Indications and Important Safety Information Including Boxed Warning
OTREXUP® (methotrexate) injection, for subcutaneous use
Indications:
OTREXUP is indicated in:
- the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children 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).
- in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.
Limitations of Use:
OTREXUP is not indicated for the treatment of neoplastic diseases.
This product includes the following Boxed Warning:
WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.
- Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with OTREXUP.
- Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
- Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
- Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
- Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
- Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.
- Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
- Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Contraindications:
OTREXUP is contraindicated in the following:
- Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
- Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
- Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
- Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
- Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.
Warnings and Precautions:
- Organ System Toxicity: OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of
administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on OTREXUP closely.
- Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
- Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
- Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
- Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
- Embryo-Fetal Toxicity: 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 OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
- Effects on Reproduction: 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 of reproductive potential.
- Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
- Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
- Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
- Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Adverse Reactions:
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Drug Interactions:
- 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,. 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. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
- Proton Pump Inhibitors (PPIs): The 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.
- Oral Antibiotics: Certain oral 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. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
- Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
- Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
- Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
- Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
- 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.
- Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.
Use in Special Populations:
- Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
- Nursing Mothers: Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with OTREXUP and for one week after the final dose.
- Females and Males of Reproductive Potential: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of OTREXUP. OTREXUP 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. OTREXUP 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.
- Pediatric Use: The safety and effectiveness of methotrexate, including OTREXUP, have not been established in pediatric patients with psoriasis. The safety and effectiveness of OTREXUP have not been established in pediatric patients with neoplastic diseases.
- Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
- Renal Impairment: Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Hepatic Impairment: OTREXUP is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely.
Dosage and Administration:
OTREXUP is for once weekly subcutaneous use only.
Administer OTREXUP in the abdomen or thigh.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
For full prescribing information including boxed warning, please click here.
Otrexup Total Care Co-pay Assistance Program
Take advantage of our savings program!
Otrexup Total Care Co-pay Assistance Program may provide financial support to commercially insured patients to assist with out-of-pocket costs of Otrexup. Eligible patients* may pay as low as a $0 co-pay for each prescription filled. This card is valid for up to 13 fills and may be renewed.
After your final refill, you must sign up for a new card to continue to receive Otrexup co-pay support.
To receive co-pay assistance, click on the image below:
HERE IS HOW THE OTREXUP TOTAL CARE CO-PAY ASSISTANCE PROGRAM WORKS:
- Present this card with a valid prescription.
- You will receive co-pay assistance for up to $250 each time you fill your prescription.
- For any rejections, please reprocess using BIN# 004682 PCN: CN GRP: WCOTR4106 and the same ID that's on the savings card.
- If you have any question, please feel free to call 1-800-422-5604
MAIL-IN REBATE
If your pharmacist is unable to procide the co-pay or coinsurance savings at the time you fill your prescription, you can still take advantage of this program if eligible.
- Download the form by clicking here.
- Complete the form with your name and address.
- Circle the product name, date, your name, and amount paid on the original pharmacy receipt. (Cash register receipt NOT accepted)
- Mail the form, your pharmacy receipt and a copy of your Otrexuo Total Care Co-Pay assistance Card to:
2325 Heritage Center Drive
Suite 317
Furlong, PA 18925
Please read Important Safety Information, including Boxed Warning and full Prescribing Information.
Otrexup Auto-injector Disposal Program
*Eligibility Restrictions: Offer only valid for patients with commercial prescription insurance. Maximum benefit of up to $250 for each prescription filled. Offer not valid for prescriptions reimbursed under any federal or state healthcare program, including Medicare, Medicaid, or any state medical assistance programs. Offer void where prohibited by law, taxed, or restricted. Offer only valid in the USA. Antares Pharma, Inc. reserves the right to rescind, revoke, or amend this offer at any time without notice. By using this co-pay assistance card, you demonstrate that you understand and agree to comply with the terms and conditions of this offer as put forth on this co-pay assistance card.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. For more information, go to www.otrexup.com or call 1-855-Otrexup (1-855-687-3987).
OTX 470-21-01-02
Indications and Important Safety Information Including Boxed Warning
OTREXUP® (methotrexate) injection, for subcutaneous use
Indications:
OTREXUP is indicated in:
- the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children 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).
- in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.
Limitations of Use:
OTREXUP is not indicated for the treatment of neoplastic diseases.
This product includes the following Boxed Warning:
WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.
- Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with OTREXUP.
- Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
- Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
- Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
- Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
- Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.
- Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
- Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Contraindications:
OTREXUP is contraindicated in the following:
- Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
- Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
- Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
- Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
- Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.
Warnings and Precautions:
- Organ System Toxicity: OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of
administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on OTREXUP closely.
- Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
- Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
- Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
- Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
- Embryo-Fetal Toxicity: 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 OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
- Effects on Reproduction: 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 of reproductive potential.
- Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
- Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
- Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
- Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Adverse Reactions:
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Drug Interactions:
- 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,. 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. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
- Proton Pump Inhibitors (PPIs): The 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.
- Oral Antibiotics: Certain oral 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. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
- Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
- Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
- Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
- Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
- 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.
- Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.
Use in Special Populations:
- Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
- Nursing Mothers: Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with OTREXUP and for one week after the final dose.
- Females and Males of Reproductive Potential: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of OTREXUP. OTREXUP 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. OTREXUP 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.
- Pediatric Use: The safety and effectiveness of methotrexate, including OTREXUP, have not been established in pediatric patients with psoriasis. The safety and effectiveness of OTREXUP have not been established in pediatric patients with neoplastic diseases.
- Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
- Renal Impairment: Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Hepatic Impairment: OTREXUP is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely.
Dosage and Administration:
OTREXUP is for once weekly subcutaneous use only.
Administer OTREXUP in the abdomen or thigh.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
For full prescribing information including boxed warning, please click here.
Indications and Important Safety Information Including Boxed Warning
OTREXUP® (methotrexate) injection, for subcutaneous use
Indications:
OTREXUP is indicated in:
- the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children 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).
- in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.
Limitations of Use:
OTREXUP is not indicated for the treatment of neoplastic diseases.
This product includes the following Boxed Warning:
WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.
- Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with OTREXUP.
- Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
- Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
- Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
- Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
- Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.
- Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
- Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Contraindications:
OTREXUP is contraindicated in the following:
- Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
- Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
- Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
- Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
- Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.
Warnings and Precautions:
- Organ System Toxicity: OTREXUP should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), OTREXUP should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of
administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on OTREXUP closely.
- Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
- Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
- Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
- Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
- Embryo-Fetal Toxicity: 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 OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
- Effects on Reproduction: 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 of reproductive potential.
- Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
- Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
- Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
- Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
- Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
- Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Adverse Reactions:
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Drug Interactions:
- 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,. 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. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
- Proton Pump Inhibitors (PPIs): The 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.
- Oral Antibiotics: Certain oral 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. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
- Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
- Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
- Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
- Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
- 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.
- Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.
Use in Special Populations:
- Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
- Nursing Mothers: Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with OTREXUP and for one week after the final dose.
- Females and Males of Reproductive Potential: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of OTREXUP. OTREXUP 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. OTREXUP 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.
- Pediatric Use: The safety and effectiveness of methotrexate, including OTREXUP, have not been established in pediatric patients with psoriasis. The safety and effectiveness of OTREXUP have not been established in pediatric patients with neoplastic diseases.
- Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
- Renal Impairment: Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
- Hepatic Impairment: OTREXUP is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely.
Dosage and Administration:
OTREXUP is for once weekly subcutaneous use only.
Administer OTREXUP in the abdomen or thigh.
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