Overdose : מינון יתר

4.9   Overdose
Symptoms of an overdose
Post-marketing experience of methotrexate has shown that methotrexate overdose generally occurred after oral administration but also after intravenous, intramuscular or intrathecal administration.

The symptoms following an oral or intravenous overdose principally affect the haematopoietic and gastrointestinal system. Events included leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow depression, inflammation of the mucosa (mucositis), stomatitis, mouth ulcers, nausea, vomiting as well as gastrointestinal ulcerations and bleeding. In some cases, there were no signs of intoxication. There are reports of fatalities following an overdose. In these cases, there were also reports of sepsis, septic shock, renal failure and aplastic anaemia.

After an intrathecal overdose, CNS symptoms usually appear, associated with headache, nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In some cases, no symptoms were observed. In other cases, an intrathecal overdose had a fatal outcome; a cerebral herniation with increased intracranial pressure was reported in this context, as was acute toxic encephalopathy.

Therapeutic measures in the event of an overdose
For the prevention and therapy of toxic side effects, calcium folinate is available as the specific antidote.
a) Prevention:
At a methotrexate dose of 100 mg/m2 BSA or more, this treatment must be followed by the administration of calcium folinate. Please refer to the specialist literature for information on the dosing and duration of use of calcium folinate as an antidote.
b) Treatment:
Treatment of intoxication symptoms of a low-dose methotrexate therapy (individual dosage < 100 mg/m2 body surface area methotrexate) that can be attributed to a tetrahydrofolic acid deficiency:
Immediately administer 6–12 mg of calcium folinate intravenously or intramuscularly, followed by the same amount of calcium folinate several times (at least 4 times) at 3–6 hour intervals.

For more intensive calcium folinate rescue in the event of delayed methotrexate elimination during methotrexate therapy in medium-high and high doses, refer to the specialist literature.

The longer the time interval between methotrexate administration and calcium folinate administration, the lower the efficacy of calcium folinate. In order to determine the optimum dose and duration of calcium folinate administration, methotrexate serum levels must be monitored.

In the event of a massive overdose, hydration and urinary alkalisation may be required to prevent precipitation of methotrexate and/or its metabolites within the renal tubules. If the intoxication is caused by substantially delayed elimination (methotrexate serum levels), e.g. due to acute kidney failure, haemodialysis and/or haemoperfusion can be considered. Effective methotrexate clearance was achieved through haemodialysis with a high-flux-dialyser. Neither standard haemodialysis nor peritoneal dialysis led to an improved methotrexate elimination.

An accidental intrathecal overdose may require intensive systemic countermeasures: A high-dose, systemic, non-intrathecal administration of calcium folinate, alkaline diuresis and quick draining of cerebrospinal fluid and ventriculolumbar perfusion.