According to the Swedish catalogue of approved medical products (FASS), reboxetine should not be us

Fråga: According to the Swedish catalogue of approved medical products (FASS), reboxetine should not be used concomitantly with a monoamine oxidase inhibitor (MAOI) due to a risk of developing tyramine effects or possibly a serotonergic syndrome. Does this apply to the reversible monoamine oxidase inhibitor moclobemide (Aurorix)?

Background: A 33-year-old woman suffers from a depression with atypical symptoms such as increased appetite and hypersomnia. She also has Attention Deficit Hyperactivity Disorder (ADHD). She has been treated with the combination of reboxetin and moclobemide for two years with good clinical effect together with phototherapy. One week ago the reboxetin dose was increased from 4 mg daily to 8 mg daily. The current dose of moclobemide is 600 mg daily. The patient has no adverse reactions.

Sammanfattning: No drug interaction studies between reboxetin and monoamine oxidase inhibitors (MAOI) have been found in the literature. The manufacturer advises against the combination of reboxetin with both irreversible and reversible MAOIs. However, reboxetin is about 100-fold more potent inhibitor of noradrenaline compared with serotonin. Thus, increased serotoninergic effects are unlikely when reboxetin is combined with moclobemide. The risk for potentiated noradrenergic effects are probably small due to the selective inhibition of MAO-A by moclobemide. This patient with no adverse reactions during the combination of these drugs for two years confirms that it is possible to combine these drugs. However, if the patient is given higher doses of reboxetin and/or moclobemide, noradrenergic autonomic side-effects may become apparent and blood pressure should be measured regularly.

Svar: An extensive literature search has been performed but no data on interaction between moclobemide and reboxetine were found. The serotonin syndrome (consisting of cerebellar signs, myoclonus, hyperreflexia, confusion, hypomania, shivering, sweating, tachycardia, and mild to moderate hypertension with nausea, diarrhea and abdominal cramps), is caused by an intensified serotonin effect, presumably because of potentiated actions of drugs on serotonergic transmission (1,2). The syndrome has been reported when specific serotonin reuptake inhibitors (SSRI) have been combined with irreversible MAOI, lithium, L-tryptophan or tricyclic antidepressants. The syndrome has also been described in patients in whom L-tryptophan or clomipramin were added to an irreversible MAOI (1,2). As regards to moclobemide, the serotonin syndrome has been described when the drug is combined with SSRIs such as citalopram and tricyclic antidepressants such as clomipramine (3).

The older irreversible MAOIs have been associated with increases in blood pressure in response to consumption of tyramine rich food, in particular cheese. This effect arises because tyramine exerts an indirect sympathomimetic effect by releasing noradrenaline from the noradrenergic neurons (3). Moclobemide has been described to have a weak potentiation of the tyramine pressor response because of its selectivity for MAO-A (3).

Reboxetine is a selective noradrenaline reuptake inhibitor (4). Drug interaction studies with other antidepressants are lacking. According to the manufacturer, the recommended precautions include both reversible and irreversible MAOIs concomitantly used with reboxetin. However, these recommendations are not based on clinical studies (5). The manufacturer suggests that the combination of reboxetin and moclobemide is not strictly contraindicated.

Concerning the combination of these drugs, the risk for an amplified serotonergic effect seems to be negligible. The reason for this is that reboxetin is about 100-fold more potent inhibitor of noradrenaline compared to serotonin, determined as the IC50 in rat brains (6). Thus the reboxetin effect on serotonin is very low and has no clinical relevance. Concerning the risk for potentiated noradrenergic effects such as hyper-or hypotension, the risk is probably small since moclobemide inhibits the MAO-A in a reversible way. However, on a theoretical basis, if the dose of either reboxetin or moclobemide is increased, the inhibition of noradrenaline might be more pronounced. If this is associated with an increased risk for hypotonia is not known. If so, it is recommended that the patient´s blood pressure is measured regularly. 1 Speight TM, Holford NHG, editors. Avery´s Drug treatment. 4th ed. Auckland: Adis; 1997 2 Davies DM, Ferner RE, de Glanville H, editors. Davie´s textbook of adverse drug reactions. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1998 3 Norman RT, Burrows GD:A risk-benifit assessment of Moclobemide in the treatment of depressive disorders. Drug safety 1995; 12: 46-52 4 FASS 2000 (The Swedish catalogue of approved medical products) 5 Personal communication: Pharmacia Upjohn. Sven Langworth. Medical Advisor CNS 6 Summary product characteristics Edronax (reboxetin); Pharmacia Upjohn