Methotrexate

Neoplastic Diseases

For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate.   Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol.

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate for Injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily 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 methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

Leukemia

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.

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

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 antileukemic therapy.

Meningeal Leukemia

In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Dilute preservative free methotrexate to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area: 

In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity.  Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity.  Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.

Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued.  Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas

In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases.  Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

Mycosis fungoides (cutaneous T cell lymphoma)

Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

Osteosarcoma

An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.  

*Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

†See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

 When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

Adverse Reactions in JRA Studies

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant non-steroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%.  Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates.

Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis.

Chemically, methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)-methyl]methylamino]benzoyl]-L-glutamic acid.

The structural formula is:

C 20H 22N 8O 5                                               M.W. 454.45

Methotrexate for Injection, USP,  is sterile and non-pyrogenic and may be given by the intramuscular, intravenous, intra-arterial or intrathecal route (see DOSAGE AND ADMINISTRATION).

Methotrexate for Injection, USP, Lyophilized, Preservative Free, for single use only, is available in 1 gram vials.

Each vial of lyophilized powder contains methotrexate sodium equivalent to 1 g methotrexate.  Contains no preservative.  Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH during manufacture to 8.5 to 8.7.  The 1 g vial contains approximately 7 mEq sodium.

Pharmacokinetics

Absorption

Oral absorption appears to be dose dependent.  Peak plasma concentrations are reached within 0.75 to 6.0 hours following oral administration.  At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%.  The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect.

In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%).  A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported.  Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2 dose) and fraction of dose absorbed.  The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses.  Food has been shown to delay absorption and reduce peak concentration.  Methotrexate is generally completely absorbed from parenteral routes of injection.  After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes.  As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA.  Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.4) at 1 hour, 0.44 micromolar (range, 0.01 to 1) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours.  In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.

Distribution

After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight).  Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process.  At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound.  Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally.  High CSF concentrations of the drug may be attained by intrathecal administration.

In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints.  Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints.

Metabolism

After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase.  Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors.  A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed.  Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma.  The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.

Half-Life

The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m2).  For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours.

Excretion

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration.  With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours.  There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion.  Non-linear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg.  Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels.  Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.

Methotrexate clearance rates vary widely and are generally decreased at higher doses.  Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity.  It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved.  When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination.  Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing.  Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION.

Methotrexate has been detected in human breast milk.  The highest breast milk to plasma concentration ratio reached was 0.08:1.

Parenteral

Methotrexate for Injection, USP, Lyophilized, Preservative Free, for Single Use Only. 

Each 1 g vial of lyophilized powder contains methotrexate sodium equivalent to 1 g methotrexate.

Store at 20° to 25°C (68° to 77°F)  [see USP Controlled Room Temperature].  PROTECT FROM LIGHT.  Retain in carton until time of use.  Discard unused portion. 

The container closure is not made with natural rubber latex.

See package insert for routes of administration.

SEE BOXED WARNINGS.

For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high dose therapy because it contains benzyl alcohol.

Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy.  Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high doses), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.  In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine.  However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.