Match the Drug classification to the medication example methotrexate

Methotrexate may cause very serious, life-threatening side effects. You should only take methotrexate to treat cancer or certain other conditions that are very severe and that cannot be treated with other medications. Talk to your doctor about the risks of taking methotrexate for your condition.

Tell your doctor if you have or have ever had excess fluid in your stomach area or in the space around your lungs and if you have or have ever had kidney disease. Also tell your doctor if you are taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, choline magnesium trisalicylate (Tricosal, Trilisate), ibuprofen (Advil, Motrin), magnesium salicylate (Doan's), naproxen (Aleve, Naprosyn), or salsalate. These conditions and medications may increase the risk that you will develop serious side effects of methotrexate. Your doctor will monitor you more carefully and may need to give you a lower dose of methotrexate or stop your treatment with methotrexate.

Methotrexate may cause a decrease in the number of blood cells made by your bone marrow. Tell your doctor if you have or have ever had a low number of any type of blood cells or any other problem with your blood cells. Call your doctor immediately if you experience any of the following symptoms: sore throat, chills, fever, or other signs of infection; unusual bruising or bleeding; excessive tiredness; pale skin; or shortness of breath.

Methotrexate may cause liver damage, especially when it is taken for a long period of time. If you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease, your doctor may tell you not to take methotrexate unless you have a life-threatening form of cancer because there is a higher risk that you will develop liver damage. The risk that you will develop liver damage may also be higher if you are elderly, obese, or have diabetes. Tell your doctor if you are taking any of the following medications: acitretin (Soriatane), azathioprine (Imuran), isotretinoin (Accutane), sulfasalazine (Azulfidine), or tretinoin (Vesanoid). Ask your doctor about the safe use of alcoholic beverages while you are taking methotrexate. Call your doctor immediately if you experience any of the following symptoms: nausea, extreme tiredness, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, or flu-like symptoms. Your doctor may order liver biopsies (removal of a small piece of liver tissue to be examined in a laboratory) before and during your treatment with methotrexate.

Methotrexate may cause lung damage. Tell your doctor if you have or have ever had lung disease. Call your doctor immediately if you experience any of the following symptoms: dry cough, fever, or shortness of breath.

Methotrexate may cause damage to the lining of your mouth, stomach, or intestines. Tell your doctor if you have or have ever had stomach ulcers or ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum). If you experience any of the following symptoms, stop taking methotrexate and call your doctor right away: mouth sores, diarrhea, black, tarry, or bloody stools, or vomit that is bloody or looks like coffee grounds.

Taking methotrexate may increase the risk that you will develop lymphoma (cancer that begins in the cells of the immune system). If you do develop lymphoma, it might go away without treatment when you stop taking methotrexate, or it might need to be treated with chemotherapy.

If you are taking methotrexate to treat cancer, you may develop certain complications as methotrexate works to destroy the cancer cells. Your doctor will monitor you carefully and treat these complications if they occur.

Methotrexate may cause serious or life-threatening skin reactions. If you experience any of the following symptoms, call your doctor immediately: fever, rash, blisters, or peeling skin.

Methotrexate may decrease the activity of your immune system, and you may develop serious infections. Tell your doctor if you have any type of infection and if you have or have ever had any condition that affects your immune system. Your doctor may tell you that you should not take methotrexate unless you have life-threatening cancer. If you experience signs of infection such as a sore throat, cough, fever, or chills, call your doctor immediately.

If you take methotrexate while you are being treated with radiation therapy for cancer, methotrexate may increase the risk that the radiation therapy will cause damage to your skin, bones, or other parts of your body.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before, during, and after your treatment to check your body's response to methotrexate and to treat side effects before they become severe.

Tell your doctor if you or your partner is pregnant or plan to become pregnant. If you are female, you will need to take a pregnancy test before you begin taking methotrexate. Use a reliable method of birth control so that you or your partner will not become pregnant during or shortly after your treatment. If you are male, you and your female partner should continue to use birth control for 3 months after you stop taking methotrexate. If you are female, you should continue to use birth control until you have had one menstrual period that began after you stopped taking methotrexate. If you or your partner become pregnant, call your doctor immediately. Methotrexate may cause harm or death to the fetus.

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Embryo-Fetal Toxicity

Based on published reports and its mechanism of action, methotrexate can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate is contraindicated for use in pregnant women receiving TREXALL for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TREXALL and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during TREXALL treatment and for 3 months after the final dose [see CONTRAINDICATIONS, Use In Specific Populations].

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, can occur with TREXALL [see CONTRAINDICATIONS, ADVERSE REACTIONS].

If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue TREXALL [see DOSAGE AND ADMINISTRATION].

Myelosuppression

TREXALL suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see ADVERSE REACTIONS].

Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue methotrexate taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Gastrointestinal Toxicity

Diarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving TREXALL for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported [see ADVERSE REACTIONS]. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions [see DRUG INTERACTIONS].

Withhold or discontinue TREXALL for severe gastrointestinal toxicity taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Hepatotoxicity

TREXALL can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see ADVERSE REACTIONS]. The safety of TREXALL in patients with hepatic disease is unknown.

The risk of hepatotoxicity is increased with heavy alcohol consumption. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a total cumulative dose of 1.5 g or more.

Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue TREXALL taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Pulmonary Toxicity

Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with TREXALL [see ADVERSE REACTIONS].

Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Dermatologic Reactions

Severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with TREXALL [see ADVERSE REACTIONS].

Exposure to ultraviolet radiation while taking methotrexate may aggravate psoriasis.

TREXALL can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.

Monitor patients for dermatologic toxicity and withhold or permanently discontinue TREXALL for severe dermatologic reactions taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION]. Advise patients to avoid excessive sun exposure and use sun protection measures.

Renal Toxicity

TREXALL can cause renal toxicity, including irreversible acute renal failure [see ADVERSE REACTIONS].

Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue TREXALL for severe renal toxicity taking into account the importance of TREXALL treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Administer glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed TREXALL clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information.

Risk Of Serious Adverse Reactions With Medication Error

Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking TREXALL daily when a weekly dosing regimen was prescribed.

For patients prescribed a once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death.

Folic Acid Supplementation

Neoplastic Diseases

Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Therefore, instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider.

Non-Neoplastic Diseases

Folate deficiency may increase TREXALL adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis [see DOSAGE AND ADMINISTRATION].

Serious Infections

Patients treated with TREXALL 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 [see ADVERSE REACTIONS].

Monitor patients for infection during and after treatment with methotrexate. Withhold or discontinue methotrexate for serious infections taking into account the importance of methotrexate treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Neurotoxicity

TREXALL can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see ADVERSE REACTIONS]. The risk of leukoencephalopathy is increased in patients who received prior cranial radiation.

Monitor patients for neurotoxicity and withhold or discontinue TREXALL taking into account the importance of methotrexate treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see DOSAGE AND ADMINISTRATION].

Secondary Malignancies

Secondary malignancies can occur with TREXALL [see ADVERSE REACTIONS]. The risk of cutaneous malignancies is further increased when cyclosporine is administered to patients with psoriasis who received prior methotrexate.

In some cases, lymphoproliferative disease occurring during therapy with low-dose TREXALL regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue methotrexate [see DOSAGE AND ADMINISTRATION].

Tumor Lysis Syndrome

TREXALL can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of TREXALL.

Immunization And Risks Associated With Live Vaccines

Disseminated infections following administration of live vaccines have been reported. Immunization with live vaccines is not recommended during treatment. Follow current vaccination practice guidelines for administration of immunizations in patients receiving TREXALL.

Update immunizations according to immunization guidelines prior to initiating methotrexate. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Infertility

Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible. Discuss the risk of infertility with females and males of reproductive potential [see Use In Specific Populations].

Increased Risk Of Adverse Reactions Due To Third-Space Accumulation

Methotrexate accumulates in third-spaces (e.g., pleural effusions or ascites), which results in prolonged elimination and increases the risk of adverse reactions. Evacuate significant third- space accumulations prior to methotrexate administration taking into account the importance of methotrexate treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Embryo-Fetal Toxicity

• Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations].
• Advise females of reproductive potential to use effective contraception during treatment with TREXALL and for 6 months after the final dose [see Use In Specific Populations].
• Advise males of reproductive potential to use effective contraception during treatment with TREXALL and for 3 months after the final dose [see Use In Specific Populations].

Hypersensitivity Reactions

Advise patients and their caregivers of the potential risk of hypersensitivity and that TREXALL is contraindicated in patients with a history of hypersensitivity reactions to TREXALL. Instruct patients to seek immediate medical attention for signs of a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS].

Myelosuppression And Serious Infections

Inform patients and their caregivers that TREXALL can cause myelosuppression and the need for frequent monitoring of blood cell counts. Advise patients and their caregivers to immediately report new onset fever, symptoms of infection, easy bruising or persistent bleeding to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Toxicity

Advise patients and their caregivers to report new or worsening diarrhea, vomiting, or stomatitis to their healthcare provider. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Pulmonary Toxicity

Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Dermatologic Reactions

Advise patients and their caregivers that TREXALL can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients and their caregivers to avoid excessive sun exposure and use sun protection measures [see WARNINGS AND PRECAUTIONS].

Renal Toxicity

Advise patients and their caregivers to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see WARNINGS AND PRECAUTIONS].

Risk Of Serious Adverse Reactions With Medication Error

For patients who are prescribed a once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as a single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see WARNINGS AND PRECAUTIONS].

Neurotoxicity

Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Secondary Malignancies

Advise patients on the risk of second primary malignancies during treatment with TREXALL [see WARNINGS AND PRECAUTIONS].

Lactation

Instruct women not to breastfeed during treatment with TREXALL and for 1 week after the final dose [see Use In Specific Populations].

Infertility

Advise females and males of reproductive potential that TREXALL may impair fertility [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-thecounter drugs, vitamins, and herbal products [see DRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis Mutagenesis, Impairment Of Fertility

Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

Use In Specific Populations

Pregnancy

Risk Summary

Methotrexate is contraindicated in pregnant women with non-neoplastic diseases [see CONTRAINDICATIONS].

Based on published reports and its mechanism of action [see CLINICAL PHARMACOLOGY], methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Published data from case reports, 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 evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmune disease (17%; 95% CI: 13, 23). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI: 0.6, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

Lactation

Risk Summary

Limited published literature report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, instruct women not to breastfeed during treatment with methotrexate and for 1 week after the final dose.

Females And Males Of Reproductive Potential

Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [Pregnancy].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate [see CONTRAINDICATIONS, Pregnancy].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months after the final dose.

Males

Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate and for 3 months after the final dose.

Infertility

Females

Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with methotrexate and after the final dose. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with methotrexate and after the final dose. It is not known if the infertility may be reversed in all affected males.

Pediatric Use

The safety and effectiveness of methotrexate in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see INDICATIONS, DOSAGE AND ADMINISTRATION]. No new safety signals have been observed in pediatric patients in clinical studies [see ADVERSE REACTIONS].

The safety and effectiveness of methotrexate have not been established in pediatric patients for the other indications [see INDICATIONS].

Geriatric Use

Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Renal Impairment

Methotrexate elimination is reduced in patients with renal impairment [see CLINICAL PHARMACOLOGY]. Patients with renal impairment are at increased risk for methotrexate adverse reactions. Closely monitor patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, Cockcroft-Gault] for adverse reactions. Reduce the dosage or discontinue methotrexate as appropriate [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reactions based on the elimination characteristics of methotrexate [see CLINICAL PHARMACOLOGY]. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue methotrexate as appropriate [see WARNINGS AND PRECAUTIONS].