Health Professional Information
SUMMARY PRODUCT INFORMATION
|Dosage Form / Strength||Clinically Relevant Nonmedicinal|
|Intramuscular, intravenous, intra-arterial, intrathecal, intraventricular||Sterile solution (preservative-free) /|
10 mg/mL (20 mg/2 mL)
25 mg/mL (50 mg/2 mL)
|For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.|
|Intravenous||Sterile solution (Pharmacy Bulk vial; preservative-free) /
25 mg/mL (500 mg/20 mL; 1 g/40 mL; 2.5 g/100 mL)
|For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.|
|Intramuscular, intravenous, intra-arterial||
Sterile solution (with preservative) /
Benzyl alcohol as preservative
For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.
Indications And Clinical Use
Methotrexate Injection USP is indicated for Neoplastic diseases:
- Choriocarcinoma: Methotrexate - as single chemotherapy or in combination with other drugs.
- Intermediate, or high-grade Non-Hodgkin's Lymphoma - as part of ProMACE-CytaBOM, ProMACE-MOPP, and Magrath protocols.
- Breast Cancer - as part of CMF (cyclophosphamide-methotrexate-fluorouracil) therapy.
- Acute Lymphoblastic Leukemia - as maintenance therapy.
- Head and Neck Cancer - in combination with other chemotherapies.
- Gastric Cancer - palliative combination chemotherapy.
- Metastasis of unknown primary - as palliative combination chemotherapy.
- Osteogenic sarcoma (adjuvant) - high dose methotrexate with leucovorin rescue (HDMTX-LV)
- Bladder Cancer (advanced) - as part of the M-VAC Regimen.
- Leptomeningeal spread of malignancies (carcinomatosis/leukemia/lymphoma) as a single chemotherapy or alternating with Ara-C
- Burkitt's lymphoma.
- Advanced stages of childhood lymphoma (III and IV, St. Jude's Childrens' Research Hospital Staging System).
- Advanced cases of mycosis fungoides (cutaneous T-cell lymphoma).
Methotrexate Injection USP is indicated as a Disease Modifying Antirheumatic Drug (DMARD) in the following diseases where standard therapeutic interventions fail:
- Severe disabling psoriasis/psoriatic arthritis
- Severe disabling rheumatoid arthritis (RA)
- Severe disabling seronegative arthritides.
In the treatment of psoriasis, Methotrexate Injection USP should be restricted to severe recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established after dermatologic consultation.
Geriatrics (≥65 years of age): The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function, as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.
Pediatrics (<18 years of age): Safety and effectiveness in pediatric patients have not been established, other than in cancer chemotherapy. Therefore, Methotrexate Injection USP should not be used as a DMARD in pediatric patients.
Methotrexate Injection USP is contraindicated:
- In patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.
- In patients with severe renal impairment.
- In pregnant patients with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus.
- In women of childbearing potential until pregnancy is excluded.
- In nursing mothers.
- In patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease.
- In patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes.
- In patients with psoriasis or rheumatoid arthritis who have pre-existing blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia or significant anemia.
- With nitrous oxide anesthesia (see WARNINGS AND PRECAUTIONS: Renal and DRUG INTERACTIONS: Drug-Drug Interactions).
Methotrexate Injection USP formulations containing benzyl alcohol are also contraindicated:
- To use for intrathecal, intraventricular, or high-dose therapy.
- To use in neonates (children less than one month age).
Warnings And Precautions
Serious Warnings and Precautions
- Methotrexate Injection USP should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy because of the possibility of serious toxic reactions (see WARNINGS AND PRECAUTIONS: General).
- Methotrexate Injection USP formulations which contain benzyl alcohol are contraindicated in neonates and for intrathecal, intraventricular, or high dose therapy (see CONTRAINDICATIONS).
Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. It should be emphasized to the patient that the recommended dose is taken weekly for rheumatoid arthritis and psoriasis, and that daily use of the weekly recommended dose has led to fatal toxicity.
Fatal toxicities related to intravenous dosing miscalculation have been reported. Special attention must be given to dose calculation.
Because of the possibility of serious toxic reactions (which can be fatal), Methotrexate Injection USP should be used only in neoplastic diseases (as indicated), or in patients with severe, recalcitrant, disabling psoriasis or rheumatoid arthritis that are not adequately responsive to other forms of therapy. The patient should be informed by the physician of the risks involved and should be under a physician’s constant supervision.
The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care (see DOSAGE AND ADMINISTRATION). High dosage regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.
Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on Methotrexate Injection USP closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer (see OVERDOSAGE). If Methotrexate Injection USP therapy is re-instituted, it should be carried out with caution, with adequate consideration of further need for the drug and with increased alertness as to possible recurrence of toxicity.
Methotrexate may induce "tumour lysis syndrome" in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
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 non-steroidal anti-inflammatory drugs (NSAIDs) (see DRUG INTERACTIONS).
Bone marrow and mucosal toxicity depend on dose and duration of exposure of high levels (>2x10-8 mol/L (0.02 micromolar)) of methotrexate. Since the critical time factor has been defined for these organs as being 42 hours in humans, this has the following implications:
- when high doses of methotrexate are employed (>1g/m2), drug levels in serum should be monitored
- when drug levels exceeding 2 x 10-8 mol/L (0.02 micromolar) for >42 hours may forecast significant toxicity
- when toxicity can be minimized by appropriate administration of Leucovorin Calcium
- when high-dose methotrexate (HDMTX) is employed, it is imperative to alkalinise the urine in order to prevent crystallisation of methotrexate and its 7‑hydroxy metabolite in the urine, which may lead to acute renal failure.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate Injection USP should be used with extreme caution in the presence of debility.
The use of methotrexate high-dose regimens (≥500 mg/m2) recommended for osteosarcoma requires meticulous care. High-dosing regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.
Drug Interactions with Proton Pump Inhibitors (PPI)
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 dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydromethotrexate, 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.
Carcinogenesis and Mutagenesis
Malignant lymphomas may occur in patients receiving low-dose methotrexate. These lymphomas may regress following withdrawal of methotrexate without requiring treatment.
No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Assessment of the carcinogenic potential of methotrexate is complicated by conflicting evidence of an increased risk of certain tumours in rheumatoid arthritis. Benefit should be weighed against this potential risk before using Methotrexate Injection USP alone or in combination with other drugs, especially in children or young adults. (See TOXICOLOGY).
If vomiting, diarrhea, or stomatitis occurs, resulting in dehydration, Methotrexate Injection USP should be discontinued until recovery occurs. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. Methotrexate Injection USP should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy as concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydromethotrexate, possibly leading to methotrexate toxicities (see DRUG INTERACTIONS).
Methotrexate Injection USP should be used with caution in patients with impaired bone marrow function and previous or concomitant wide field radiotherapy. Methotrexate may produce marked bone marrow depression with resultant anemia, aplastic anemia, pancytopenia, leucopenia, neutropenia, and/or thrombocytopenia. In controlled clinical trials in rheumatoid arthritis (n=128), leucopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients.
The nadir of circulating leukocytes, neutrophils and platelets usually occurs between 5 and 13 days after an IV bolus dose (with recovery between 14 to 28 days). Leukocytes and neutrophils may occasionally show two depressions, the first occurring in 4-7 days and a second nadir after 12-21 days, followed by recovery. Clinical sequel such as fever, infections and hemorrhage from various sites may be expected.
In psoriasis and rheumatoid arthritis, Methotrexate Injection USP should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, Methotrexate Injection USP should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.
Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Acutely, liver enzyme elevations are frequently seen after methotrexate administration and are usually not a reason for modification of methotrexate therapy. Liver enzyme elevations are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Persistent liver abnormalities, and/or decrease of serum albumin may be indicators of serious liver toxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total cumulative dose of at least 1.5 grams. 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. 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. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function.
Methotrexate has caused reactivation or worsening of hepatitis B and C infections, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate. Prior to treatment with Methotrexate Injection USP, clinical and laboratory evaluation should be performed to evaluate preexisting hepatitis virus B and hepatitis virus C infection. Methotrexate Injection USP is not recommended for patients with active or chronic hepatitis B or C infection.
In psoriasis, liver damage and function tests, including serum albumin and prothrombin time, should be performed several times prior to dosing, but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy: 1) before the start of therapy or shortly after initiation of therapy (4-8 weeks); 2) after a total cumulative dose of 1.5 grams; and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low-grade portal inflammation are relatively common pre-therapy. Although these mild changes are usually not a reason to avoid or discontinue Methotrexate Injection USP therapy, the drug should be used with caution.
Clinical experience with liver disease in rheumatoid arthritis is limited, but the same risk factors would be anticipated. Liver function tests are also usually not reliable predictors of histological changes in this population.
In rheumatoid arthritis, advanced age at first use of methotrexate, and increasing duration of therapy have been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid population. Liver function tests should be performed at baseline and at 4-8 week intervals in patients receiving Methotrexate Injection USP for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values, or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities, or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), Methotrexate Injection USP may be continued and the patient monitored according to the recommendations listed above. Methotrexate Injection USP should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1500 mg) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Methotrexate Injection USP should be used with extreme caution in the presence of active infection, and is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes (see CONTRAINDICATIONS).
Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. Hypogammaglobulinemia has been reported rarely.
There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intravenous methotrexate (1 g/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leukoencephalopathy has also been reported in patients with osteosarcoma who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. There are also reports of leukoencephalopathy in patients who received low oral doses (4-8 mg/week) of methotrexate therapy for rheumatoid arthritis or psoriatic arthritis.
Discontinuation of Methotrexate Injection USP does not always result in complete recovery.
A transient acute neurologic syndrome has been observed in patients treated with high dosage regimens. Manifestations of this neurologic disorder may include behavioural abnormalities, focal sensorimotor signs, including transient blindness and abnormal reflexes. The exact cause is unknown.
After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; paresis, usually transient, manifested by paraplegia associated with involvement with one or more spinal nerve roots; leucoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, and occasionally major convulsions.
Intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.
Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given methotrexate in combination with intravenous cytarabine.
Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution, and at reduced dosages, because renal dysfunction will prolong methotrexate elimination. Methotrexate may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration.
Nephritis has been reported on co-administration with nitrous oxide anesthesia in rheumatoid arthritis patients (see CONTRAINDICATIONS and DRUG INTERACTIONS: Drug-Drug Interactions).
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion which may occur at any time during therapy and which has been reported at low doses. It is not always fully reversible and fatalities have been reported. Cases of pleural effusion with or without interstitial pneumonitis have also been reported at any time during therapy at low doses. Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii should be considered.
Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy (see TOXICOLOGY). The risk of effects on reproduction should be discussed with both male and female patients taking Methotrexate Injection USP. (See TOXICOLOGY).
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’s Syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular or intravenous methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic diseases, rheumatoid arthritis or psoriasis. Recovery has been reported with discontinuation of therapy.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Pregnant Women: Methotrexate Injection USP is contraindicated in pregnant patients with psoriasis or rheumatoid arthritis (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Serious Warnings and Precautions) and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Methotrexate can cause fetal death, embryotoxicity, abortion, or teratogenic effects when administered to a pregnant woman.
Methotrexate Injection USP is contraindicated in women of childbearing potential until pregnancy is excluded and should be fully counselled on the serious risk to the fetus should they become pregnant while undergoing treatment (see CONTRAINDICATIONS). Pregnancy should be avoided if either partner is receiving Methotrexate Injection USP. The optimal time interval between the cessation of methotrexate treatment of either partner and pregnancy has not been clearly established. Published literature recommendations for time intervals vary from 3 months to one year. The risk of effects on reproduction should be discussed with both male and female patients taking Methotrexate Injection USP.
Nursing Women: Methotrexate Injection USP is contraindicated in nursing mothers because of the potential for serious adverse reactions from methotrexate in breast-fed infants.
Pediatrics (<18 years of age): Safety and effectiveness in pediatric patients have not been established, other than in cancer chemotherapy.
Overdose by intravenous miscalculation of dosage (particularly in juveniles) have occurred. Special attention must be given to dose calculation.
Methotrexate Injection USP formulations containing the preservative benzyl alcohol are contraindicated for use in neonates (children less than one month of age) (see CONTRAINDICATIONS). The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping syndrome”, and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.
Geriatrics (≥65 years of age): The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function, as well as decreased folate stores in this population, relatively low doses should be considered. Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
Renal Impairment: Methotrexate Injection UPS is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS).
Monitoring and Laboratory Tests
General: Patients undergoing Methotrexate Injection USP therapy should be informed of the early signs and symptoms of toxicity and closely monitored so that toxic effects are detected promptly. Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures. Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: e.g., pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria, and impaired renal function. Some patients may have delayed methotrexate clearance in the absence of these features. It is important that patients be identified within 48 hours since methotrexate toxicity may not be reversible if adequate leucovorin rescue is delayed for more than 42 to 48 hours.
Monitoring of methotrexate concentrations should include determination of a methotrexate level at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue leucovorin rescue).
Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.
During therapy of rheumatoid arthritis and psoriasis, monitor:
- Hematologic: Patients should have their blood tests checked at least monthly.
- Hepatic: Liver biopsies prior to Methotrexate Injection USP therapy are not indicated routinely. Liver function tests should be determined prior to the initiation of therapy with Methotrexate Injection USP and they should be monitored every 1 to 2 months. A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established. Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of Methotrexate Injection USP therapy. Persistent liver function test abnormalities just prior to dosing and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
- Renal: Renal function should be monitored every 1 to 2 months.
- Respiratory: Pulmonary function tests may be useful if methotrexate-induced lung disease (e.g. interstitial pneumonitis) is suspected, especially if baseline measurements are available.
During therapy of neoplastic disease:
More frequent monitoring is usually indicated during antineoplastic therapy for hematologic, hepatic, renal and respiratory.
Adverse Drug Reaction Overview
In general, the incidence and severity of acute side effects are related to dose, frequency of administration, and the duration of the exposure to significant blood levels of methotrexate to the target organs. The most serious reactions are discussed under WARNINGS AND PRECAUTIONS section. The most frequently reported adverse reactions include ulcerative stomatitis, leucopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.
Adverse Drug Reactions by Organ System
|Blood and lymphatic system disorders:||Leucopenia, anemia, aplastic anemia, thrombopenia, pancytopenia, agranulocytosis, lymphadenopathy and lymphoproliferative disorders (including reversible), neutropenia and eosinophilia have also been observed.|
|Cardiac disorders:||Pericarditis and pericardial effusion (damage to heart, rarely).|
|Eye disorders:||Conjunctivitis, blurred vision, serious visual changes of unknown etiology, and transient blindness/vision loss.|
|Gastrointestinal disorders:||Gingivitis, stomatitis, enteritis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, pancreatitis, intestinal perforation, non-infectious peritonitis, glossitis.|
|General disorders and administration site conditions:||
Anaphylactoid reactions, vasculitis, fever, conjunctivitis, infection, sepsis, nodulosis, hypogammaglobulinaemia, and sudden death.
|Hepatobiliary disorders:||Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations, hepatic failure.|
|Infection:||Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, and disseminated H. simplex, cytomegalovirus infection, including cytomegaloviral pneumonia.|
|Metabolism and nutrition disorders:||Diabetes mellitus.|
|Musculoskeletal, connective tissue and bone disorders:||Stress fractures, soft tissue necrosis, osteonecrosis, arthralgia, myalgia and osteoporosis.|
|Neoplasms benign, malignant and unspecified (including cysts and polyps):||Tumour lysis syndrome. 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 Injection USP first and, if the lymphoma does not regress, appropriate treatment should be instituted.|
|Nervous system:||Cerebrospinal fluid pressure increased, neurotoxicity, arachnoiditis, paresthesia, headache, dizziness, drowsiness, speech impediment including dysarthria and aphasia; hemiparesis, paresis and convulsions. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy.|
|Renal and urinary disorders:||Renal failure, severe nephropathy or renal failure, azotemia, dysuria, cystitis, hematuria, urogenital dysfunction. Proteinuria has also been observed.|
|Reproductive system and breast disorders:||Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge and gynecomastia; infertility, abortion, fetal defects, loss of libido/impotence.|
|Respiratory, thoracic and mediastinal disorders:||Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, pulmonary fibrosis, Pneumocystis carinii pneumonia, pleural effusion. Dyspnea, chest pain, hypoxia, respiratory fibrosis, pharyngitis, and chronic interstitial obstructive pulmonary disease and alveolitis have occasionally occurred.|
|Skin disorders:||Erythema, pruritus, photosensitisation, petechiae, loss of hair, skin necrosis, exfoliative dermatitis, painful erosion of psoriatic plaques, herpes zoster, vasculitis, urticaria, pigmentary changes, acne, ecchymosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), furunculosis and telangiectasia. Drug reaction with eosinophilia and systemic symptoms.|
|Vascular disorders:||Hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), vasculitis.|
Adverse Reactions Reported in Rheumatoid Arthritis:
- Alopecia (common)
- Diarrhea (common)
- Dizziness (common)
- Elevated liver enzymes (very common)
- Leucopenia (common)
- Nausea/vomiting (very common)
- Pancytopenia (common)
- Rash/pruritus/dermatitis (common)
- Stomatitis (common)
- Thrombocytopenia (common)
Adverse Reactions in Psoriasis:
The adverse reaction rates reported are very similar to those in the rheumatoid arthritis studies. Rarely, painful psoriatic plaque erosions may appear.
Abnormal Hematologic and Clinical Chemistry Findings
See WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests section.
Post-Market Adverse Drug Reactions
Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse events have also been reported during post-marketing experience with methotrexate:
System Organ Class
Infections and Infestations
Infections (including fatal sepsis); Pneumonia; Pneumocystis carinii pneumonia; Nocardiosis; Histoplasmosis; Cryptococcosis; Herpes zoster; H. simplex hepatitis; Disseminated H. simplex; Cytomegalovirus infection (including cytomegaloviral pneumonia); Reactivation of hepatitis B infection; Worsening of hepatitis C infection
Blood and Lymphatic System Disorders
Agranulocytosis; Pancytopenia; Leukopenia; Neutropenia; Lymphadenopathy and lymphoproliferative disorders (including reversible); Eosinophilia; Anemia megaloblastic; Renal vein thrombosis; Lymphoma; Aplastic anemia; Hypogammaglobulinemia
Nervous System Disorders
CSF pressure increased; Neurotoxicity; Arachnoiditis; Paraplegia; Stupor; Ataxia; Dementia; Dizziness; Paresthesia
Respiratory, Thoracic and Mediastinal Disorders
Chronic interstitial pulmonary disease; Alveolitis; Dyspnea; Chest pain; Hypoxia; Cough; Plural effusion
Intestinal perforation; Noninfectious peritonitis; Glossitis; Nausea; Pancreatitis
Skin and Subcutaneous Tissue Disorders
Drug reaction with eosinophilia and systemic symptoms; Dermatitis; Petechiae
Musculoskeletal, Connective Tissue and Bone Disorders
Renal and Urinary Disorders
Pregnancy, Puerperium and Perinatal Conditions
Fetal death, Abortion
Reproductive System and Breast Disorders
General Disorders and Administration Site Conditions
Pyrexia; Chills; Malaise; Fatigue; Anaphylactic reactions
Transient blindness/vision loss
Serious Drug Interactions
The use of nitrous oxide anesthesia with methotrexate is contraindicated (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: Renal and DRUG INTERACTIONS: Drug-Drug Interactions).
Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that undergo tubular secretion, can markedly increase methotrexate serum levels. Laboratory studies demonstrate that methotrexate may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol and phenytoin.
Non-steroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate. Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic (including bone marrow suppression and aplastic anemia) and gastrointestinal toxicity. These drugs have been reported to reduce the tubular secretion of methotrexate, in an animal model, and may enhance its toxicity by increasing methotrexate levels.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of Methotrexate Injection USP. In treating rheumatoid arthritis with methotrexate, the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. 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 toxicity.
Disease Modifying Antirheumatic drugs (DMARDs)
Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, or sulfasalazine has not been studied and may increase the incidence of adverse effects.
Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.
The administration of L-asparaginase has been reported to antagonize the effect of methotrexate.
Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.
Methotrexate in combination with leflunomide may increase the risk of pancytopenia.
Drugs Highly Bound to Plasma Proteins
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by other highly bound drugs, such as sulfonylureas, aminobenzoic acid, salicylates, phenylbutazone, phenytoin, sulfonamides, some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid, and chloramphenicol.
Packed Red Blood Cells
Care should be exercised whenever packed red blood cells and Methotrexate Injection USP are given concurrently. Patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum-Methotrexate concentrations.
Renal tubular transport is also diminished by probenecid; use of Methotrexate Injection USP with this drug should be carefully monitored.
Proton Pump Inhibitors
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Concomitant use of PPIs and high-dose methotrexate should be avoided especially in patients with renal impairment. 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 dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydromethotrexate, 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.
Psoralen Plus Ultraviolet Light (PUVA) Therapy
Skin cancer has been reported in patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy.
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 clearance is decreased by cisplatinum.
Although not documented, other nephrotoxic drugs such as aminoglycosides, Amphotericin B and Cyclosporin could theoretically increase methotrexate toxicity by decreasing its elimination.
The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis, neurotoxicity (with intrathecal administration of methotrexate) and nephritis (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Renal). In case of accidental co-administration, this effect can be reduced by the use of leucovorin rescue.
Penicillins and Sulfonamides
Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity have been observed in combination with methotrexate. Use of Methotrexate Injection USP with penicillins should be carefully monitored.
Renal tubular transport is diminished by ciprofloxacin; use of Methotrexate Injection USP 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. For example: Neomycin, Polymyxin B, Nystatin, and Vancomycin decrease methotrexate absorption, whereas Kanamycin increases methotrexate absorption.
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. Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive antifolate effect.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Methotrexate Injection USP.
Methotrexate increases the plasma levels of mercaptopurine. Combination of Methotrexate Injection USP and mercaptopurine may therefore require dose adjustment.
Vitamin preparations containing folic acid or its derivatives may decrease responses to methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the cerebrospinal fluid primarily as 5-methyl tetrahydrofolate 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.
In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes.
Before taking a folate supplement, it is advisable to check B12 levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B12 deficiency.
Folate deficiency states may increase methotrexate toxicity.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
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 Injection USP and other potential hepatotoxic agents (e.g., leflunomide, azathioprine, sulfasalazine, retinoids) should be closely monitored for possible increased risk of hepatotoxicity.
Cytarabine and other cytotoxic agents
Methotrexate given concomitantly with IV cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke-like episodes (see WARNINGS AND PRECAUTIONS: Neurologic).
Combined use of methotrexate with other cytotoxic agents has not been studied and may increase the incidence of adverse effects.
The effects of herbal products on the pharmacokinetics of methotrexate have not been studied.
Interactions with laboratory tests have not been established.
Use of alcohol with Methotrexate Injection USP is contraindicated (see CONTRAINDICATIONS). The effects of smoking, on the pharmacokinetics of methotrexate have not been specifically studied.
Some of the effects (e.g., dizziness and fatigue) may have an influence on the ability to drive or operate machinery.
Dosage And Administration
- Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
- Methotrexate Injection USP without preservative may be given by the intramuscular, intravenous (as a bolus), intra-arterial, intrathecal or intraventricular (via Ommaya reservoir into the CNS) routes.
- Methotrexate Injection USP formulations which contain benzyl alcohol as preservative are contraindicated in neonates and for intrathecal, intraventricular, or high-dose therapy (see CONTRAINDICATIONS).
- Methotrexate Injection USP may only be administered by physicians experienced in the treatment of neoplasia. Typical dosages reported in the literature for the following malignancies are listed in the following section.
Psoriasis and Rheumatoid Arthritis:
- The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see WARNINGS AND PRECAUTIONS).
- All dosage 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.
- 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.
Recommended Dose and Dosage Adjustments
Breast Cancer: The initial doses of CMF will be cyclophosphamide 100 mg/m2 p.o. days 1 through 14, methotrexate 40 mg/m2 IV day 1, 8, and 5 - Fluorouracil 600 mg/m2 IV day 1, 8. Cycle length will be 28 days ("2 weeks-on, 2 weeks-off"). In patients over 60 years of age, the dosage of methotrexate will be 30 mg/m2 IV day 1, 8. If total bilirubin exceeds 1.5 mg/dL, decrease the dose of methotrexate only by 50%.
Bladder Cancer: Typical dosage regimens for bladder cancer are the CMV Regimen and the “M-VAC Regimen" which are represented in the following tables.
Head and Neck Cancer: Methotrexate remains the standard of therapy for patients with recurrent or metastatic disease. It has been given in a wide variety of doses and schedules (a few of which are represented in the table below).
0.8 mg/kg every 4 days IV
25 - 50 mg every 4 to 7 days
60 mg/m2 weekly IV or 40 mg/m2 biweekly IV
40 - 60 mg/m2 weekly IV
80 mg/m2 for 30 h every 2 wk with escalation to toxicity
40 mg/m2 weekly IV
40 - 200 mg/m2 IV on days 1, 4 weekly; leucovorin on days 2,5
60 mg/m2 IV weekly
For palliation of patients with advanced, incurable disease and acceptable renal function, it is appropriate to begin intravenous methotrexate with weekly doses of 40-50 mg/m2 or biweekly doses of 15 to 20 mg/m2 and escalate the dose in weekly increments until either mild toxicity or therapeutic response is achieved.
Gastric Cancer: A regimen used in a clinical trial in Belgium in patients with resectable gastric cancer follows: methotrexate (1.5 g/m2 IV day 1) + 5-Fluorouracil (1.5 g/m2 IV) + Leucovorin (15 mg/m2 orally or IV every 6 hours for 72 hours) + Adriamycin (30 mg/m2 IV, day 15). The schedule is repeated on day 29 for 6 cycles.
Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered intramuscularly in doses of 15 to 30 mg daily for a 5-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 hormone (beta-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 beta-HCG are usually recommended. Before each course of the drug, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumour 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.
Lymphomas: In Burkitt's tumour, Stages I-II, methotrexate has produced prolonged remissions in some cases. In Stage III, methotrexate is commonly given concomitantly with other antitumour 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.
The treatment of choice for localized histologically aggressive lymphoma is primary combination chemotherapy with or without involved-field radiation therapy. Frequently used regimens for intermediate, or high grade NHL that include methotrexate include groups: the ProMACE/MOPP, ProMACE-CytaBOM, Magrath Protocols. Represented in the table below for example, is the ProMACE-CytaBOM Regimen.
Cyclophosphamide 650 mg/m2 I.V.
Doxorubicin 25 mg/m2 I.V.
Etoposide 120 mg/m2 I.V.
Cytarabine 300 mg/m2 I.V.
Bleomycin 5 mg/m2 I.V.
Vincristine 1.4 mg/m2 I.V.
Methotrexate 120 mg/m2 I.V.
x with leucovorin rescue
Prednisone 60 mg/m2 PO
Co-trimoxazole 2 PO bid throughout 6 cycles of therapy
In early stage childhood non-Hodgkin's lymphoma, methotrexate is used effectively in combination chemotherapy regimens.
Mycosis Fungoides (cutaneous T-cell lymphoma): Therapy with methotrexate appears to produce clinical responses in up to 50% of patients treated, but chemotherapy is not curative. Dose levels of drug and adjustment of dose regimen by reduction or cessation of drug are guided by patient response and hematologic monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg of methotrexate twice weekly.
Leukemia: Acute lymphoblastic leukemia (ALL) in children 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 ALL. 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 twice weekly 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, re-induction 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 ALL.
Meningeal Leukemia: In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.
For intrathecal administration, preservative free methotrexate is diluted 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 children and high concentrations and neurotoxicity in adults.
The following dosage regimen is based on age instead of body surface area:
3 or older
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 children 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.
Leptomeningeal Carcinomatosis: Intrathecal administration of methotrexate as a single-drug or in combination regimens, is the most common therapy for carcinomatous leptomeningitis.
Treatment is optimally administered through an Ommaya reservoir and is usually started with methotrexate (10 mg/m2) given twice weekly until the cerebrospinal fluid cytology becomes negative. The treatment regimen is gradually decreased, first to a weekly course, and eventually to a single administration every two months.
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.
Treatment Week After Surgery
12 g/m2 IV as 4 hour infusion (starting dose)
15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.
Doxorubicin** as a single drug
30 mg/m2/day IVx3 days
50 mg/m2 IV
100 mg/m2 IV
15 units/m2 IV x 2 days
600 mg/m 2 IV x 2 days
0.6 mg/m2 IV x 2 days
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 Injection USP 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 Injection USP infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the Methotrexate Injection USP infusion, and for 2 days after the infusion has been completed.
- Alkalinize urine to maintain pH above 7.0 during Methotrexate Injection USP 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 Injection USP and at least once daily until the methotrexate level is below 5x10-8 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 non-reversible 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 Injection USP (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.
Leucovorin Dosage and Duration
Normal Methotrexate Elimination
Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.
15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate Elimination
Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.
Continue 15 mg PO, IM or IV q six hours, until Methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury
Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).
150 mg IV q three hours, until methotrexate level is less than 1 micromolar; than 15 mg IV q three hours, until methotrexate level is less than 0.05 micromolar.
Recommended starting dose schedule:
- Weekly single intramuscular or intravenous dose schedule: 10 to 25 mg per week until adequate response is achieved.
Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 25 mg/week should not ordinarily be exceeded.
Once optimal clinical response has been achieved, the dosage schedule should be reduced to the lowest possible effective dose and to the longest possible rest period.
Recommended starting dosage schedule:
Dosages may be gradually adjusted to achieve optimal clinical response, but not ordinarily to exceed a total weekly dose of 20 mg.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. Upon achieving the therapeutically desired result, dosage should be reduced gradually to the lowest possible effective maintenance dose. The optimal duration of therapy is unknown; limited data from long-term studies indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy.
Renal Impairment: Methotrexate is excreted to a significant extent by the kidneys, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide inter subject pK variability. Methotrexate Injection USP is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS).
% Standard Dose to Administer
Use alternative therapy
Pediatrics (<18 years of age): Safety and effectiveness in pediatric patients have not been established, other than in cancer chemotherapy (see WARNINGS AND PRECAUTIONS: Special Populations, Pediatrics).
Geriatrics (≥65 years of age): Due to diminished hepatic and renal function as well as decreased folate stores in elderly population, relatively low doses (especially in rheumatoid arthritis and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity. See Table 5 for reduced doses in oncology patients with renal impairment.
If a scheduled dose is missed, contact your doctor for instructions.
Methotrexate Injection USP may be diluted with any of the solutions for IV infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL. Dilutions should be used within 24 hours if kept at room temperature. Unused solution should be discarded after this time in order to avoid risk of microbial contamination.
0.9% Sodium Chloride Injection
5% Dextrose Injection
4% Dextrose and 0.18% Sodium Chloride Injection
Since methotrexate is poorly soluble in acid media, use of potassium chloride solution is not advisable.
If a preservative-free diluent is used, the solution should be used immediately because of the possibility of microbial growth. It is advisable to protect diluted solutions from light.
Due to the number of brands available, stability data of methotrexate in plastic syringes and bags are not available.
Unused preservative-free products should be discarded due to the possibility of microbial growth.
Dispensing of Pharmacy Bulk Vials:
Pharmacy Bulk Vials contain 25 mg/mL methotrexate (as methotrexate sodium) in 20 mL, 40 mL or 100 mL of sterile, unpreserved, isotonic solution (see Composition).
The availability of Pharmacy Bulk Vials is restricted to hospitals with a recognized intravenous admixture program. It is recommended that the vial remains in the carton until time of use. The Methotrexate Injection USP vial should be inspected for damage and visible signs of leaks. If there are signs of breakage or leakage from the vial, do not use. Incinerate the unopened package.
Pharmacy Bulk Vials are intended for multiple dispensing FOR INTRAVENOUS USE ONLY, employing a single puncture (see SPECIAL HANDLING INSTRUCTIONS).
The Pharmacy Bulk Vial content should be dispensed within eight hours. Any unused solution should be discarded. The diluted solutions prepared from the Pharmacy Bulk vial should be used within 24 hours from the time of the initial puncture of the Pharmacy Bulk Vial, when kept at room temperature.
Pharmacy Bulk Vials contain no preservatives. Care must be taken to minimize the potential for inadvertent introduction of micro‑organisms during manipulation in the hospital environment.
Incompatibilities: Other drugs should not be mixed with methotrexate in the same infusion bottle. Methotrexate has been reported to be incompatible with cytarabine, fluorouracil, and prednisolone sodium phosphate; however, its incompatibility with fluorouracil has been questioned and subsequent studies documented in the literature indicate that methotrexate and cytarabine are physically and chemically stable in intravenous admixtures over a range of concentrations and in a variety of typical vehicles. A mixture of methotrexate with cytarabine and hydrocortisone sodium succinate in various infusion fluids has been reported to be visually compatible for at least 8 hours at 25°C, although precipitation did not occur on storage for several days. In general, compatibility of any medicinal product admixed with Methotrexate Injection USP must be assured prior to patient administration.
Contact with acidic solutions should be avoided since Methotrexate Injection USP is sparingly soluble in acid media and precipitation may occur (see WARNINGS AND PRECAUTIONS for clinical incompatibilities).
Overdose with methotrexate has occurred with intrathecal administration, although intravenous and intramuscular overdose have also been reported.
Discontinue or reduce dosage at the first sign of ulceration or bleeding, diarrhea, or marked depression of the hematopoietic system. Leucovorin is indicated to diminish the toxicity and counteract the effect of 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, neither standard hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.
There are published case reports of intravenous carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdoses.
Action And Clinical Pharmacology
Mechanism of Action
Methotrexate is a folate antagonist.
Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated via the DHFR-catalyzed reaction in order to maintain the intracellular pool of tetrahydrofolate one-carbon derivatives for both thymidylate and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines and thus in a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication.
Methotrexate is most active against rapidly multiplying cells, because its cytotoxic effects occur primarily during the S phase of the cell cycle. Since cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. As a result, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to DHFR inhibition effects of methotrexate.
The cytotoxicity of methotrexate results from three important actions: inhibition of DHFR, inhibition of thymidylate synthase, and alteration of the transport of reduced folates. The affinity of DHFR to methotrexate is far greater than its affinity for folic acid or dihydrofolic acid, therefore, large doses of folic acid given simultaneously will not reverse the effects of methotrexate. However, Leucovorin calcium, a derivative of tetrahydrofolic acid may block the effects of methotrexate if given shortly after the antineoplastic agent. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma.
The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamination of methotrexate. The actual mechanism of action is unknown.
Methotrexate has immunosuppressive activity. This may be a result of inhibition of lymphocyte multiplication. The mechanisms of action in the management of rheumatoid arthritis of the drug are not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.
Absorption: Methotrexate is generally completely absorbed following parenteral administration, and after intramuscular injection peak serum concentrations occur in 30 to 60 minutes.
Distribution: Methotrexate is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver and skin. Methotrexate in serum is approximately 50% protein-bound. 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 does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally.
Metabolism: At low doses, methotrexate does not appear to undergo significant metabolism; following high-dose therapy, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes.
These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate syntheses. 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 tumours. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound.
Excretion: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. Total clearance averages 12 L/h, but there is wide interindividual variation. Excretion of single daily doses occurs through the kidneys in amounts from 80% to 90% within 24 hours. Repeated daily doses result in more sustained serum levels and some retention of methotrexate over each 24-hour period, which may result in accumulation of the drug within the tissues. The liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High concentrations of the drug, when needed, may be attained by direct intrathecal administration.
The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours.
Methotrexate clearance rates vary widely and are generally decreased at higher doses.
Special Populations and Conditions
Nursing Women: Methotrexate has been detected in human breast milk and is contraindicated during breast-feeding. The highest breast milk to plasma concentration ratio reached was 0.08:1.
Pediatrics: In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours.
Geriatrics: The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses (especially in RA and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity.
Renal Impairment: Since the renal excretion of methotrexate is the primary route of elimination with 80% to 90% of the single daily doses of methotrexate excreted through the kidneys within 24 hours, methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug.
Hepatic Impairment: Hepatic excretion of methotrexate is a minor route of elimination. However, the liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function.
Storage And Stability
Keep in a safe place out of the reach of children.
Methotrexate Injection USP (preservative-free) and Methotrexate Injection USP (Pharmacy Bulk Vial, preservative-free): store single-use vials between 15°C and 25°C. Protect from light and freezing. Discard unused portion.
Methotrexate Injection USP (with benzyl alcohol as preservative): store multidose vials between 15°C and 25°C. After the vials are punctured, the vials should be stored between 2°C and 8°C for a maximum of four weeks (30 days). Protect from light and freezing. Aseptic techniques should be used when handling punctured vials to avoid contamination.
It is recommended that the vial remains in the carton until time of use. The Methotrexate Injection USP vial should be inspected for damage and visible signs of leaks. If there are signs of breakage or leakage from the vial, do not use. Incinerate the unopened package.
Special Handling Instructions
General: Individuals who have contact with anti-cancer drugs, or work in areas where these drugs are used, may be exposed to these agents in air or through direct contact with contaminated objects.
Safe Handling and Disposal: Good medical practice will minimize exposure of persons involved with frequent handling of this drug as outlined below:
- Methotrexate has no vesicant properties and does not show acute toxicity on topical contact with the skin or mucous membranes. However, persons involved with handling cytotoxic drugs should avoid contact with skin and inhalation of airborne particles.
- Preparation of antineoplastic solutions should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II).
- Personnel preparing methotrexate solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks.
- Personnel regularly involved in the preparation and handling of antineoplastics should have bi-annual blood examinations.
- Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.
- All needles, syringes, vials and other materials for disposal which have come in contact with Methotrexate Injection USP should be segregated in plastic bags, sealed and marked as hazardous waste. Incinerate at 1000°C or higher. Sealed containers may explode if a tight seal exists.
- If incineration is not available, rinse all needles, syringes, tubing and other materials for disposal which have come in contact with methotrexate solutions with water and discard in the sewer system with running water.
Rinse vials with the appropriate quantity of water with the aid of a hypodermic syringe. Withdraw the solution and discard in the sewer system with running water. Dispose of rinsed equipment and vials in a safe manner.
Cleaning: Non-disposable equipment that has come in contact with Methotrexate Injection USP may be rinsed with water and washed thoroughly with soap and water.
Spillage/Contamination: Wear gloves, mask and protective clothing. Place spilled material in an appropriate container (i.e. cardboard for broken glass) and then in a polyethylene bag; absorb remains with gauze pads or towels; wash area with water and absorb with gauze or towels again and place in bag; seal, double bag and mark as a hazardous waste. Dispose of waste by incineration or by other methods approved for hazardous materials. Personnel involved in clean up should wash with soap and water.
Dosage Forms, Composition And Packaging
(1) Methotrexate Injection USP is supplied in a carton containing 20 mg, 50 mg and 500 mg of methotrexate (as the sodium salt) as follows:
10 mg/mL methotrexate
20 mg/2 mL* (contains no preservative)
25 mg/mL methotrexate
50 mg/2 mL* (contains no preservative)
25 mg/mL methotrexate
50 mg/2 mL+ (contains preservative)
25 mg/mL methotrexate
500 mg/20 mL+ (contains preservative)
Note: The 10 mg/mL presentation is available in packs of 5 vials. The 25 mg/mL presentations are available in packs of 5 vials (2 mL) or as single vials (2 mL and 20 mL).
(2) Methotrexate Injection USP Pharmacy Bulk Vials which are packaged in a carton, are for intravenous use only and are supplied to hospitals with a recognized intravenous admixture program only, as follows:
25 mg/mL methotrexate
500 mg/20 mL (contains no preservative)
25 mg/mL methotrexate
1 g/40 mL (contains no preservative)
25 mg/mL methotrexate
2.5 g/100 mL (contains no preservative)
Composition: Methotrexate Injection USP is a sterile, isotonic solution containing:
- Methotrexate Sodium equivalent to 10 mg/mL Methotrexate with 7.0 mg/mL Sodium Chloride, (unpreserved), with Sodium Hydroxide and Hydrochloric Acid as pH adjusters.
- Methotrexate Sodium equivalent to 25 mg/mL Methotrexate with 4.9 mg/mL Sodium Chloride, (unpreserved), with Sodium Hydroxide and Hydrochloric Acid as pH adjusters.
- Methotrexate Sodium equivalent to 25 mg/mL Methotrexate with 2.6 mg/mL Sodium Chloride and 0.9% v/v Benzyl alcohol (preserved), with Sodium Hydroxide and Hydrochloric Acid as pH adjusters.
Note: 50 mg/2 mL and 500 mg/20 mL Methotrexate Injection USP, with benzyl alcohol (as preservative) are supplied as multidose vials. Please see STORAGE AND STABILITY for special storage conditions once the vials are punctured.
Latex-free Stoppers – Stoppers contain no dry natural rubber
Submission Control No.: 207725
October 13, 2017