methotrexate 2.5 MG (as methotrexate sodium) Oral Tablet
WARNINGS
– SEE BOXED .
Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy.
DRUG INTERACTIONS
Drug Interactions 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 20 mg/wk) 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.
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 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, sulfa-salazine) 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.
Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate.
Trimethoprim/sulfa-methoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
OVERDOSAGE
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate.
Leucovorin administration should begin as promptly as possible.
As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases.
Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules.
Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination.
However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis28(6): 846-854, 1996).
In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.
Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses).
Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction.
For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding.
In some cases, no symptoms were reported.
There have been reports of death following overdose.
In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.
DESCRIPTION
Methotrexate, USP (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: C20H22N8O5 M.W.
454.45 Methotrexate Tablets USP for oral administration, are available in bottles of 36 and 100.
Methotrexate Tablets USP contain an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate, USP.
Inactive Ingredients: Hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized corn starch, propylene glycol, sodium carbonate monohydrate and talc.
structural formula
HOW SUPPLIED
Product: 50090-2345 NDC: 50090-2345-4 12 TABLET in a BOTTLE NDC: 50090-2345-9 36 TABLET in a BOTTLE
GERIATRIC USE
Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e.
that interfere with renal function, methotrexate or folate metabolism) in this population (see PRECAUTIONS, Drug Interactions ).
Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatine clearance) should be considered.
Serum methotrexate levels may also be helpful.
Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
In chronic use situations, certain toxicities may be reduced by folate supplementation.
Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.
See Boxed WARNINGS and ADVERSE REACTIONS .
INDICATIONS AND USAGE
Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.
Methotrexate is used in maintenance therapy in combination with other chemotherapeutic agents.
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.
Psoriasis Methotrexate is indicated in 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.
Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate is indicated in the management of selected adults with severe, active, rheumatoid arthritis (ACR criteria), or 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 non-steroidal anti-inflammatory agents (NSAIDs).
Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored.
(See PRECAUTIONS, Drug Interactions .) Steroids may be reduced gradually in patients who respond to methotrexate.
Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.
Rest and physiotherapy as indicated should be continued.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis.
(See CLINICAL PHARMACOLOGY , ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION .)
PREGNANCY
Pregnancy Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X.
See CONTRAINDICATIONS .
NUSRING MOTHERS
Nursing Mothers See CONTRAINDICATIONS .
BOXED WARNING
WARNINGS METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL): 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.
1.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 .) 2.Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions.
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.
3.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 non-steroidal anti-inflammatory drugs (NSAIDs).
(See PRECAUTIONS, Drug Interactions .) 4.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.) 5.Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week.
It is not always fully reversible.
Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
6.Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
7.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.
8.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.
9.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).
10.Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
11.Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
INFORMATION FOR PATIENTS
Information for Patients Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity.
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity.
Prescriptions should not be written or refilled on a PRN basis.
Patients should be informed of the potential benefit and risk in the use of methotrexate.
The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate.
DOSAGE AND ADMINISTRATION
Neoplastic Diseases Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
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.
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 anti-tumor 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.
Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules 1.
Single oral doses of 7.5 mg once weekly.
2.
Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.
Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.
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 1.0 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.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
(See Information for Patients under PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy.
(See PRECAUTIONS .) Appropriate steps should be taken to avoid conception during methotrexate therapy.
(See PRECAUTIONS and CONTRAINDICATIONS .) 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 ADVERSE REACTIONS .) Maximal myelosuppression usually occurs in seven to ten days.
Psoriasis: Recommended Starting Dose Schedules 1.
Weekly single oral, IM or IV dose schedule: 10 to 25 mg per week until adequate response is achieved.
2.
Divided oral dose schedule: 2.5 mg at 12-hour intervals for three doses.
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.