INTERACTIONS Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.1 ). Proton pump inhibitors : concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.2 ).
7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. 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 hematologic and gastrointestinal toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including Otrexup. 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 rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. 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. Steroids may be reduced gradually in patients who respond to methotrexate.
7.2 Proton Pump Inhibitors (PPIs) Use caution if high-dose methotrexate is administered to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.
7.3 Oral Antibiotics Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of Otrexup with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.
7.4 Hepatotoxins 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 Otrexup and other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
7.5 Theophylline Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Otrexup.
7.6 Folic Acid and Antifolates Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.
7.7 Mercaptopurine Methotrexate increases the plasma levels of mercaptopurine. The combination of Otrexup and mercaptopurine may therefore require dose adjustment.
7.8 Nitrous Oxide The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate.
7.9 Other Drugs Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of Otrexup with this drug should be carefully monitored. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.
CONTRAINDICATIONS: Methotrexate can cause fetal 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 fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS ) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients (see BOXED WARNINGS ). Because of the potential for serious adverse reactions from methotrexate in breast fed 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 rheumatoid arthritis who have pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive methotrexate. Patients with a known hypersensitivity to methotrexate should not receive the drug.
AND PRECAUTIONS
- Serious Infections : Monitor patients for infection during and after treatment with Methotrexate Tablets. Withhold or discontinue Methotrexate Tablets for serious infections as appropriate. ( 5.11 )
- Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue Methotrexate Tablets as appropriate. ( 5.12 )
- Secondary Malignancies : Can occur with methotrexate. ( 5.13 )
- Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of Methotrexate Tablets. ( 5.14 )
- Immunizations and Risk Live Vaccines : Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. ( 5.15 )
- Infertility : Can cause impairment of fertility, oligospermia, and menstrual dysfunction. ( 5.16 , 8.3 )
5.1 Embryo-Fetal Toxicity and its mechanism of action, Methotrexate Tablets can cause fetal harm, including fetal death, when administered to a pregnant woman.
Methotrexate
Tablets is contraindicated for use in pregnant women receiving Methotrexate Tablets 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 Methotrexate Tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Tablets treatment and for 3 months after the final dose Based on published reports and its mechanism of action, Methotrexate Tablets can cause fetal harm, including fetal death, when administered to a pregnant woman.
Methotrexate
Tablets is contraindicated for use in pregnant women receiving Methotrexate Tablets 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 Methotrexate Tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Tablets treatment and for 3 months after the final dose [see Contraindications ( 4 ), Use in Specific Populations ( 8.1 , 8.3 )].
5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Adverse Reactions ( 6.1 )]</span>. If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue Methotrexate Tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.3 Myelosuppression hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. 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 Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.4 Gastrointestinal Toxicity vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions Diarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>. or discontinue Methotrexate Tablets for severe gastrointestinal toxicity taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Withhold or discontinue Methotrexate Tablets for severe gastrointestinal toxicity taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.5 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure The safety of Methotrexate Tablets in patients with hepatic disease is unknown. Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. The safety of Methotrexate Tablets in patients with hepatic disease is unknown. 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. 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 Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.6 Pulmonary Toxicity toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. patients for pulmonary toxicity and withhold or discontinue Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Monitor patients for pulmonary toxicity and withhold or discontinue Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.7 Dermatologic Reactions , including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with Methotrexate Severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with Methotrexate <span class="opacity-50 text-xs">[see Adverse Reactions (( 6.1 , 6.2 )]</span>. to ultraviolet radiation while taking Methotrexate may aggravate psoriasis. Methotrexate can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation. Exposure to ultraviolet radiation while taking Methotrexate may aggravate psoriasis. Methotrexate can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation. patients for dermatologic toxicity and withhold or permanently discontinue Methotrexate Tablets for severe dermatologic reactions taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Advise patients to avoid excessive sun exposure and use sun protection measures. Monitor patients for dermatologic toxicity and withhold or permanently discontinue Methotrexate Tablets for severe dermatologic reactions taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>. Advise patients to avoid excessive sun exposure and use sun protection measures.
5.8 Renal Toxicity can cause renal toxicity, including irreversible acute renal failure Methotrexate can cause renal toxicity, including irreversible acute renal failure <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue Methotrexate Tablets for severe renal toxicity taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue Methotrexate Tablets for severe renal toxicity taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>. glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information. Administer glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information.
5.9 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 methotrexate 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.
5.10 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 methotrexate adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 , 2.4 , 2.5 )]</span>.
5.11 Serious Infections treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections, including opportunistic infections such as jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. patients for infection during and after treatment with Methotrexate Tablets. Withhold or discontinue Methotrexate Tablets for serious infections taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Monitor patients for infection during and after treatment with Methotrexate Tablets. Withhold or discontinue Methotrexate Tablets for serious infections taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.12 Neurotoxicity can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal The risk of leukoencephalopathy is increased in patients who received prior cranial radiation. Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. The risk of leukoencephalopathy is increased in patients who received prior cranial radiation. patients for neurotoxicity and withhold or discontinue Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy Monitor patients for neurotoxicity and withhold or discontinue Methotrexate Tablets taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.13 Secondary Malignancies malignancies can occur with methotrexate The risk of cutaneous malignancies is further increased when cyclosporine is administered to patients with psoriasis who received prior methotrexate. Secondary malignancies can occur with methotrexate <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. The risk of cutaneous malignancies is further increased when cyclosporine is administered to patients with psoriasis who received prior methotrexate. lymphoproliferative disease occurring during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue methotrexate Tablets In some cases, lymphoproliferative disease occurring during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue methotrexate Tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span>.
5.14 Tumor Lysis Syndrome 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 Methotrexate Tablets. Methotrexate 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 Methotrexate Tablets.
5.15 Immunization and Risks Associated with Live Vaccines 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 Methotrexate Tablets. 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 Methotrexate Tablets. immunizations according to immunization guidelines prior to initiating Methotrexate Tablets. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations according to immunization guidelines prior to initiating Methotrexate Tablets. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
5.16 Infertility 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 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span>.
5.17 Increased Risk of Adverse Reactions Due to Third-Space Accumulation 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 Tablets administration taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy. 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 Tablets administration taking into account the importance of Methotrexate Tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy.