Are hemorrhage, increased INR-value and/or hyperbilirubinemia possible side-effects of methylphenid

Fråga: Are hemorrhage, increased INR-value and/or hyperbilirubinemia possible side-effects of methylphenidate (Concerta)? The question concerns a boy born 1991 who suffers from attention deficit hyperactivity disorder (ADHD) and who started treatment with oral methylphenidate two years ago. One year ago he had an epidural bleeding after a minor trauma. INR 1.6 (reference value <1.2) was then discovered. Hb was 75 g/L (reference value 110-160 g/L). A few months later, the mother thought that he had yellow eyes and bilirubin was then 48 umol/L (reference value <22 umol/L). Concerta was withdrawn for eight weeks and bilirubin then decreased to 26 umol/L and INR to 1.2. When treatment with Concerta was restarted, bilirubin increased to 47 umol/L (9 conjugated) and INR to 1.3. Other laboratory findings: transaminases, bile acids, cupper and factor VII normal. Factor II slightly low. No concomitant pharmacological treatment, except for oral phytomenadion (Konakion) as treatment of the bleeding tendency. The dose of methylphenidate is unknown. No known cause of vitamin K-deficiency.

Sammanfattning: There is little documentation concerning bleedings or liver dysfunction as side-effects of methylphenidate, even though it is a well established treatment of ADHD. However, since in the present case there is a positive de- and rechallenge, a causal relationship between the drug and the bleeding tendency and the laboratory findings, cannot be excluded.

Svar: Data found searching the literature and relevant databases concerning hyperbilirubinemia, hemorrhage, bleeding, increased INR-value and liver dysfunction as side-effects of methylphenidate are sparse.

Hepatic side effects of methylphenidate have been reported occasionally in relation to intravenous abuse of the drug. There is only one report concerning methylphenidate given orally in therapeutic doses. The indication for treatment with methylphenidate in that case was a reactive depression because of hemiplegia after a cerebrovascular accident. The bilirubin value was normal at all times, but lactic dehydrogenase (LD), alkaline phosphatase (ALP) and liver enzymes were elevated and there was both a positive de- and rechallenge (1). Two other reports describe hepatic side-effects during intravenous abuse of methylphenidate (2, 3). The manufacturer has listed hepatic side effects as rare adverse events (4).

In the Swedish adverse drug register, there is one recent report of hyperbilirubinemia evaluated as possibly related to methylphenidate, and we assume that this report relates to the same patient as in this question. There are also three reports of epistaxis which were evaluated as possibly caused by methylphenidate, but no other reports of bleeding. There are 74 reports in total on methylphenidate (5).