Methotrexate

• FOR INTRATHECAL AND HIGH-DOSE THERAPY, USE THE PRESERVATIVE-FREE FORMULATION OF METHOTREXATE.

  DO NOT

  USE THE PRESERVED FORMULATION FOR INTRATHECAL OR HIGH-DOSE THERAPY BECAUSE IT CONTAINS BENZYL ALCOHOL.
• METHOTREXATE 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 METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.
• PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
• PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
• THE USE OF METHOTREXATE HIGH-DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH-DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED.
• Methotrexate 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 considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate (See CONTRAINDICATIONS).
• 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 methotrexate administration.
• Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.)
• Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also 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 appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity,
  Hepatic
  .)
• Methotrexate-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 methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
• Like other cytotoxic drugs, methotrexate 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 methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity,
  Skin
  .)
• Potentially fatal opportunistic infections, especially
  Pneumocystis carinii
  pneumonia, may occur with methotrexate therapy.
• Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. 

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.

In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia.

Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.

Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor.

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 sodium (preservative free) injectable products may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.

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.

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.

The cerebrospinal fluid volume is dependent on age and not 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 the 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.

^* Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity.

^† 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.

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE

• Administration of methotrexate should be delayed until recovery if:
  • the 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 U
  • mucositis is present, until there is evidence of healing
  • persistent pleural effusion is present; this should be drained dry prior to infusion.
• Adequate renal function must be documented.
  • Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy.
  • Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range).
• Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization.
  • Administer 1,000 mL/m² of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m²/hr (3 liters/m²/day) during the methotrexate infusion, and for 2 days after the infusion has been completed.
  • Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution.
• Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10^-8 mol/L (0.05 micromolar).
• The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below.^‡)

  Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients.

• Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

• Single oral doses of 7.5 mg once weekly.^†
• Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.^†

^†Methotrexate Sodium Tablets for oral administration are available.

For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an 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/wk in adults. Although there is experience with doses up to 30 mg/m²/wk in children, there are too few published data to assess how doses over 20 mg/m²/wk might affect the risk of serious toxicity in children.

Experience does suggest, however, that children receiving 20 to 30 mg/m²/wk (0.65 to 1 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See

• Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.^†
• Divided oral dose schedule: 2.5 mg at 12 hour intervals for three doses.^†

^†Methotrexate Sodium Tablets for oral administration are available.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

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 methotrexate may permit the return to conventional topical therapy, which should be encouraged.

Methotrexate for injection should be reconstituted with an appropriate sterile, preservative free medium such as 5% dextrose solution, USP or sodium chloride injection, USP.

For intrathecal injection, reconstitute to a concentration of 1 mg/mL with an appropriate sterile, preservative free medium such as sodium chloride injection, USP.

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

IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTIONS SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.

Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, and osteonecrosis. Anaphylactoid reactions have been reported.

Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.

Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.

In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin).

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored.

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increased toxicity such as stomatitis, myelosuppression, and neurotoxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate. Use caution when administering methotrexate after a recent history of nitrous oxide administration.