For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only OR for Specialist Use only
Black Box 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):
Each uncoated tablet contains:
Methotrexate .................. 2.5 mg
Each uncoated tablet contains:
Methotrexate .................. 7.5 mg
Each uncoated tablet contains:
Methotrexate .................. 10 mg
IMUTREX Injection 30 mg/2 ml
Each ml contains:
Methotrexate .................. 15 mg
(as Methotrexate Sodium)
Sodium Chloride ............ 6.4 mg
Sodium Hydroxide, IP, to adjust pH
Water for Injection .............. q.s.
Contains no antimicrobial preservative
Tablet for oral use.
Injection for intramuscular or intravenous use.
Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult RA.
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, buccal and intestinal mucosa and cells of the urinary bladder are, in general, more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate's effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies.
In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity.
Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy.
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.
In adults, oral absorption appears to be dose-dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect.
In leukaemic paediatric patients, oral absorption of methotrexate also appears to be dose-dependent and has been reported to vary widely (23% to 95%). A twentyfold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hours after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukaemic paediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in paediatric patients with juvenile RA (JRA). Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in paediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range: 0.03 to 1.40) at 1 hour, 0.44 micromolar (range: 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range: 0.06 to 0.58) at 3 hours. In paediatric patients receiving methotrexate for acute lymphocytic leukaemia (6.3 to 30 mg/m2) or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.
After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein-bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds, including sulphonamides, salicylates, tetracyclines, chloramphenicol and phenytoin.
Methotrexate does not penetrate the blood-cerebrospinal fluid (CSF) barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration.
After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms, which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumours. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.
The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours.
Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80 to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.
Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.
Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.
The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION.
Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1.
Methotrexate tablets are indicated in the treatment of gestational choriocarcinoma, chorio-adenoma destruens and hydatidiform mole.
Methotrexate tablets are used in maintenance therapy in combination with other chemotherapeutic agents.
Methotrexate tablets are 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 tablets are also used in combination with other chemotherapeutic agents in the treatment of advanced stage non- Hodgkin’s lymphomas.
IMUTREX 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.
RA, Including Polyarticular-Course Juvenile Rheumatoid
IMUTREX is indicated in the management of selected adults with severe, active, RA (ACR criteria), or children with active polyarticular-course JRA, 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 WARNINGS AND PRECAUTIONS; Drug Interactions). Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulphasalazine or cytotoxic agents has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.
Dosage and Administration
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 tablets are 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 tablets 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 tablets has been recommended.
Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate tablets are 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 tablets 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 tablets included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate tablets 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 tablets 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 tablets are 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 tablets 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 tablets are 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 tablets given in doses of 0.625 to 2.5 mg/kg daily.
Mycosis Fungoides (cutaneous T cell lymphoma): Therapy with methotrexate tablets 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 tablets 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
Single oral doses of 7.5 mg once weekly.
Divided oral dosages of 2.5 mg at 12-hour intervals for three 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/week in adults. Although there is experience with doses up to 30 mg/m2/week in children, there are too few published data to assess how doses over 20 mg/m2/week might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/week (0.65 to 1.0 mg/kg/week) 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 2 years with continued therapy. When methotrexate tablets are 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. Assessment of haematologic, hepatic, renal and pulmonary function should be made by history, physical examination and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. Appropriate steps should be taken to avoid conception during methotrexate therapy.
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. Maximal myelosuppression usually occurs in 7 to 10 days.
Psoriasis: Recommended Starting Dose Schedules
Weekly, single oral, intramuscular or intravenous dose schedule: 10 to 25 mg per week until adequate response is achieved.
Divided oral dose schedule: 2.5 mg at 12-hour intervals for three doses.
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.
Important Warning about the Dosage of IMUTREX Tablets (methotrexate)
In the treatment of psoriasis and Rheumatoid arthritis, 2.5 mg requiring dosing once a week e.g. rheumatologic and dermatological diseases, Methotrexate must only be taken once a week. Dosage errors in the use of IMUTREX Tablets (methotrexate) can result in serious adverse reactions, including death. Please read this section of the prescribing information very carefully.
Use in Patients with Renal Impairment – Dose adjustments
Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function. 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 intersubject pK variability.
Creatinine Clearance (mL/min)
% of dose to Administer
Methotrexate must not be administered
Creatinine Clearance (mL/min)
% of dose to Administer
= ῀ 60
Methotrexate must not be administered
Patients with Hepatic Impairment
Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Methotrexate in contraindicated if bilirubin values are > 5 mg/dl (85.5 μmol/l).
Patients with Pathological Fluid Accumulation
Methotrexate elimination is reduced in patients with pathological fluid accumulation (third space fluids) such as ascites or pleural effusions that may lead to prolonged methotrexate plasma elimination half-life and unexpected toxicity. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment. Methotrexate dose should be reduced according to the serum methotrexate concentrations.
Methotrexate should be used with extreme caution in elderly patients. Dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.
Methotrexate is not recommended for children under 3 years as insufficient data on efficacy and safety is available for this population
- Methotrexate can cause foetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women 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 foetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counselled on the serious risk to the foetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of 3 months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients.
- Because of the potential for serious adverse reactions from methotrexate in breastfed infants, it is contraindicated in nursing mothers.
- Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
- Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.
- Patients with psoriasis or RA who have pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia, should not receive methotrexate.
- Patients with profound impairment of renal or hepatic function or haematological impairment should not receive methotrexate.
- Methotrexate is contra-indicated in the presence of severe/significant renal impairment (creatinine clearance less than 30 ml/min) for methotrexate doses <100 mg/m2, and moderate renal impairment (creatinine clearance less than 60 ml/min) for methotrexate doses >100 mg/m2 or significant hepatic impairment. Liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s). Serious cases of anaemia, leucopenia or thrombocytopenia. IMUTREX Tablets should not be used concomitantly with drugs with antifolate properties (eg co-trimoxazole).
- Patients with a known hypersensitivity to methotrexate should not receive the drug.
Warnings and Precautions
Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high-dose methotrexate therapy.
Methotrexate has the potential for serious toxicity. 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 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 haemodialysis with a high-flux dialyser. If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity.
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.
Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During therapy of RA and psoriasis, monitoring of these parameters is recommended with haematology at least monthly, and renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. 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.
Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not a cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the RA population.
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
Organ System Toxicity
If vomiting, diarrhoea or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leucopenia, neutropenia and/or thrombocytopenia. In patients with malignancy and pre-existing hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in RA (n=128), leucopenia (white blood cells <3,000/mm3) was seen in 2 patients, thrombocytopenia (platelets <1,00,000/mm3) in 6 patients, and pancytopenia in 2 patients.
In psoriasis and RA, methotrexate should be stopped immediately if there is a significant drop in blood counts. 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. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally 2 years or more) and after a total dose of at least 1.5 gm. 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.
In psoriasis, liver function tests, including serum albumin, should be performed periodically 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 at 1) pre-therapy or shortly after initiation of therapy (2 to 4 months); 2) a total cumulative dose of 1.5 gm; and, 3) after each additional 1 to 1.5 gm. 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 therapy, the drug should be used with caution.
In RA, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in RA but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 RA patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 gm) 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.
Liver function tests should be performed at baseline and at 4- to 8-week intervals in patients receiving methotrexate for RA. Pre-treatment 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 RA).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate 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).
Infection or Immunologic States
Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy.
Hypogammaglobulinaemia has been reported rarely.
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 pneumonia should be considered.
Pulmonary symptoms (especially a dry, non-productive 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, dyspnoea, hypoxaemia, and an infiltrate on chest X-ray; hence, infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.
In addition, pulmonary alveolar haemorrhage has been reported with MTX used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.
Methotrexate should be withdrawn from patients with pulmonary symptoms, and a thorough investigation should be made to exclude infection. .If methotrexate-induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Pleuropulmonary manifestation of rheumatoid arthritis has been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically alerted to the potential for Methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea
Methotrexate may cause renal damage that may lead 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, is essential for safe administration.
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Methotrexate should be used with extreme caution in the presence of debility.
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.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be ‘recalled’ by the use of methotrexate.
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 haematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs or 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 RA have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in RA (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin and sulphonamides. 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 non-absorbable, 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 haematologic and gastrointestinal toxicity have been observed with high- and low-dose methotrexate. Use of methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g. azathioprine, retinoids, sulphasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Diuretics, hypoglycaemics, diphenylhydantoins, tetracyclines, chloramphenicol, p-aminobenzoic acid, and the acidic anti-inflammatory drugs, may cause a potential for increased toxicity when used concurrently.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate. Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate. Folate deficiency states may increase methotrexate toxicity.
Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination.
Severe antigenic reactions may occur if a live vaccine is given concurrently.
Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, penicillines, ciprofloxacin, diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenicid or sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indometacin (NSAID's) is commenced, as concomitant use of NSAID's has been associated with fatal methotrexate toxicity.
Concomitant administration of folate antagonists such as trimethoprim, cotrimoxazole and nitrous oxide should be avoided. The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. While this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.
Hepatic and nephrotoxic drugs should be avoided.
Acitretin (a treatment for psoriasis) is metabolised to eretinate. Methotrexate levels may be increased by eretinate and severe hepatitis has been reported following concomitant use.
Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.
Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate.
Relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.
Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination.
Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given.
If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m2 not be given.
Treatment with methotrexate doses of >100 mg/m2 should not be initiated at urinary pH values of less than 7.0.
Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.
Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and renal function are recommended.
As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.
If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.
If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.
Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.
Patients receiving low-dose methotrexate should:
- Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.
- Patients should report all symptoms and signs suggestive of infection, especially sore throat. If acute methotrexate toxicity occurs, patients may require treatment with folinic acid.
Relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.
Psoriasis and RA: Methotrexate is a Pregnancy Category X drug.
Methotrexate is contra-indicated during pregnancy in non-oncological indications.
Methotrexate has been shown to be teratogenic- reproductive risk; it causes embryotoxicity, abortion and foetal malformations in humans.
Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age
If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development.
In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester.
Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).
Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.
Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment
(less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.
Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate.
Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications. When methotrexate was discontinued prior to conception, normal pregnancies have been reported.
Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases.
Women of childbearing potential/Contraception in females
Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter. Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.
Contraception in Males
It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week).
For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.
As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate.
Because of the potential for serious adverse reactions from methotrexate in breastfed infants, it is contraindicated in nursing mothers.
Safety and effectiveness in paediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile RA.
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 with that observed in adults with RA.
Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 years 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. Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may overestimate renal function in the elderly, more accurate methods (i.e. creatinine 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. Postmarketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.
IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.
The most frequently reported adverse reactions include ulcerative stomatitis, leucopenia, nausea and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.
In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows:
Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows:
Blood and Lymphatic System Disorders: Suppressed haematopoiesis causing anaemia, aplastic anaemia, pancytopenia, leucopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinaemia has been reported rarely. Infection or septicaemia and haemorrhage from various sites may result.
Cardiovascular: Pericarditis, pericardial effusion, hypotension and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep-vein thrombosis, retinal vein thrombosis, thrombophlebitis and pulmonary embolus).
Central Nervous System: Headaches, drowsiness, blurred vision, transient blindness, speech impairment, including dysarthria and aphasia, hemiparesis, paresis and convulsions, have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy or encephalopathy.
Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses. There have been reports of leucoencephalopathy following intravenous Methotrexate in high doses, or low doses following cranial-spinal radiation.
Other reports include eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. Also opportunistic infections such as herpes zoster. Osteoporosis, abnormal (usually "megaloblastic") red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death in relation to or attributed to the use of Methotrexate. Although very rare, anaphylactic reactions to methotrexate have been reported.
Hepatobiliary Disorders: Hepatoxicity, Elevations in liver enzymes, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration
Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia and, sepsis, nocardiosis), histoplasmosis, cryptococcosis, herpes zoster, herpes simplex hepatitis, and disseminated herpes simplex.
Musculoskeletal System: Stress fracture.
Ophthalmic: Conjunctivitis, serious visual changes of unknown aetiology.
Pulmonary System: Respiratory fibrosis, respiratory failure, pulmonary oedema, pulmonary fibrosis, alveolitis, and interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.
Skin: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and, rarely, painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation- and solar-damaged skin.
Urogenital System: Severe nephropathy or renal failure, azotaemia, cystitis, haematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, vaginitis, vaginal ulcers and gynaecomastia; infertility, abortion, foetal death, foetal defects, nephropathy
Other rarer reactions related to or attributed to the use of methotrexate include nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma including reversible lymphomas, tumour lysis syndrome, soft tissue necrosis, and osteonecrosis. Anaphylactoid reactions have been reported.
Adverse Reactions in Double-Blind RA Studies
The approximate incidences of methotrexate attributed (i.e. placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies of patients (n=128) with RA treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant NSAIDs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies.
Incidence greater than 10%: Elevated liver function tests (15%), nausea/vomiting (10%).
Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 1,00,000/mm3).
Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhoea, alopecia, leucopenia (WBC less than 3,000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with RA on 7.5 to 15 mg/week oral doses showed an incidence of interstitial pneumonitis of 1%.
Other less common reactions included decreased haematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.
Adverse Reactions in Psoriasis Studies
There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to 4 years. With the exception of alopecia, photosensitivity, and ‘burning of skin lesions’ (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the RA studies. Rarely, painful plaque erosions may appear.
Adverse Reactions in JRA Studies
The approximate incidences of adverse reactions reported in paediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant NSAIDs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g. nausea, vomiting, diarrhoea), 11%; stomatitis, 2%; leucopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/week in JRA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.
If you experience any side effects, talk to your doctor or pharmacist or write to firstname.lastname@example.org. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 18002677779 from within India and on +91 821-6643551 from outside India (except the USA and EU)
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 haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high-flux dialyser.
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 haematologic and gastrointestinal reaction, e.g. leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following chronic overdose in the self-administered dosage for rheumatoid arthritis and psoriasis. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.
Storage and Handling Instructions
Store in a cool, dark place.
IMUTREX-2.5 is available in a blister pack of 10 tablets
IMUTREX-7.5 is available in a blister pack of 10 tablets
IMUTREX-10 is available in a blister pack of 4 tablets
IMUTREX Injection is available in a vial of 2 ml
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 RA 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.
Last Updated: Feb 2019
Last Reviewed: Feb 2019