ZIMULTI 20mg tablets medication leaflet

ZIMULTI 20 mg film-coated tablets

Each tablet contains 20 mg rimonabant.

The tablets contain approx. 115 mg lactose.

For a full list of excipients, see section 6.1.

Film-coated tablet

Biconvex, teardrop-shaped, white tablets debossed with “20” on one side.

As an adjunct to diet and exercise for the treatment of obese patients (BMI ≥ 30 kg/m2), or overweightpatients (BMI > 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia (seesection 5.1).

In adults, the recommended dosage is one 20 mg tablet daily to be taken in the morning beforebreakfast.

The treatment should be introduced with a mildly reduced calorie diet.

The safety and efficacy of rimonabant have not been evaluated beyond 2 years.

* Special Populations

No dosage adjustment is required in elderly (see section 5.2). ZIMULTI should be used with cautionin patients over 75 years of age (see section 4.4).

Patients with hepatic insufficiency:

No dosage adjustment is required for patients with mild or moderate hepatic impairment. ZIMULTIshould be used with caution in patients with moderate hepatic impairment. ZIMULTI should not beused in patients with severe hepatic impairment (see section 4.4 and 5.2).

No dosage adjustment is required for patients with mild and moderate renal impairment (see section5.2). ZIMULTI should not be used in patients with severe renal impairment (see section 4.4 and 5.2).

Paediatrics:

ZIMULTI is not recommended for use in children below age 18 due to a lack of data on efficacy andsafety.

Hypersensitivity to the active substance or to any of the excipients

Ongoing major depressive illness and/or ongoing antidepressive treatment (see section 4.4)

* Depressive disorders

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 withcurrent suicidal ideations and/or with a history of suicidal ideation and depressive disorder rimonabantshould not be used unless the benefits of treatment are considered to outweigh these risks in anindividual patient. (See section 4.3 and 4.8).Obesity is a condition that can be associated withdepressive disorders. Depressive disorders can be associated with an increased risk of suicidalthoughts, self harm and suicide.

The prescriber should carefully investigate if the patient has had a depressive disorder in the past inorder 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 doso 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, particularlydepression 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 orother relevant persons) should be alerted about the need to monitor for the emergence of suchsymptoms and to seek medical advice immediately if these occur.

* Other psychiatric conditions

Therapy with rimonabant is not recommended in patients with uncontrolled psychiatric illness.

If psychiatric illness is diagnosed during rimonabant therapy, treatment must be stopped.

* Seizures

Rimonabant has not been studied in patients being treated for epilepsy. In clinical trials no differencein 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.

* Hepatic impairment

Rimonabant is metabolised by the liver, thus caution is advised in patients with moderate hepaticimpairment. The pharmacokinetics and safety of rimonabant have not been studied in patients withsevere hepatic impairment; its use in these patients is not recommended.

* Renal impairment

There are limited data in patients with moderate renal impairment and no data in patients with severerenal impairment. Rimonabant should not be used in patients with severe renal impairment (see section4.2 and 5.2).

* Elderly

The efficacy and safety of rimonabant treatment in patients over 75 years of age has not sufficientlybeen established. Rimonabant should be used with caution in this population (see section 5.2).

* Race

The clinical effect (weight loss) of rimonabant in Black patients was lower than in Caucasians. Thiscould be caused by a higher rimonabant clearance than in Caucasians resulting in a lower exposure(see section 5.2).

* Diabetic patients

Due to the effect of rimonabant on the blood glucose level, when rimonabant is administered indiabetic patients, hypoglyceamia can occur (see section 4.8). Monitoring of blood glucose level isrecommended in these patients.

* Drug Interaction

Rimonabant should be used with caution in combination with potent CYP3A4 inhibitors (e.g.ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone)(see section 4.5).

* Lactose

Since ZIMULTI tablets contain lactose, patients with rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take thismedicine.

Patients should be instructed not to increase their dose of ZIMULTI.

Patients who had a cardiovascular event (myocardial infarction, stroke, etc.) less than 6 months agowere excluded in the studies for rimonabant.

Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways invitro. Concomitant administration of CYP3A4 inhibitors will lead to increased exposure ofrimonabant. Concomitant administration of CYP3A4 inducers is expected to reduce the exposure ofrimonabant.

Potential for other medicinal products to affect rimonabant:

Concomitant administration of ketoconazole (a potent CYP3A4 inhibitor) increased rimonabant AUCby 104% (95% prediction interval: 40% - 197%). A similar increase in exposure is expected with otherpotent CYP3A4 inhibitors. Caution is advised during concomitant use of ZIMULTI 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 ofpotent CYP3A4 inducers may reduce the plasma concentration of rimonabant and may result in loss ofefficacy.

Concomitant administration of orlistat, ethanol or lorazepam had no significant effect on the plasmalevels of rimonabant.

Potential for rimonabant to affect other medicinal products:

The in vivo inhibitory effect on CYP2C8 has not been studied. However, in vitro, rimonabant had amild 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 wasconfirmed 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 oralcontraceptive were not significantly altered by concomitant administration of rimonabant.

There are no adequate or well-controlled studies in pregnant women. Animal data are inconclusive butsuggest possible deleterious effects on embryonal/foetal development (see section 5.3). The potentialrisk for humans is unknown. Use in pregnancy is, therefore, not recommended. Patients should notifytheir physician if they become pregnant during treatment with ZIMULTI.

Rimonabant has been detected in the milk of lactating rats and rimonabant may inhibit the sucklingreflex. It is not known if rimonabant is excreted in human milk. ZIMULTI is contraindicated duringbreast-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 ofany significant cognitive or sedative effect.

ZIMULTI 20 mg has been evaluated for safety in approximately 2500 patients enrolled in studies thatexamined the metabolic and weight loss effects in overweight and obese patients and in approximately3800 patients in other indications. In placebo-controlled studies, the discontinuation rate due toadverse reactions was 15.7% for patients receiving rimonabant. The most common adverse reactionsresulting in discontinuation were: nausea, mood alteration with depressive symptoms, depressivedisorders, anxiety and dizziness.

Depressive disorders were reported in 3.2% of obese patients, or overweight patients with associatedrisk factor(s) treated with rimonabant 20 mg. These were usually mild or moderate in severity andresulted in recovery in all cases either after corrective treatment or discontinuation of rimonabant anddid 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-controlledstudies in patients treated for weight loss and related metabolic disorders when these incidences werestatistically significantly greater than the corresponding placebo rate (for events ≥1%) or consideredclinically 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%); Veryrare (<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:

System Organ Very common Common Uncommon Rare

Class

Infections and Upper respiratory Gastroenteritisinfestations tract infection

Metabolism and Hypoglycaemia*nutrition disorders

Psychiatric Depressive Panic symptoms Hallucinationsdisorders disorders Anger

Mood alterations Dysphoriawith depressive Emotionalsymptoms disorder

Anxiety Suicidal ideation

Irritability Aggressiveness

Nervousness Aggressive

Sleep disorders behaviour

Insomnia

Parasomnias

Nervous system Memory loss Lethargydisorders Dizziness Tremor

Hypoaesthesia

Sciatica

Paresthesia

Vascular disorders Hot flush

Respiratory, Hiccupsthoracic andmediastinaldisorders

Gastrointestinal Nausea Diarrhoeadisorders Vomiting

Skin and Pruritus Night sweatssubcutaneous tissue Hyperhidrosisdisorders

Musculoskeletal Tendonitisand Muscle crampconnective Muscle spasmstissue disorders

General disorders Asthenia/fatigue

Influenza

Injury, Poisoning Falland procedural Contusioncomplications 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 commonlyreported:− infections and infestations: sinusitis− metabolism and nutrition disorders: anorexia, decreased appetite,− gastrointestinal disorders:stomach discomfort, dry mouth.

Post-Marketing

In addition the following adverse reactions were reported during postmarketing (frequency notknown):− Psychiatric disorder: psychotic disorders including hallucinations, delusion and paranoia.− Skin and subcutaneous tissue disorders: rash.− Nervous disorders: convulsions, disturbance in attention, headache.− gastrointestinal disorders: abdominal pain.

Laboratory adverse events

ZIMULTI has not been shown to alter laboratory test values.

Experience with rimonabant in overdosage is limited. In a single-dose tolerability study, doses up to300 mg were administered to a limited number of subjects with only minor symptoms reported. Theseincluded headache, euphoria, fatigue and insomnia. The pharmacokinetic profile demonstrates that aplateau in exposures is reached at 180 mg. There is no specific antidote for rimonabant; therefore,appropriate supportive measures should be initiated in case of overdose. Treatment should consist ofthe general measures employed in the management of overdoses, such as keeping airwaysunobstructed, monitoring cardiovascular function and general symptomatic and supportive measures.

Pharmaco-therapeutic group: Anti obesity agent

ATC code: A08AX01

Rimonabant is a selective cannabinoid-1 receptor (CB1) antagonist that inhibits the pharmacologicaleffects of cannabinoid agonists in vitro and in vivo.

The endocannabinoid system is a physiological system present in brain and peripheral tissues(including adipocytes) that affects energy balance, glucose and lipid metabolism and body weight, andin neurons of the mesolimbic system modulates the intake of highly palatable, sweet or fatty foods.

Clinical study results

Weight Management

In total more than 6800 patients were included in the Phase 2 and Phase 3 clinical studies. The patientsincluded in the phase 3 trials followed a restrictive diet during the trial prescribed by a dietician andthey were advised to increase their physical activity. Patients had a BMI ≥30 kg/m² or BMI>27 kg/m²with hypertension and/or dyslipidemia at inclusion. Approximately 80% of the population werewomen, 87% Caucasian and 9% Black. Experience in patients over 75 years and Orientals/Asians waslimited.

Significant mean weight reductions from baseline to one year for ZIMULTI 20 mg versus placebowere demonstrated in three studies conducted in non-diabetic patients. A mean weight loss of 6.5 kgfrom baseline to one year was shown for ZIMULTI 20 mg versus a mean weight loss of 1.6 kg forplacebo (Difference -4.9 kg CI95% -5.3;-4.4, p< 0.001).

The percentage of patients who lost 5% and 10% of their baseline body weight after 1 year oftreatment are given in table 2:

Table 2:

Non-diabetic studies Diabetic study

Placebo ZIMULTI Placebo ZIMULTI20 mg 20 mgnITT 1254 2164 348 339

Weight at baseline 101 101 96 95(kg)

Subjects with a 5% 19.7% 50.8% 14.5% 49.4%weight reduction

Difference (CI 95%) 31.1% (28%; 34%) 34.9% (28%; 41%)

Subjects with a 10% 7.8% 27.0% 2.0% 16.2%weight reduction

Difference (CI 95%) 19.2% (17%; 22%) 14.2% (10%; 19%)

Most of the observed weight reduction was obtained within the first nine months of treatment.

ZIMULTI 20 mg was effective in maintaining weight loss up to two years. Weight loss at two yearswas 5.1 kg for patients who received ZIMULTI 20 mg and 1.2 kg for placebo (Difference -3.8 kg;

CI95% -4.4, -3.3; p<0.001).

Rimonabant 20 mg reduced the risk of weight regain. Patients who received ZIMULTI 20 mg for oneyear were re-randomized to ZIMULTI 20 mg or placebo. At two years, patients continuing onrimonabant had a mean total weight loss of 7.5 kg over 2 years whereas patients re-randomized toplacebo group during the second year had a mean total weight loss of 3.1 kg over 2 years. At twoyears, the difference in total weight loss between ZIMULTI and placebo was -4.2 kg (CI95% -5.0;-3.4,p<0.001).

Treatment with rimonabant was associated with significant reductions in waist circumference, aknown marker of intra-abdominal fat.

The effects on body weight appeared to be consistent among men and women. In the limited numberof Black patients weight loss was less pronounced (mean difference to placebo -2.9 kg). Noconclusions can be drawn with regard to effects in patients over 75 years or in Asian/Oriental patientsdue to the low number of patients.

Weight management and additional risk factors

In the non-diabetic studies including a mixed population of subjects with/without (treated)dyslipidemia, an increase in HDL-C and decrease in triglycerides (at one year) was observed. For

HDL-C an average increase of 16.4% was seen under rimonabant 20 mg (baseline HDL-C 1.24mmol/l) compared to an increase of 8.9% for placebo (baseline HDL-C 1.21 mmol/l). The differencewas statistically significant (Difference 7.9% CI95% 6.6%; 9.2%, p<0.001). For the triglycerides anaverage decrease of 6.9% was seen under rimonabant 20 mg (baseline TG 1.62 mmol/l) compared toan increase of 5.8% for placebo (baseline TG 1.65 mmol/l). The difference was statistically significant(Difference -13.3% CI95% -16.5; -10.2% p<0.001). It is estimated that approximately half of theobserved improvement in HDL-C and triglycerides in patients who received rimonabant 20 mg wasbeyond that expected from weight loss alone.

Generally ZIMULTI 20 mg had no significant effect on Total-C or LDL-C levels.

In the trial in type 2 diabetic patients (RIO-Diabetes) who were overweight or obese treated withmetformin or sulfonylurea improvements in HbA1c and body weight were observed. The absolutechange in HbA1c at one year was -0.6 for rimonabant 20 mg (baseline 7.3%) and +0.1 on placebo(baseline 7.2%). Differences were statistically significant (Difference -0.7%, CI95% -0.80;-0.5,p<0.001).

At one year a mean weight loss of 5.3 kg was shown for ZIMULTI 20 mg versus a loss on placebo of1.4 kg (Difference -3.9 kg CI95% -4.6;-3.3 p<0.001). The percentage of patients who lost 5% and 10%of their baseline body weight after 1 year of treatment are given in the table 2.

In a second trial in treatment naïve type 2 diabetic obese patients (Serenade), the absolute change in

HbA1c (with a baseline of 7.9% for both groups) at six months was -0.8 for rimonabant 20 mg and

- 0.3 under placebo (Difference -0.51 CI95% -0.78, -0.24 p<0.001). The percentage of patients reaching

HbA1c <7% was 51% in the rimonabant group and 35% in the placebo group. The difference in meanbody weight change between the 20 mg and placebo groups was 3.8 kg (CI95% -5.0, -2.6 p<0.001).

Changes in HDL-C and TG in this population were similar to that of the non-diabetic population. It isestimated that approximately half of the mean improvement in HbA1c in patients receivingrimonabant 20 mg was beyond that expected from weight loss alone.

Rimonabant pharmacokinetics are fairly dose proportional up to about 20 mg. AUC increased less thanin proportion to dose above 20 mg.

Rimonabant displays high in vitro permeability and is not a substrate of P-glycoprotein. The absolutebioavailability of rimonabant has not been determined. Following multiple once-daily doses of 20 mgto healthy subjects in the fasted state, maximum plasma concentrations of rimonabant are achieved inapproximately 2 hours with steady state plasma levels achieved within 13 days (Cmax = 196 ± 28.1ng/ml; Ctrough = 91.6 ± 14.1 ng/ml; AUC0-24 = 2960 ± 268 ng.h/ml). Steady state rimonabant exposuresare 3.3-fold higher than those observed after the first dose. Population pharmacokinetic analysisdemonstrated less fluctuation in peak to trough plasma concentration but no differences in steady state

AUC as weight increases. As weight increases from 65 to 200 kg, Cmax is expected to decrease 24%and Ctrough is expected to increase by 5%. Time to steady state is longer in obese patients (25 days) as aconsequence of the higher volume of distribution in these patients. Population pharmacokineticanalysis indicated that rimonabant pharmacokinetics are similar between healthy non-smokingsubjects and patients who smoke.

Administration of rimonabant to healthy subjects in the fasted state or with a high fat mealdemonstrated that Cmax and AUC were increased 67% and 48% respectively, under fed conditions. Inclinical studies, ZIMULTI 20 mg was taken in the morning usually before breakfast.

The in vitro human plasma protein binding of rimonabant is high (>99.9%) and non-saturable over awide concentration range. The apparent peripheral volume of distribution of rimonabant appears to berelated to body weight, with obese patients having a higher volume of distribution than normal-weightsubjects.

Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways invitro. Circulating metabolites do not contribute to its pharmacologic activity.

Rimonabant is mainly eliminated by metabolism and subsequent biliary excretion of metabolites. Onlyan approximate 3% of the dose of rimonabant is eliminated in the urine, while approximately 86% ofthe dose is excreted in the faeces as unchanged drug and metabolites. In obese patients, the eliminationhalf-life is longer (about 16 days) than in non-obese patients (about 9 days) due to a larger volume ofdistribution.

In single- and repeat-dose studies, the Cmax and AUC of rimonabant were similar in healthy Japaneseand Caucasian subjects, whereas elimination half-life was shorter in Japanese subjects (3-4 days)compared to Caucasian subjects (about 9 days). The difference in half-life was due to differences inperipheral volume of distribution as a consequence of lower weight in Japanese subjects.

Black patients may have up to a 31% lower Cmax and a 43% lower AUC than patients of other races.

The pharmacokinetics of rimonabant are similar in female and male patients.

Elderly patients have slightly higher exposure than young patients. Based on a populationpharmacokinetic analysis (age range 18 - 81 years) a 75 year old patient is estimated to have a 21%higher Cmax and a 27% higher AUC than a 40 year old patient.

Patients with hepatic insufficiency:

Mild hepatic impairment does not alter rimonabant exposure. Data are insufficient to draw conclusionsregarding pharmacokinetics in moderate hepatic impairment. Patients with severe hepatic impairmentwere not evaluated.

The effect of renal function on the pharmacokinetics of rimonabant has not been studied specifically.

Based on data from population pharmacokinetic studies, mild renal impairment do not seem to affectthe pharmacokinetics of rimonabant. Limited data suggest an increased exposure in patients withmoderate renal impairment (40% increase in AUC). There are no data in severe renal impairment.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:

Convulsions were observed sporadically in studies in rodents and macaques. No convulsions wereobserved in dogs during a 3 month study. In some, but not all cases, initiation of convulsions appearedto be associated with procedural stress such as handling of the animals. A proconvulsant activity ofrimonabant was found in one of two safety pharmacology studies. No adverse effect of rimonabanttreatment was observed on EEG patterns in rats.

Increased incidence and/or severity of clinical signs suggestive of increased tactile hyperesthesia wereobserved in rodent studies. A direct effect of rimonabant cannot be ruled out.

Liver steatosis and a dose-related increase in centrilobular necrosis were observed in long-term studiesin the rat. A direct effect of rimonabant cannot be ruled out.

In standard fertility studies in female rats (dosing for 2 weeks prior to mating) there was abnormaloestrous cyclicity and a decrease in corpora lutea and fertility index at doses of rimonabant thatinduced maternal toxicity (30 and 60 mg/kg/day). Following dosing for a longer treatment durationprior to mating (9 weeks) that permitted recovery from the initial effects of rimonabant, no adverseeffects were seen on fertility or oestrous cyclicity. Regarding reproductive parameters, at 30 mg/kg nodifferences were observed between treated animals and controls , at 60 mg/kg effects were stillobserved (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 comparablewith the clinical exposures. Although maternal toxicity was observed at these doses, a relation totreatment 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 to10 mg/kg/day. There was a treatment related increase in pup mortality in the pre-weaning period. Theincreased pup mortality might be attributable to a failure of the dam to nurse or ingestion ofrimonabant in milk and/or inhibition of the suckling reflex that is reported in the literature to beinitiated in neonatal mice by endocannabinoid signalling via CB1 receptors. There are reports in theliterature that, in both rodents and humans, the spatial distribution and density of CB1 receptors in thebrain changes during development. The potential relevance of this to administration of a CB1antagonist is unknown. In the pre- and post-natal development study in rats, exposure to rimonabantin utero and via lactation produced no alterations on learning or memory, but equivocal effects onmotor activity and auditory startle response were observed in the pups as a result of rimonabantexposure.

Tablet core:maize starch,lactose monohydrate,povidone K 30 (E1201),croscarmellose sodium (E468),sodium laurilsulfate (E487),microcrystalline cellulose (E460),magnesium stearate

Tablet coating:lactose monohydrate,hypromellose 15 mPa.s (E464),titanium dioxide (E171),macrogol 3000

Tablet polishing:carnauba wax (E903)

Not applicable

3 years

This medicinal product does not require any special storage conditions.

PVC-aluminium blister packs containing 14, 28, 30, 56, 84, 90 and 98 film-coated tablets.70 x 1 film-coated tablets in PVC-aluminium perforated unit dose blister packs.

Opaque white HDPE bottles containing 28, 98 and 500 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements

sanofi-aventis.174 Avenue de France

F-75013 Paris

France

EU/1/06/345/001-011

19 June 2006

Detailed information on this product is available on the website of the European Medicines Agency(EMEA) http://www.emea.europa.eu.