In vitro findings as well as clinical evidence point towards insignificant capacity for CYP-induction or CYP-inhibition. The secondary effects on intermediary metabolism of effective caloric restriction are expected to be porphyrogenic, which is probably the reason for the porphyrogenicity reported in one publication. In carriers of acute porphyria the weight reduction treatment should be carried out at a gentle pace, i.e. under monitoring of urinary color/PBG-excretion, and after informing the patient regarding the risk for porphyric manifestations.

(±)-1-(p-Chlorophenyl)-α-isobutyl-N,N-dimethylcyclobutanemethylamine hydrochloride monohydrate, structurally related to amfetamine. M =334.3

Sibutramine is a serotonin and noradrenaline reuptake inhibitor; it also inhibits dopamine reuptake but to a lesser extent. It is an anorectic agent, acting via the two metabolites 1 and 2, which are inhibitors of reuptake of noradrenalin, serotonin and dopamine in human brain. Sibutramine is used in the management of obesity. Weight reduction is aschieved by a reduction in the feeling of satisfaction (full)after meal. It may also be used in overweight patients (body-mass index of 27 kg/m2 or more) if other risk factors such as hypertension, diabetes mellitus, or hyperlipidaemias are present. Commonly reported adverse effects of sibutramine are among others insomnia and constipation. Less frequently reported adverse effects include nausea, dysmenorrhoea, paraesthesia, skin rashes, tachycardia, hypertension, anxiety, nervousness, drowsiness and depression. ATTENTION! European Medicines Agency (EMA) recommends a temporary withdrawal of Sibutramine because according to some studies the risk of heart disease is considered to be greater than the benefits of this drug.

Possibly significant exposure to sibutramine and its metabolites.

Extensive first-pass hepatic CYP 3A4 metabolism giving rise to the pharmacologically active mono- and didemethyl derivatives (metabolites 1 and 2), which are further metabolized by CYP 2C9 and CYP 3A4. In repeated administration the plasma steady-state concentration is reached within four days, with about 2-fold accumulation of the active metabolites. In vitro studies show that there is no significant effect on the activitiy of major CYPs, including CYP 3A4. No reports of interactions with the CYP-metabolism of other drugs in clinical use.

There is one report of an attack of acute porphyria after use of sibutramine for weight reduction (Reiser M, Eickmann S, Haverkamp T, Finckh U. Variegate porphyria in a 46-year-old patient prescribed sibutramine. Obes Rev. 2009). Symptoms were not observed until one week after start of medication and the patient lost 6 kg in 10 days. Comment: The symptoms were probably triggered by the severe, and relatively acute caloric deprivation and not dependent on pharmacokinetic properties of the substance sibutramine. Used with uttermost caution and under the close supervision of the patient sibutramine may be a beneficial drug for the treatment of obesity in carriers of acute porphyria.

Uneventful use reported in 2 patients with acute porphyria.