DRUGS & SUPPLEMENTS
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Methotrexate can cause the following severe or fatal adverse reactions.
Monitor closely and modify dose or discontinue Methotrexate as appropriate.
WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY
See full prescribing information for complete boxed warning.
Methotrexate is a folate analog metabolic inhibitor indicated for the:
Methotrexate is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.
Methotrexate is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) 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).
Methotrexate is intended for oral use only. Use another formulation of Methotrexate for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .
It is important that Methotrexate be measured with an accurate measuring device . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.
The recommended starting dose of Methotrexate, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2 given one time weekly. After initiating Methotrexate, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.
The recommended starting dose of Methotrexate is 10 mg/m2 given one time weekly.
Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week in pediatric patients, doses greater than 20 mg/m2/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if Methotrexate is administered by an alternative route using another formulation.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
Certain side effects such as mouth sores may be reduced by folate supplementation with Methotrexate in pJIA.
Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with Methotrexate . Exclude pregnancy in females of reproductive potential before starting Methotrexate .
Methotrexate is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
Methotrexate is a clear yellow to orange oral solution that contains 2.5 mg of Methotrexate per milliliter.
Oral solution: 2.5 mg/mL (3)
Methotrexate is contraindicated in the following:
Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.
Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue Methotrexate as needed.
Patients treated with Methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections.
Monitor patients for the signs and symptoms of infection during and after treatment with Methotrexate and treat promptly. Consider dose modification or discontinuation of Methotrexate in patients who develop serious infections .
Methotrexate can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.
Consider administration of glucarpidase in patients with toxic plasma Methotrexate concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function .
Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.
Interrupt or discontinue Methotrexate and institute appropriate supportive care as needed.
Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of Methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) .
Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of Methotrexate in patients with chronic liver disease.
Assess liver function prior to initiating Methotrexate and monitor liver function tests during treatment. Interrupt or discontinue Methotrexate as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.
Other risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age.
Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue Methotrexate as appropriate.
Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with Methotrexate. Discontinue Methotrexate if severe dermatologic reactions occur.
Anaphylaxis can occur with Methotrexate. If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate and institute appropriate therapy. Methotrexate is contraindicated for use in patients with a history of severe hypersensitivity.
Radiation dermatitis and sunburn may be “recalled” by the use of Methotrexate.
Secondary malignancies can occur at all dose levels of Methotrexate.
There have been instances of lymphoproliferative disease associated with low-dose oral Methotrexate which have regressed completely following withdrawal of Methotrexate without institution of antineoplastic therapy. Discontinue Methotrexate first and institute appropriate treatment if the lymphoma does not regress.
Based on published reports and methotrexate’s mechanism of action, Methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, Methotrexate is contraindicated. Consider the benefits and risks of Methotrexate and risks to the fetus when prescribing Methotrexate to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final Methotrexate dose .
Immunization may be ineffective when given during Methotrexate therapy.
Immunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving Methotrexate therapy.
Based on published reports, Methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients .
Methotrexate can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Methotrexate administration .
Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with Methotrexate.
Closely monitor patients undergoing Methotrexate therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions ].
Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated Methotrexate blood levels (e.g., dehydration).
Liver Function Tests
Transient liver function test abnormalities are observed frequently after Methotrexate administration and are usually not 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 .
Pulmonary Function Tests
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available .
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .
Advise patients to measure Methotrexate with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .
The following adverse reactions are discussed in more detail in other sections of the labeling.
Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection (6).
To report SUSPECTED ADVERSE REACTIONS, contact Silvergate Pharmaceuticals at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase Methotrexate toxicity.
Polyarticular Juvenile Idiopathic Arthritis
The approximate incidences of adverse reactions reported in pediatric patients with JIA 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 nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 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 JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.
Additional adverse reactions which have been identified during postmarketing use of Methotrexate are listed below by organ system.
Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphaden-opathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia
Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension
Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia
Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis
Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations
Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions
Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex
Metabolism: Hyperglycemia and tumor lysis syndrome
Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis
Nervous System Disorders: 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 reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Renal Disorders: Azotemia, hematuria, proteinuria, cystitis
Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia
Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis
Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens‑Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.
Penicillins may reduce the renal clearance of Methotrexate; increased serum concentrations of Methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with Methotrexate. Monitor patients accordingly .
Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving Methotrexate. Monitor patients accordingly .
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. Monitor patients receiving Methotrexate with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.
Probenecid may reduce renal elimination of Methotrexate. Consider alternative drugs.
Methotrexate may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with Methotrexate.
Lactation: Advise women not to breastfeed.
Based on published reports and methotrexate’s mechanism of action, Methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman . In pregnant women with non-malignant disease, Methotrexate is contraindicated. Consider the benefits and risks of Methotrexate and risks to the fetus when prescribing Methotrexate to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Published data from cases, literature reviews, and observational studies report that Methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because Methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception Methotrexate exposure.
A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking Methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to Methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to Methotrexate after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to Methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
Limited published literature report the presence of Methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of Methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from Methotrexate in breastfed infants, advise women not to breastfeed during Methotrexate therapy.
Test for pregnancy prior to initiating therapy with Methotrexate.
Methotrexate can cause fetal harm when administered to a pregnant woman .
Advise females of reproductive potential to use effective contraception during and for 6 months after the final Methotrexate dose.
Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final Methotrexate dose.
Based on published reports of female infertility after therapy with Methotrexate, advise females of reproductive potential that Methotrexate can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.
Based on published reports of male infertility after therapy with Methotrexate, advise males of reproductive potential that Methotrexate can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.
Safety and effectiveness of Methotrexate in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) .
Methotrexate elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue Methotrexate administration .
The effect of hepatic impairment on Methotrexate pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.
Fatal overdosage has occurred with Methotrexate. Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.
Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of Methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum Methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum Methotrexate concentrations may cause renal damage leading to acute renal failure.
Glucarpidase is indicated for the treatment of toxic Methotrexate concentrations in patients with delayed Methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.
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. Neither 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.
Methotrexate contains Methotrexate, a folate analog metabolic inhibitor.
Chemically Methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:
For Oral Use Only
READY TO USE
Each 1 mL contains 2.5 mg
Methotrexate (equivalent to
2.74 mg Methotrexate sodium).
See prescribing information.
2° - 8°C (36° - 46°F).
After dispensing, may be
stored at room temperature
15° - 30°C (59° - 86°F)
for 60 days.
KEEP THIS AND ALL
MEDICATIONS OUT OF THE
REACH OF CHILDREN
Silvergate Pharmaceuticals, Inc.
Greenwood Village, CO 80111
|Apo-Methotrexate 2.5 mg Tablet||0.66 USD|
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Depending on the reaction of the Methotrexate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Methotrexate not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Methotrexate addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology