Source: European Medicines Agency (EU) Revision Year: 2009 Publisher: sanofi-aventis, 174 Avenue de France, F-75013, Paris, France
Depressive disorders or mood alterations with depressive symptoms have been reported in up to 10%, and suicidal ideation in up to 1%, of patients receiving rimonabant (see section 4.8). In patients with current suicidal ideations and/or with a history of suicidal ideation and depressive disorder rimonabant should not be used unless the benefits of treatment are considered to outweigh these risks in an individual patient. (See section 4.3 and 4.8). Obesity is a condition that can be associated with depressive disorders. Depressive disorders can be associated with an increased risk of suicidal thoughts, self harm and suicide.
The prescriber should carefully investigate if the patient has had a depressive disorder in the past in order to evaluate the potential risks with rimonabant treatment.
Depressive reactions may occur in patients who have no obvious risk factors, apart from obesity itself. In postmarketing experience, more than half of the patients who develop such reactions appear to do so within 1 month of starting treatment, approximately 80% appear to do so within 3 months. Patients should be actively monitored for signs and symptoms of psychiatric disorders, particularly depression following the start of treatment. If depression is diagnosed during rimonabant therapy, rimonabant treatment must be stopped. The patient should be monitored and treated appropriately.
Patients, especially those with a history of depressive disorders/mood alterations, (and relatives or other relevant persons) should be alerted about the need to monitor for the emergence of such symptoms and to seek medical advice immediately if these occur.
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, see also section 5.3.
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.
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 (see section 4.2 and 5.2).
The efficacy and safety of rimonabant treatment in patients over 75 years of age has not sufficiently been established. Rimonabant should be used with caution in this population (see section 5.2).
The clinical effect (weight loss) of rimonabant in Black patients was lower than in Caucasians. This could be caused by a higher rimonabant clearance than in Caucasians resulting in a lower exposure (see section 5.2).
Due to the effect of rimonabant on the blood glucose level, when rimonabant is administered in diabetic patients, hypoglyceamia can occur (see section 4.8). Monitoring of blood glucose level is recommended in these patients.
Rimonabant should be used with caution in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone)(see section 4.5).
Since ACOMPLIA tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Patients should be instructed not to increase their dose of ACOMPLIA.
Patients who had a cardiovascular event (myocardial infarction, stroke, etc.) less than 6 months ago were excluded in the studies for 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 CYP3A4 inducers is expected to reduce the 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 ACOMPLIA and potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone).
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.
Concomitant administration of orlistat, ethanol or lorazepam had no significant effect on the plasma levels of rimonabant.
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 does not inhibit or induce other CYP enzymes or P-glycoprotein (P-gp) in vitro. This was confirmed clinically with specific probe studies using midazolam (CYP 3A4 substrate) and warfarin (CYP 2C9 substrate) and digoxin (a P-gp substrate).
The steady-state pharmacokinetics of an ethinyl estradiol/levonorgestrel combination oral contraceptive were not significantly altered by concomitant administration of rimonabant.
There are no adequate or well-controlled studies in pregnant women. Animal data are inconclusive but suggest possible deleterious effects on embryonal/foetal development (see section 5.3). 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 ACOMPLIA.
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. ACOMPLIA is contraindicated during breast-feeding (see section 4.3).
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.
ACOMPLIA 20 mg has been evaluated for safety in approximately 2500 patients enrolled in studies that examined the metabolic and weight loss effects in overweight and obese patients and in approximately 3800 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 table (table 1) 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.
Table 1:
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):
ACOMPLIA has not been shown to alter laboratory test values.
Not applicable.
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