April 26, 2017
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"(Reuters) - Sanofi SA and Regeneron Pharmaceuticals Inc on Friday said U.S. regulators had declined to approve their experimental treatment for rheumatoid arthritis because of manufacturing deficiencies.

The companies, in a release, s"...





Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996).

Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion.

In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.

Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported.

There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported.

There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.


Otrexup is contraindicated in the following:


Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman. Otrexup is contraindicated in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Nursing Mothers

Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is contraindicated in nursing mothers [see Use in Specific Populations].

Alcoholism Or Liver Disease

Patients with alcoholism, alcoholic liver disease or other chronic liver disease [see WARNINGS AND PRECAUTIONS].

Immunodeficiency Syndromes

Patients who have overt or laboratory evidence of immunodeficiency syndromes [see WARNINGS AND PRECAUTIONS].

Preexisting Blood Dyscrasias

Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia [see WARNINGS AND PRECAUTIONS].


Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/30/2017


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