Indicated for:

Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis:

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).

Psoriasis:

Otrexup is indicated 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.

Otrexup is not indicated for the treatment of neoplastic diseases.

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.

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 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.

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.

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. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population.

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

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. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.

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.

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.

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.

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.

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.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Otrexup.

Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate.

Methotrexate increases the plasma levels of mercaptopurine. The combination of Otrexup and mercaptopurine may therefore require dose adjustment.

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.

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.

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.

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.

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.

GoToSource

• Use in patients under 18 years of age for psoriasis. GoToSource

• Ectopic pregnancy. GoToSource

• Systemic sclerosis. GoToSource

• Sarcoidosis. GoToSource

• Alopecia areata. GoToSource

• Systemic lupus erythematosus. GoToSource

• Morphea. GoToSource

• Osteoarthritis. GoToSource

• Adjunct treatment for acute lymphoblastic leukaemia, acute myeloid leukaemia, meningeal leukaemia, lymphoma, osteosarcomas, non-Hodgkin’s lymphoma, breast and bladder cancer. GoToSource

• Relapsing-remitting multiple sclerosis. GoToSource

• Inflammatory bowel disease. GoToSource

Non-melanoma skin cancer. GoToSource

Bone marrow suppression (decreased ability of bone marrow to produce blood cells). GoToSource

Kidney failure. GoToSource

Liver injury, development of fatty liver disease, fibrosis and cirrhosis, portal hypertension ( increased blood pressure within the portal vein that carries blood from digestive organs to liver), stomatitis (inflammation of mouth and lips), oral ulcers, tumor lysis syndrome, fetal death and reactivation of hepatitis B. GoToSource

Pulmonary toxicity. GoToSource

Methotrexate toxicity and death. GoToSource

Skin ulceration. GoToSource

Pancytopenia (low levels of red and white blood cells and platelets), mucositis (inflammation of lining of digestive system), and ulceration or erosion of gastrointestinal system. GoToSource

Leukoencephalopathy (diseases affecting white matter of brain), seizures, transient paresis (partial paralysis), blurred vision, aphasia (partial or complete loss of language function), anarthria (speechlessness), pseudobulbar palsy (inability to control facial movements), loss of consciousness, opisthotonus (spasm of muscles causing backward arching of head, neck, and spine) and confusion. GoToSource

Erythema multiforme, stevens–johnson syndrome and toxic epidermal necrolysis (severe skin disorders). GoToSource

Periorbital edema (swelling around eyes), ocular pain, blurred vision, photophobia (light sensitivity),  conjunctivitis (inflammation of membrane covering surface of eyeball), blepharitis (inflammation of eyelid), decreased reflex tear secretion and non-arteritic ischemic optic neuropathy (loss of blood flow to optic nerve). GoToSource

Opportunistic infections. GoToSource

Hodgkin lymphoma. GoToSource

Osteonecrosis of the jaw (bone of lower or upper jaw becomes exposed). GoToSource

Lawsuits filed for skin cancer.