Metoject (Methotrexate) Pre-Filled Syringe 25mg/0.5ml

Antineoplastic; antirheumatic; Disease Modifying Immunosuppressant Agent (DMARD)

“ALERT: US Boxed Warning

Intrathecal and high-dose therapy:

Use only preservative-free methotrexate formulations and diluents for intrathecal and high-dose therapy. Do NOT use formulations or diluents containing preservatives for intrathecal and high-dose therapy because they contain benzyl alcohol.

Appropriate use:

Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in life threatening neoplastic diseases or 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.

The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens of methotrexate injection for other neoplastic diseases are investigational, and a therapeutic advantage has not been established.

Pregnancy:

Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis (pJIA), and psoriasis is contraindicated in pregnancy. Consider the benefits and risks of methotrexate and risks to the fetus when prescribing methotrexate to a pregnant patient with a neoplastic disease. 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 methotrexate.

Bone marrow suppression:

Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).

Renal impairment:

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 methotrexate administration.

Hepatotoxicity:

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 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.

Pneumonitis:

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.

Gastrointestinal toxicity:

Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some NSAIDs. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.

Secondary malignancy:

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 methotrexate 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. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Dermatologic toxicity:

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.

Opportunistic infections:

Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.

Radiotherapy:

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Experienced physician (injection):

Methotrexate should be used only by health care providers whose knowledge and experience include the use of antimetabolite therapy.”

CSA NA – FDA Approved – REMS (N) – Can Ship

Methotrexate, Otrexup/Rasuvo/Trexall/Xatmep/Metoject inhibits dihydrofolate reductase which normally forms reduced folates and thymidylate synthetase thereby reducing the production of purine and thymidylic acid.  These agents are important in the S-phase of DNA replication, so methotrexate essentially interferes with DNA synthesis, repair and cellular replication.  Fast dividing cells are more sensitive to this medication since DNA replication is required to divide.  The mechanism for the treatment of various autoimmune conditions is not fully understood but it is expected to do with immunomodulation.  For psoriasis it is believed that the rapidly proliferating epithelial cells in the skin are slowed by the medication. 

Methotrexate, Otrexup/Rasuvo/Trexall/Xatmep/Metoject is officially indicated for rheumatoid arthritis, psoriasis, and various cancers.  It is also prescribed off-label for dermatomyositis/polymyositis, Crohn disease, sarcoidosis, and systemic lupus erythematosus. (may be used for conditions not listed)

Before starting Methotrexate, Otrexup/Rasuvo/Trexall/Xatmep/Metoject make sure your physician is aware of any allergies, medications you currently take, knows your full medical background and current/past medical conditions, or are pregnant or breastfeeding.   Bloodwork will likely be required before initiating this medication for long term use.

Patients must be monitored closely by their physicians while on this medication.  Risk of acute kidney failure, bone marrow suppression, neurotoxicity, dermatological reactions, gastrointestinal toxicity, liver toxicity, increased risk of infections, secondary malignancy etc.

Most of these are a concern when this medication is used for chemotherapy and the much lower dosages used for autoimmune conditions such as rheumatoid arthritis, but the patient should still be monitored closely in case any of them do occur.

For higher dosages, these effects are shared by many antineoplastic agents as inhibiting cell division affects every cell in your body, with fast dividing tissues such as stomach lining, skin, hair and nails being affected the most.  Fast dividing cancer cells are also susceptible to these effects, but since cancer cells are almost identical to regular human cells it is very difficult to create an agent that is toxic to them but not normal human cells whereas with something such as antibiotics for bacteria we can target cell components or functions that humans do not have which is much easier.

The dosage and frequency of methotrexate varies greatly based on the condition it is used for.  2.5-25mg orally or injected once weekly are common for autoimmune diseases such as rheumatoid arthritis but much larger doses are calculated based off body surface area are common for various cancers and some other conditions.  Commonly combined with folic acid or folinic acid (Leucovorin Calcium) to reduce toxicity/adverse reactions.

How to Take: Follow instructions provided by physician/pharmacy label, administer consistently at same days and times unless otherwise directed, store at room temperature, take after food or milk to reduce gastrointestinal upset if administered orally.

You Need to Avoid: Avoid excessive alcohol consumption as it may increase liver toxicity, do not skip blood tests or follow up appointments while on this medication they are important to monitor for serious adverse reactions

Methotrexate, Otrexup/Rasuvo/Trexall/Xatmep/Metoject has many potential side effects, some of which are profoundly serious.  The risk varies with dosage.  For lower dosages dizziness, diarrhea, nausea, and abdominal distress are common.  Other common side effects are more likely to show up in blood work such as elevated liver enzymes, leukopenia, and thrombocytopenia.  

Note this is not a complete list of side effects.

1. What do I do if side effects are intolerable?
   If side effects are causing a lot of distress speak to your physician as soon as possible to discuss options.
2. Why would my physician prescribe a medication with such serious side effects?
   Your physician takes the most recent clinical guidelines to make evidence-based decisions on what medication is appropriate in which situations.  Your current medications, your allergies, age, cost of medication, comorbid conditions and many other factors will further complicate or limit which medications are appropriate.  Methotrexate is used for many serious conditions and your physician has determined the benefits outweigh the risks.   Furthermore, they will be monitoring your bloodwork and symptoms closely to see if any serious complications are starting to arise and be able to adjust therapy to prevent progression.