Chemical formula: C₂₂H₂₁Cl₃N₄O Molecular mass: 463.787 g/mol PubChem compound: 104850
Rimonabant interacts in the following cases:
The in vivo inhibitory effect on CYP2C8 has not been studied. However, in vitro, rimonabant had a mild inhibitory effect on CYP2C8. The potential for inhibition of CYP2C8 in vivo appears to be low.
Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways in vitro. Concomitant administration of CYP3A4 inducers is expected to reduce the exposure of rimonabant.
Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways in vitro. Concomitant administration of CYP3A4 inhibitors will lead to increased exposure of rimonabant.
Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways in vitro. Concomitant administration of CYP3A4 inhibitors will lead to increased exposure of rimonabant.
Concomitant administration of ketoconazole (a potent CYP3A4 inhibitor) increased rimonabant AUC by 104% (95% prediction interval: 40%-197%). A similar increase in exposure is expected with other potent CYP3A4 inhibitors. Caution is advised during concomitant use of rimonabant and potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone).
Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways in vitro. Concomitant administration of CYP3A4 inducers is expected to reduce the exposure of rimonabant.
Although concomitant administration of CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) has not been studied, it is expected that concomitant administration of potent CYP3A4 inducers may reduce the plasma concentration of rimonabant and may result in loss of efficacy.
There are limited data in patients with moderate renal impairment and no data in patients with severe renal impairment. Rimonabant should not be used in patients with severe renal impairment.
Rimonabant is metabolised by the liver, thus caution is advised in patients with moderate hepatic impairment.
The pharmacokinetics and safety of rimonabant have not been studied in patients with severe hepatic impairment; its use in these patients is not recommended.
In standard fertility studies in female rats (dosing for 2 weeks prior to mating) there was abnormal oestrous cyclicity and a decrease in corpora lutea and fertility index at doses of rimonabant that induced maternal toxicity (30 and 60 mg/kg/day). Following dosing for a longer treatment duration prior to mating (9 weeks) that permitted recovery from the initial effects of rimonabant, no adverse effects were seen on fertility or oestrous cyclicity. Regarding reproductive parameters, at 30 mg/kg no differences were observed between treated animals and controls, at 60 mg/kg effects were still observed (decreased number of corpora lutea, implantations, total and viable fetuses).
Sporadic malformations (anencephaly, micro-ophthalmia, widened brain ventricles and omphalocele) were observed in the rabbit embryofetal toxicity studies at doses resulting in exposures comparable with the clinical exposures. Although maternal toxicity was observed at these doses, a relation to treatment cannot be excluded. No treatment-related malformations were seen in the rat.
Effects of rimonabant on pre- and post-natal development were assessed in the rat at doses up to 10 mg/kg/day. There was a treatment related increase in pup mortality in the pre-weaning period. The increased pup mortality might be attributable to a failure of the dam to nurse or ingestion of rimonabant in milk and/or inhibition of the suckling reflex that is reported in the literature to be initiated in neonatal mice by endocannabinoid signalling via CB1 receptors. There are reports in the literature that, in both rodents and humans, the spatial distribution and density of CB1 receptors in the brain changes during development. The potential relevance of this to administration of a CB1 antagonist is unknown. In the pre- and post-natal development study in rats, exposure to rimonabant in utero and via lactation produced no alterations on learning or memory, but equivocal effects on motor activity and auditory startle response were observed in the pups as a result of rimonabant exposure.
Concomitant administration of orlistat, ethanol or lorazepam had no significant effect on the plasma levels of rimonabant.
Therapy with rimonabant is not recommended in patients with uncontrolled psychiatric illness. If psychiatric illness is diagnosed during rimonabant therapy, treatment must be stopped.
Rimonabant has not been studied in patients being treated for epilepsy. In clinical trials no difference in the incidence of seizures was seen in patients receiving rimonabant or placebo. Rimonabant, however, should be used with caution in these patients.
There are no adequate or well-controlled studies in pregnant women. Animal data are inconclusive but suggest possible deleterious effects on embryonal/foetal development. The potential risk for humans is unknown. Use in pregnancy is, therefore, not recommended. Patients should notify their physician if they become pregnant during treatment with rimonabant.
Rimonabant has been detected in the milk of lactating rats and rimonabant may inhibit the suckling reflex. It is not known if rimonabant is excreted in human milk. Rimonabant is contraindicated during breast-feeding.
No studies on the effects on the ability to drive and use machines have been performed. Cognitive investigations in clinical pharmacology studies demonstrated that rimonabant is devoid of any significant cognitive or sedative effect.
Rimonabant has been evaluated for safety in approximately 2,500 patients enrolled in studies that examined the metabolic and weight loss effects in overweight and obese patients and in approximately 3,800 patients in other indications. In placebo-controlled studies, the discontinuation rate due to adverse reactions was 15.7% for patients receiving rimonabant. The most common adverse reactions resulting in discontinuation were: nausea, mood alteration with depressive symptoms, depressive disorders, anxiety and dizziness.
Depressive disorders were reported in 3.2% of obese patients, or overweight patients with associated risk factor(s) treated with rimonabant 20 mg. These were usually mild or moderate in severity and resulted in recovery in all cases either after corrective treatment or discontinuation of rimonabant and did not exhibit any differentiating characteristics compared to cases reported in the control groups.
The following list shows all treatment-emergent adverse reactions from placebo-controlled studies in patients treated for weight loss and related metabolic disorders when these incidences were statistically significantly greater than the corresponding placebo rate (for events ≥1%) or considered clinically relevant (for events <1%).
Classification of expected frequencies of undesirable effects: Very common (≥10%); Common (≥1, <10%); Uncommon (≥0.1, <1%); Rare (≥0.01, <0.1%); Very rare (<0.01%), Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common: Upper respiratory tract infection
Common: Gastroenteritis
Uncommon: Hypoglycaemia*
Common: Depressive disorders, Mood alterations with depressive symptoms, Anxiety, Irritability, Nervousness, Sleep disorders, Insomnia, Parasomnias
Uncommon: Panic symptoms, Anger, Dysphoria, Emotional disorder, Suicidal ideation, Aggressiveness, Aggressive behaviour
Rare: Hallucinations
Common: Memory loss, Dizziness, Hypoaesthesia, Sciatica, Paresthesia
Uncommon: Lethargy, Tremor
Common: Hot flush
Uncommon: Hiccups
Very common: Nausea
Common: Diarrhoea, Vomiting
Common: Pruritus, Hyperhidrosis
Uncommon: Night sweats
Common: Tendonitis, Muscle cramp, Muscle spasms
Common: Asthenia/fatigue, Influenza
Common: Fall, Contusion, Joint sprain
* frequency is based only on reports in obese or overweight diabetic patients.
In clinical studies for other indications, the following additional adverse reactions were commonly reported:
In addition the following adverse reactions were reported during postmarketing (frequency not known):
Rimonabant has not been shown to alter laboratory test values.
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