Guest guest Posted May 21, 2001 Report Share Posted May 21, 2001 methotrexate Pronunciation: meth oh TREX ate Brand: Rheumatrex Dose Pack WARNINGS Methotrexate (MTX) should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy. Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease, infectious hepatitis or other chronic liver disease should not receive MTX. Alcohol should be avoided during MTX therapy. Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive MTX. Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive MTX. Some experts consider renal insufficiency, preexisting pulmonary disease, and depressed serum albumin levels to be relative contraindications to the use of MTX. The use of MTX high-dose regimens recommended for osteosarcoma requires meticulous care. High-dosage regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established. Because of the possibility of serious toxic reactions, the patient should be informed by the physician of the risks involved and should be under a physician's constant supervision. Deaths have been reported with the use of MTX in the treatment of malignancy, psoriasis, and rheumatoid arthritis. In the treatment of psoriasis or rheumatoid arthritis, MTX use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established and after appropriate consultation. Due to the risk of serious nausea, vomiting, diarrhea, or stomatitis, with the possibility of resultant symptomatic dehydration, the manufacturer recommends caution if this drug must be used in patients with peptic ulcer disease or ulcerative colitis. SIDE EFFECTS 1. Myelosuppression is one of the primary toxic effects of methotrexate. Methotrexate can suppress hematopoiesis and cause anemia, leukopenia, and/or thrombocytopenia. Preexisting myelosuppression or low hematologic cell counts are contraindications to the use of this drug, particularly in patients with rheumatoid arthritis or psoriasis. Close monitoring of the CBC is mandatory. Profound count nadirs may require therapy discontinuation, at least temporarily. Folate therapy and/or leucovorin rescue may be preventive or palliative. Treated patients who become febrile should be assumed to have neutropenia until proven otherwise. Cytopenia occurs in 5% to 25% of patients with rheumatoid arthritis (RA) who receive long-term therapy. Risk factors include renal dysfunction, preexisting folate deficiency, increased mean corpuscular volume value, advanced age, concomitant use of other anti-folate medications (such as trimethoprim-sulfamethoxazole), and possibly hypoalbuminemia, concomitant infection, history of bone marrow injury, surgery, and concurrent use of NSAIDs or probenecid. Pancytopenia is rarely observed in patients with rheumatoid arthritis. Bone marrow recovery typically occurs within two weeks after the withdrawal of MTX. 2. Gastrointestinal side effects, especially with high-dose administration, may be expected. Serious nausea, vomiting, diarrhea, or stomatitis (10% to 80% of patients followed in long-term studies) may result in symptomatic dehydration. Other frequently reported GI side effects, particularly after high-dose therapy, include gingivitis, pharyngitis, stomatitis, anorexia, hematemesis, melena, gastrointestinal ulceration and bleeding, and enteritis. GI symptoms are often eliminated by folate supplementation. Folate does not affect efficacy of MTX. Gastrointestinal side effects are usually controlled by folate supplementation (1 to 5 mg orally, given 4 hours before MTX or 1 mg orally once a day if on low dose therapy, as in rheumatoid arthritis), dosage reduction, dividing the dose over a 12 to 24-hour period, withholding the drug, or giving it parenterally. Extremely rare cases of colitis and toxic megacolon have been associated with the use of MTX. 3. Methotrexate can cause acute elevations of liver function tests (elevated serum transaminases in 15% of patients with rheumatoid arthritis (RA) on low-dose therapy) or chronic hepatotoxicity (fibrosis and cirrhosis). The incidence of liver fibrosis and cirrhosis in patients with RA (low doses) averages 3% to 7% and 0.1%, respectively. Meta-analysis has revealed the incidence of progression of liver disease (worsening of 1 grade on the histologic classification of Roenigk) in patients with RA or psoriatic arthritis averages 27%, or 7% per gram of MTX (total dose) given. Chronic hepatotoxicity typically develops only after chronic use of higher doses (2 years or more of total doses of 1.5 grams or more), is more likely in patients who ingest ethanol, who are aged, who are obese, who have chronic renal insufficiency, or who have diabetes. In general, the following serve as guidelines for patients with non-oncologic conditions: 1) Screen all patients to be treated with complete liver blood tests (transaminases, albumin, alkaline phosphatase, bilirubin), hepatitis B and C serologic studies (some experts recommend viral serology's only in patients with abnormal liver function tests), baseline serum creatinine and complete blood count (CBC); 2) Baseline liver biopsy if the patient has preexisting liver disease, persistently abnormal baseline AST (aspartate aminotransferase), history of excessive alcohol consumption (greater than 3 drinks/day), or chronic hepatitis B or C infection; 3) Monitor hepatic enzymes every 4 to 8 weeks (with the understanding that they are not necessarily predictive of fibrosis/cirrhosis), discontinuing MTX if serum transaminase levels meet or exceed 2 to 3x baseline (some guidelines recommend withholding MTX for 1 to 2 weeks if significant abnormalities persist); 4) Liver biopsy should be considered if significant hepatic enzyme abnormalities persist for 2 to 3 months. Liver biopsy should be performed if 6 of 12 monthly AST levels are above the upper limit of normal or serum albumin levels are less than normal in the setting of well-controlled disease; 5) If liver biopsy shows Roenigk grade I, II, or IIIA (mild fibrosis), MTX may be resumed with monitoring as described above; if liver biopsy show Roenigk grade IIIB (moderate fibrosis) or IV (cirrhosis), MTX should be discontinued; 6) MTX should be discontinued in patients with significant liver abnormalities, as described above, who refuse liver biopsy; 7) It is still debated whether post-therapy biopsy should be performed every 2 to 3 years or after each 1.5 to 2.0 grams cumulative dose given, regardless of liver chemistries. *Pre-biopsy coagulation studies and withholding of aspirin and other NSAIDs are recommended. 4. New and/or opportunistic infection can arise during or after therapy with methotrexate due to drug-induced immune suppression. Infections during MTX therapy may occur in up to 58% of patients during low-dose therapy (as in RA). Patients are at great risk after high-dose therapy. Of concern are infections associated with severe immunosuppression, such as disseminated herpes zoster, Listeria meningitis, Pneumocystis carinii pneumonia, Mycobacterium avium intracellulare pneumonia, and systemic fungal infections (cryptococcosis, nocardiosis, aspergillosis and histoplasmosis). MTX should be held prior to and during elective surgery to minimize the risk of infectious complications. Limited data have shown that the use of low-dose MTX for patients with rheumatoid arthritis is associated with decreased CD8 and naive CD4 T lymphocytes after only 8 weeks of therapy. Methotrexate 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 immunization in patients receiving methotrexate therapy. 5. Common nervous system side effects include headaches, dizziness, drowsiness, blurred vision, subtle cognitive dysfunction, moodiness, tinnitus or unusual cranial sensations. After intrathecal administration, headache, back pain, fever, and even transient paraplegias have been reported. Serious neurotoxicity has been associated with the use of high-dose MTX after intrathecal or intraventricular administration to patients who have undergone craniospinal irradiation, but has also been described in other patients who have received low-dose oral therapy. The development of serious neurotoxicity is more likely if MTX is given in high doses to patients who have undergone craniospinal irradiation. Significant neurotoxicity can present as an acute stroke-like encephalopathy or a chronic leukoencephalopathy. Unique features of the former include its acute onset (seizures, confusion, hemiparesis, speech problems, loss of consciousness) and reversibility within days. The use of high-dose IV MTX has been associated with the development of chronic delayed leukoencephalopathy in patients with or without a history of craniospinal irradiation. A syndrome of subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis, and stupor may begin several months after the initiation of therapy. Affected patients often improve after discontinuation of therapy. Intrathecal or intraventricular administration of MTX has been associated with the acute onset of headache, nausea, vomiting, fever, back pain, dizziness, and meningismus. Acute symptoms usually resolve within one to two days. In some cases, subacute neurotoxicity, with myelopathy or encephalopathy, may occur within days to weeks. Subacute neurotoxicity is usually characterized by paresis/plegia, dementia, confusion, tremor, ataxia, irritability, and somnolence. Delayed leukoencephalopathy, as described above, has also been associated with the use of intrathecal MTX. The condition can improve but can be progressive and fatal. Progressive dementia and leukoencephalopathy has been reported in at least one case after low-dose, oral administration of MTX for the treatment of rheumatoid arthritis. 6. Pulmonary toxicity can occur at any dosage in 3% to 11% of patients, and can mimic infectious pneumonia. Interstitial pneumonitis has emerged as one of the most unpredictable and potentially life-threatening side effects from low-dose MTX therapy. It presents as fever, dry/non-productive cough, dyspnea, hypoxemia, and/or epistaxis, usually with chest X-ray infiltration. Signs or symptoms of infection must be treated seriously due to the possibility of MTX-induced neutropenia. Two patterns of pulmonary toxicity have been reported: a hypersensitivity reaction and a toxic reaction with diffuse alveolar damage and nonspecific lung injury. Risk factors are unknown, but may include male gender, cigarette smoking, and concomitant use of an NSAID. The hypersensitivity reaction is characterized by interstitial pneumonitis, granuloma formation, and the development of bronchopneumonia. Some patients have asthmatic symptoms. Interstitial pneumonitis may be associated with duration of treatment or weekly or cumulative dose. The prevalence of this complication ranges from 2.5% to 7.5% in patients with psoriatic or rheumatoid arthritis. One prospective study has shown that the cumulative dose of MTX is independently related to small, but significant, increases in residual volume and that MTX may cause mild degrees of air trapping after long-term therapy. The differential diagnosis of MTX pneumonitis includes infectious pneumonia, hypersensitivity pneumonitis caused by other drugs and autoimmune alveolitis due to rheumatoid arthritis (RA). Pneumocystis carinii pneumonia (PCP) can resemble MTX pneumonitis, and bronchoalveolar lavage (BAL) is a useful tool to distinguish between the two. BAL is not necessarily helpful in distinguishing MTX pneumonitis from RA alveolitis, however, since an elevated lymphocyte count and an increased CD4/CD8 ratio are observed in both conditions. Pulmonary function tests in affected patients reflect a restrictive ventilatory defect and decreased oxygen diffusing capacities. A mild peripheral eosinophilia is often present. 7. Renal insufficiency is most commonly associated with high-dose MTX since, after these doses, the concentration of a major circulating metabolite, 7-OH MTX, can precipitate in the renal tubule. Concomitant use of other potentially nephrotoxic drugs, including NSAIDs, and preexisting renal insufficiency are risk factors. Aggressive and adequate hydration and urinary alkalinization helps minimize the risk of MTX-induced nephropathy, cystitis, and hematuria. If monitoring reveals renal dysfunction, decreasing MTX doses or discontinuing the drug altogether may improve renal function. 8. There is an increased risk of methotrexate (MTX) toxicity in patients who have "third space" accumulations of fluid, such as pleural effusions. MTX accumulates in these spaces and becomes cleared from these spaces slowly. These "deep pools" of MTX markedly increase the risk of toxicity, particularly gastrointestinal toxicity (mucositis) and should be evacuated before therapy begins. General, frequently reported side effects include malaise, fatigue, and chills. Less commonly reported effects include arthralgias and myalgias. Leucovorin is typically given to diminish toxicity and counteract the adverse effects of high-dose therapy. 9. Genitourinary toxicity may seriously affect either sex (see also "Pregnancy"). Women may experience menstrual dysfunction, vaginal discharge, abortion, or infertility. Decreased libido has been described in each sex. Defective oogenesis and spermatogenesis is usually transient. 10. Dermatologic side effects include erythematous rashes, desquamation, epidermal necrosis, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, cutaneous vasculitis, and furunculosis. Alopecia that typically resolves several months after discontinuation. Cases of severe, sometimes fatal, dermatologic reactions, such as toxic epidermal necrolysis, s- 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 have been observed after single or multiple, low, intermediate or high doses of methotrexate for the treatment of neoplastic and non-neoplastic diseases. 11. Musculoskeletal complications from low-dose MTX in patients with rheumatoid arthritis include rare instances of accelerated nodulosis. This problem is more commonly associated with MTX than other second-line agents. The use of MTX may be associated with decreased bone density in a syndrome called "MTX osteopathy" (this potential complication requires further investigation). This syndrome may be especially important in post-menopausal women. 12. Rare cases of hypersensitivity reactions, including anaphylaxis, have been reported 13. Although large, retrospective studies have not shown a definitive association between the use of MTX and the development of cancer, some evidence suggests that methotrexate may be oncogenic, particularly with respect to the development of some lymphomas and leukemias. Large retrospective studies have shown that hematologic malignancies are uncommon in patients with RA treated with disease-modifying antirheumatic drugs, including MTX. These studies have shown that there does not appear to be a relationship between the peak or cumulative dose of the duration of MTX therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancies seen in MTX-treated patients do not appear different from those seen in patients with RA treated with other disease-modifying antirheumatic drugs. Underlying rheumatoid arthritis (RA) or Sjogren's syndrome are independent risk factors for the development of non-Hodgkin's lymphoma. 14. Rare cases of cardiovascular side effects, including pericarditis, pericardial effusion, myocardial ischemia, hypotension and ventricular arrhythmias, have been associated with MTX. Thromboembolic events including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus have also been reported with methotrexate use. Chemical pleuritis secondary to MTX has been identified as the cause of chest pain in some patients after high-dose therapy. 15. The only reported endocrinologic side effect is gynecomastia associated with the use of low-dose MTX in patients with rheumatoid arthritis. 16. Ocular side effects reported with methotrexate include conjunctivitis and serious visual changes of unknown origin. Pharmacology Methotrexate (MTX) is a folate analogue/antimetabolite. MTX competes with folate for binding to dihydrofolate reductase (DHFR), an enzyme that catalyzes the conversion of dihydrofolate to tetrahydrofolate, the active form of folic acid. Since tetrahydrofolate is necessary for the synthesis of thymidylate and purines, MTX depletes the pool of reduced folates which are necessary for the production of DNA synthesis, repair and cellular replication. MTX exerts its activity on dividing cells during the S phase. The mechanism of action of low-dose MTX as an "anti-inflammatory" agent for conditions, such as rheumatoid arthritis and psoriasis, is not known. Methotrexate is approved by the FDA for the treatment of recalcitrant, disabling rheumatoid arthritis or psoriasis and the following neoplastic conditions: gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphocytic leukemia, and meningeal leukemia. MTX is also used alone or in combination with other chemotherapy agents for the treatment of breast cancer, head and neck cancer, advanced mycosis fungoides, lung cancer (squamous cell and small cell types), and advanced stage non-Hodgkin's lymphomas. It is also used in high doses, followed by leucovorin rescue, with other chemotherapeutic agents in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation of the primary tumor. MTX has been used without FDA approval for asthma, abortion induction in ectopic pregnancy, systemic lupus erythematosus, and ulcerative colitis What is the most important information I should know about methotrexate? • Do not take more of this medication than is prescribed for you. Too much methotrexate can lead to death. For the treatment of psoriasis and rheumatoid arthritis, one dose of methotrexate is usually taken once a week. Alternatively, the dose is divided into three parts, which are taken at 12-hour intervals each week. Follow your doctor's instructions very closely. • Notify your doctor immediately if you develop fever; chills; a sore throat; unusual bruising or bleeding; unexplained shortness of breath, coughing, or wheezing; diarrhea; abdominal pain; black, tarry stools; sores in or around the mouth; yellow skin or eyes; blood in the urine; darkened urine; swelling of the feet or legs; or joint pain. These symptoms could be early signs of dangerous side effects. • Do not take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, Nuprin, others), ketoprofen (Orudis KT, Orudis, Oruvail), or naproxen (Aleve, Naprosyn, Anaprox) without first talking to your doctor. A dangerous drug interaction could result, possibly leading to death. • Do not drink alcohol while taking methotrexate. What is methotrexate? • Methotrexate interferes with the production and maintenance of DNA, which is the genetic material in the cells of your body. Methotrexate has a greater effect on cells that reproduce often such as cancer cells, bone marrow cells, fetal cells, skin cells, the cells lining the mouth and intestines, and cells of the bladder. It is not known exactly how methotrexate works in the treatment of rheumatoid arthritis. • Methotrexate is used to treat certain types of cancer, psoriasis, and rheumatoid arthritis. • Methotrexate may also be used for purposes other than those listed in this medication guide. Who should not take methotrexate? • Before taking methotrexate, tell your doctor if you have · liver disease or a history of liver problems; · kidney disease; · alcoholism or alcoholic liver disease; · an immune system disorder; · an infection; · a stomach ulcer; · ulcerative colitis; · diabetes; · fluid around your lungs or in your abdomen; · blood problems; or · asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, or any other lung disease. • You may not be able to take methotrexate, or you may require a dosage adjustment or special monitoring during therapy if you have any of the conditions listed above. • Do not take this medication if you are pregnant. Methotrexate is in the FDA pregnancy category X. This means that it will cause birth defects in an unborn baby. Methotrexate can affect a baby both when a woman is treated and when a man is treated. If the woman is being treated with methotrexate, pregnancy must be avoided during treatment and for one ovulatory cycle following treatment. If the man is being treated with methotrexate, pregnancy must be avoided during treatment and for 3 months following treatment. • Since methotrexate may harm a nursing infant, breast-feeding is not recommended during treatment with methotrexate. How should I take methotrexate? • Take methotrexate exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you. • Take each dose with a full glass of water. • Do not take more of this medication than is prescribed for you. Too much methotrexate can lead to death. For the treatment of psoriasis and rheumatoid arthritis, one dose of methotrexate is usually taken once a week. Alternatively, the dose is divided into three parts, which are taken at 12-hour intervals each week. Follow your doctor's instructions very closely. • Your doctor will want you to have regularly scheduled blood tests while taking methotrexate. • Store methotrexate at room temperature away from moisture and heat. What happens if I miss a dose? • Contact your doctor if you miss a dose of methotrexate. What happens if I overdose? • Seek emergency medical attention. • A methotrexate overdose can lead to death. What should I avoid while taking methotrexate? • Do not take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, Nuprin, others), ketoprofen (Orudis KT, Orudis, Oruvail), and naproxen (Aleve, Naprosyn, Anaprox) without first talking to your doctor. A dangerous drug interaction could result, possibly leading to death. • Do not drink alcohol while taking methotrexate. • Avoid prolonged exposure to sunlight. Methotrexate may increase the sensitivity of your skin to sunlight. Use a sunscreen and wear protective clothing when exposure to the sun is unavoidable. What are the possible side effects of methotrexate? • If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately: · an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives); · fever or chills; · a sore throat; · unusual bleeding or bruising; · unexplained shortness of breath, coughing, or wheezing; · diarrhea; · abdominal pain; · black, tarry stools; · sores in or around the mouth; · yellow skin or eyes; · blood in the urine; · darkened urine; · swelling of the feet or legs; · joint pain; or · confusion, unusual behavior, or seizures. • Other, less serious side effects may be more likely to occur. Continue to take methotrexate and notify your doctor if you experience · nausea, vomiting, or decreased appetite; · itching or a skin rash; · hair loss; · boils or acne; · dizziness; · increased sensitivity of the skin to sunlight; · headache; · drowsiness; or · blurred vision. • Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. What other drugs will affect methotrexate? • Do not take methotrexate without first talking to your doctor if you are taking any of the following medicines: · aspirin; or · a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen (Advil, Motrin, Nuprin, others), ketoprofen (Orudis KT, Orudis, Oruvail), naproxen (Aleve, Naprosyn, Anaprox), indomethacin (Indocin), oxaprozin (Daypro), sulindac (Clinoril), tolmetin (Tolectin), ketorolac (Toradol), diclofenac (Cataflam, Voltaren), etodolac (Lodine), fenoprofen (Nalfon), flurbiprofen (Ansaid), nabumetone (Relafen), or piroxicam (Feldene). • The medicines listed above may interact dangerously with methotrexate. Death could result. Your doctor will need to monitor your treatment if you need to take any of these medicines. • Before taking methotrexate, tell your doctor if you are taking any of the following medicines: · etretinate (Tegison); · theophylline (Theo-Dur, Theolair, Theochron, Elixophyllin, Slo-Phyllin, others); · phenytoin (Dilantin); · probenecid (Benemid); · procarbazine (Matulane); · folic acid or a vitamin supplement that contains folic acid; · a penicillin antibiotic such as ampicillin (Principen, others), amoxicillin (Amoxil, Trimox, Augmentin, others), dicloxacillin (Dynapen, others), penicillin (Pen-Vee-K, Veetids, others), and others; · a tetracycline antibiotic such as minocycline (Minocin, Dynacin, others), doxycycline (Vibramycin, Vibra-Tabs, others), tetracycline (Sumycin, others), and others; or · a sulfa-based medicine such as sulfamethoxazole (Bactrim, Septra, Sulfatrim, Gantanol), sulfisoxazole (Gantrisin), and others. • You may not be able to take methotrexate, or you may require a dosage adjustment or special monitoring if you are taking any of the medicines listed above. • Drugs other than those listed here may also interact with methotrexate. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines. Where can I get more information? • Your pharmacist has additional information about methotrexate written for health professionals that you may read. Quote Link to comment Share on other sites More sharing options...
Recommended Posts
Join the conversation
You are posting as a guest. If you have an account, sign in now to post with your account.
Note: Your post will require moderator approval before it will be visible.