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IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR OTREXUP^®

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.

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.

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.
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 and kidney toxicities.
Otrexup has the potential for serious toxicity. 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.
- Gastrointestinal: Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death may occur. OTREXUP should be discontinued until recovery occurs. Use with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. OTREXUP may cause unexpectedly severe (sometimes fatal) gastrointestinal toxicity when used with NSAIDs.
- Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, OTREXUP should be used with caution, if at all. OTREXUP should be stopped immediately if there is a significant drop in blood counts. Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) with NSAIDs.
- Hepatic: OTREXUP has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal. Liver function should be monitored.
- Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection, and is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes.
- Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia. Chronic leukoencephalopathy has also been reported in patients who received repeated high doses of methotrexate with leucovorin rescue even without cranial irradiation. A transient acute neurologic syndrome has been observed.
- Pulmonary: 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.
- Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
- Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
- 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. During therapy, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected.
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/distress, dyspepsia, ulcerative stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions.” Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, 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: 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, resulting in hematologic and gastrointestinal toxicity. 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 (e.g., azathioprine, retinoids, and sulfasalazine) 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 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.

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: Methotrexate is present in human milk in low amounts following oral methotrexate administration. Because of the potential for serious adverse reactions including myelosuppression, 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. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia treated with intermediate-dose intravenous methotrexate.
Geriatric Use: Use caution in dose selection for elderly patients due to the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease, or other drug therapy in this population. 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.

Please see Full Prescribing Information, including BOXED WARNING and Patient Information at www.otrexup.com/PI.

To report SUSPECTED ADVERSE REACTIONS, contact Assertio Therapeutics at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.