• One to two courses of therapy after normalization of hCG is usually recommended.
• Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with this drug has been recommended.
• Chorioadenoma destruens is an invasive form of hydatidiform mole. This drug is administered in these disease states in doses like those recommended for choriocarcinoma.

Use: Gestational trophoblastic disease (GTD) including gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole

Usual Adult Dose for 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

Uses:

• Burkitt's tumor
• Lymphoma

Usual Adult Dose for 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

Uses:

• Burkitt's tumor
• Lymphoma

Usual Adult Dose for 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

Comments:

• Administration at intervals of less than 1 week may result in increased subacute toxicity.
• The preserved formulations of this drug contain benzyl alcohol and must not be used for intrathecal or high dose therapy.

Use: Treatment and prophylaxis of meningeal leukemia

Usual Adult Dose for 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

Comments:

• Therapy with this drug as a single agent appears to produce clinical responses in up to 50% of patients treated.
• Dose reduction or cessation is guided by patient response and hematologic monitoring.

Use: Mycosis fungoides (cutaneous T cell lymphoma)

Usual Adult Dose for 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.

Comments:

• If the patient is vomiting or unable to tolerate oral medication, leucovorin given IV or IM should be added to this regimen at the same dose and schedule as the methotrexate.
• Consult product labeling or local protocol for dosage of concomitant medications in the chemotherapy regimen.

Use: Osteosarcoma

Usual Adult Dose for 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

Comments:

• Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period.
• The use of MTX may permit the return to conventional topical therapy, which should be encouraged.

Use: For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses.

Usual Adult Dose for 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
Duration of therapy: Unknown

Comments:

• Dosages may be adjusted gradually to achieve optimal response.
• Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg per week.
• Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Use: For severe active rheumatoid arthritis in patients who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs)

Usual Pediatric Dose for Acute Lymphoblastic Leukemia

Note: A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in anti-leukemic therapy.

• 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 days

Comments:

• When relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regimen.
• Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Use: Acute lymphoblastic leukemia (ALL)

Usual Pediatric Dose for 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

Comments:

• Administration at intervals of less than 1 week may result in increased subacute toxicity.
• The preserved formulations of this drug contain benzyl alcohol and must not be used for intrathecal or high dose therapy.

Use: Treatment and prophylaxis of meningeal leukemia

Usual Pediatric Dose for Juvenile 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 [0.65 to 1 mg/kg/week] may have better absorption and fewer GI side effects if this drug is administered either IM or subcutaneously)

Comments:

• Dosages may be adjusted gradually to achieve optimal response.
• Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg per week.
• Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Use: For children with active polyarticular-course juvenile rheumatoid arthritis who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs)

Renal Dose Adjustments

CrCl should be greater than 60 mL/min before initiation of therapy

Liver Dose Adjustments

• Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease: Use is not recommended.
• Severe liver disease (Child-Pugh C): Contraindicated

Dose Adjustments

Administration of this drug should be delayed until recovery if:

• The white blood cell (WBC) count is less than 1500/microliter
• The neutrophil count is less than 200/microliter
• The platelet count is less than 75,000/microliter
• The serum bilirubin level is greater than 1.2 mg/dL
• The SGPT level is greater than 450 Units
• Mucositis is present, until there is evidence of healing
• Persistent pleural effusion is present; this should be drained dry prior to infusion

Precautions

US BOXED WARNINGS:

• This drug should only be used by physicians whose knowledge and experience include the use of antimetabolite therapy.
• For intrathecal and high dose therapy, the preservative-free formulation of this drug should be used because it does not contain benzyl alcohol.
• Oral administration in tablet form is preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
• The injectable form of this drug can be given by the IM, IV, or intraarterial route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• This drug should be used only in life threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy.
• Deaths have been reported with the use of this drug in the treatment of malignancy, psoriasis, and rheumatoid arthritis.
• Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.
• Patients should be informed by their physician of the risks involved and be under physician care throughout therapy.
• The use of high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.
• This drug has been reported to cause fetal death and/or congenital anomalies; therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the risks.
• Pregnant women with psoriasis or rheumatoid arthritis should not receive this drug.
• Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of therapy.
• Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant administration of this drug (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
• This drug causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acute liver enzyme elevations are frequently seen; these are usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long term treatment. Persistent abnormalities in liver function tests may precede the appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
• MTX-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
• Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
• Malignant lymphomas, which may regress following withdrawal of therapy, may occur in patients receiving low-dose MTX and, thus, may not require cytotoxic treatment. Discontinue MTX first and, if the lymphoma does not regress, appropriate treatment should be instituted.
• Like other cytotoxic drugs, this drug may induce "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
• Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of this drug. Reactions have occurred within days of oral, IM, IV, or intrathecal administration. Recovery has been reported with discontinuation of therapy.
• Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with MTX therapy.
• When this drug is given concomitantly with radiotherapy, the risk of soft tissue necrosis and osteonecrosis may be increased.

• Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
• Do not use the IV formulation in children less than one month old because there have been reports of fatal "gasping syndrome" in this population because the solution contains benzyl alcohol.

Consult WARNINGS section for additional precautions.

Dialysis

This drug is dialyzable via hemodialysis using a high flux dialyzer; however, no dose adjustment guidelines have been reported.

Other Comments

Administration advice:

• This drug should be used only by physicians who have knowledge and experience in the use of antimetabolite therapy because of the possibility of serious toxic reactions.
• Oral tablets are preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
• The injectable form of this drug can be given by the IM, IV, subcutaneous, or intraarterial route. For intrathecal and high-dose therapy, the preservative-free formulation should be used (not the preserved formulation because it contains benzyl alcohol).

General:

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Monitoring:

• Patients should be closely monitored for toxic effects.
• Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray.
• During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy.
• During initial dosing, when changing doses, or during periods of increased risk of elevated MTX blood levels (e.g., dehydration), more frequent monitoring may be indicated.
• Transient liver function test abnormalities are observed frequently after administration and are usually not cause for modification of therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
• A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
• Pulmonary function tests may be useful if MTX-induced lung disease is suspected, especially if baseline measurements are available.

Frequently asked questions

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