SYCREST 5mg sublingual tablets medication leaflet

Sycrest 5 mg sublingual tablets

Each sublingual tablet contains 5 mg asenapine (as maleate).

For the full list of excipients, see section 6.1.

Sublingual tablet

Round, white to off-white, sublingual tablets debossed with “5” on one side.

Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar Idisorder in adults.

The recommended starting dose of Sycrest as monotherapy is 5 mg twice daily. One dose should betaken in the morning and one dose should be taken in the evening. The dose can be increased to 10 mgtwice daily based on individual clinical response and tolerability. See section 5.1. For combinationtherapy a starting dose of 5 mg twice daily is recommended. Depending on the clinical response andtolerability in the individual patient, the dose can be increased to 10 mg twice daily.

Sycrest should be used with care in the elderly. Limited data on efficacy in patients 65 years of ageand older are available. Available pharmacokinetic data are described in section 5.2.

No dose adjustment is required for patients with renal impairment. There is no experience withasenapine in patients with severe renal impairment who have a creatinine clearance less than15 mL/min.

No dose adjustment is required for patients with mild hepatic impairment. The possibility of elevatedasenapine plasma levels cannot be excluded in some patients with moderate hepatic impairment(Child-Pugh B) and caution is advised. In subjects with severe hepatic impairment (Child-Pugh C), a7-fold increase in asenapine exposure was observed. Thus, Sycrest is not recommended in patientswith severe hepatic impairment.

A pharmacokinetic study and a short term efficacy and safety study were performed in a paediatricpopulation (ages 10-17 years) with manic or mixed episodes associated with bipolar I disorder. Longterm safety in this population was explored in a 50-week, open-label, uncontrolled extension study.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on aposology can be made.

The tablet should not be removed from the blister until ready to take it. Dry hands should be usedwhen touching the tablet. The tablet should not be pushed through the tablet pack. The tablet packshould not be cut or torn. The coloured tab should be peeled back and the tablet should be removedgently. The tablet should not be crushed.

To ensure optimal absorption, the Sycrest sublingual tablet should be placed under the tongue andallowed to dissolve completely. The tablet will dissolve in saliva within seconds. Sycrest sublingualtablets should not be chewed or swallowed. Eating and drinking should be avoided for 10 minutesafter administration.

When used in combination with other medicinal products, Sycrest should be taken last.

Treatment with Sycrest is not advised in patients who are unable to comply with this method ofadministration, as the bioavailability of asenapine when swallowed is low (< 2 % with an oral tabletformulation).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic substances are at anincreased risk of death.

Sycrest is not approved for the treatment of patients with dementia-related psychosis and is notrecommended for use in this particular group of patients.

Neuroleptic malignant syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomicinstability, altered consciousness and elevated serum creatine phosphokinase levels, has been reportedto occur with antipsychotics, including asenapine. Additional clinical signs may includemyoglobinuria (rhabdomyolysis) and acute renal failure.

If a patient develops signs and symptoms indicative of NMS Sycrest must be discontinued.

In clinical trials, cases of seizure were occasionally reported during treatment with asenapine.

Therefore, Sycrest should be used with caution in patients who have a history of seizure disorder orhave conditions associated with seizures.

Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder and closesupervision of high-risk patients should accompany treatment.

Asenapine may induce orthostatic hypotension and syncope, especially early in treatment, probablyreflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk forexperiencing orthostatic hypotension (see section 4.8). In clinical trials, cases of syncope wereoccasionally reported during treatment with Sycrest. Sycrest should be used with caution in elderlypatients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction orischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patientto hypotension (e.g., dehydration and hypovolemia).

Medicinal products with dopamine receptor antagonistic properties have been associated with theinduction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly ofthe tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported duringtreatment with asenapine. The onset of extrapyramidal symptoms is a risk factor for tardivedyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Sycrest, discontinuationof treatment should be considered.

Increases in prolactin levels were observed in some patients with Sycrest. In clinical trials, there werefew adverse reactions related to abnormal prolactin levels reported.

Clinically relevant QT prolongation does not appear to be associated with asenapine. Caution shouldbe exercised when Sycrest is prescribed in patients with known cardiovascular disease or familyhistory of QT prolongation, and in concomitant use with other medicinal products thought to prolongthe QT interval.

Hyperglycaemia or exacerbation of pre-existing diabetes has occasionally been reported duringtreatment with asenapine. Assessment of the relationship between atypical antipsychotic use andglucose abnormalities is complicated by the possibility of an increased background risk of diabetesmellitus in patients with schizophrenia or bipolar disorder and the increasing incidence of diabetesmellitus in the general population. Appropriate clinical monitoring is advisable in diabetic patients andin patients with risk factors for the development of diabetes mellitus.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic treatment. Cases ofdysphagia were occasionally reported in patients treated with Sycrest.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychoticmedicinal products. From the clinical trials, it is concluded that clinically relevant body temperaturedysregulation does not appear to be associated with asenapine. Appropriate care is advised whenprescribing Sycrest for patients who will be experiencing conditions that may contribute to anelevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receivingconcomitant medicinal products with anticholinergic activity or being subject to dehydration.

Patients with severe hepatic impairment

Asenapine exposure is increased 7-fold in patients with severe hepatic impairment (Child-Pugh C).

Therefore, Sycrest is not recommended in such patients.

Physicians should weigh the risks versus the benefits when prescribing Sycrest to patients with

Parkinson’s disease or dementia with Lewy Bodies (DLB) since both groups may be at increased riskof neuroleptic malignant syndrome as well as having an increased sensitivity to antipsychotics.

Manifestation of this increased sensitivity can include confusion, obtundation, postural instability withfrequent falls, in addition to extrapyramidal symptoms.

Falls

Asenapine may cause adverse effects such as somnolence, orthostatic hypotension, dizziness andextrapyramidal symptoms, which may lead to falls and, consequently, fractures or other injuries.

Patients at risk for fall should be evaluated prior to prescribing asenapine.

Given the primary effects of asenapine on the central nervous system (CNS) (see section 4.8), cautionshould be used when it is taken in combination with other centrally acting medicinal products. Patientsshould be advised to avoid alcohol while taking Sycrest.

Potential for other medicinal products to affect Sycrest

Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolismby cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and aninducer of several of these enzyme pathways on asenapine pharmacokinetics were studied, specificallyfluvoxamine (CYP1A2 inhibitor), paroxetine (CYP2D6 inhibitor), imipramine (CYP1A2/2C19/3A4inhibitor), cimetidine (CYP3A4/2D6/1A2 inhibitor), carbamazepine (CYP3A4/1A2 inducer) andvalproate (UGT inhibitor). Except for fluvoxamine, none of the interacting medicinal products resultedin clinically relevant alterations in asenapine pharmacokinetics.

During combined administration with a single dose of asenapine 5 mg, fluvoxamine 25 mg twice dailyresulted in a 29 % increase in asenapine AUC. The full therapeutic dose of fluvoxamine would beexpected to produce a greater increase in asenapine plasma concentrations. Therefore,co-administration of asenapine and fluvoxamine should be approached with caution.

Potential for Sycrest to affect other medicinal products

Because of its α1-adrenergic antagonism with potential for inducing orthostatic hypotension (seesection 4.4), Sycrest may enhance the effects of certain antihypertensive agents.

Asenapine may antagonise the effect of levodopa and dopamine agonists. If this combination isdeemed necessary, the lowest effective dose of each treatment should be prescribed.

In vitro studies indicate that asenapine weakly inhibits CYP2D6. Clinical drug interaction studiesinvestigating the effects of CYP2D6 inhibition by asenapine showed the following results:

− Following co-administration of dextromethorphan and asenapine in healthy subjects, the ratio ofdextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured.

Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in afractional decrease in DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mgdaily decreased the DX/DM ratio to 0.032.

− In a separate study, co-administration of a single 75 mg dose of imipramine with a single 5 mgdose of asenapine did not affect the plasma concentrations of the metabolite desipramine (a

CYP2D6 substrate).

− Co-administration of a single 20 mg dose of paroxetine (a CYP2D6 substrate and inhibitor)during treatment with 5 mg asenapine twice daily in 15 healthy male subjects resulted in analmost 2-fold increase in paroxetine exposure.

In vivo asenapine appears to be at most a weak inhibitor of CYP2D6. However, asenapine mayenhance the inhibitory effects of paroxetine on its own metabolism.

Therefore, Sycrest should be co-administered cautiously with medicinal products that are bothsubstrates and inhibitors for CYP2D6.

There are no adequate data from the use of Sycrest in pregnant women. Asenapine was not teratogenicin animal studies. Maternal and embryo toxic effects were found in animal studies (see section 5.3).

Newborn infants exposed to antipsychotics (including Sycrest) during the third trimester of pregnancyare at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary inseverity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia,tremor, somnolence, respiratory distress, or feeding disorder in newborn infants. Consequently,newborn infants should be monitored carefully.

Sycrest should not be used during pregnancy unless the clinical condition of the woman requirestreatment with asenapine and only if the potential benefit outweighs the potential risk to the foetus.

Asenapine was excreted in milk of rats during lactation. It is not known whether asenapine or itsmetabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with

Sycrest.

No impairment of fertility has been observed in nonclinical studies (see section 5.3).

Asenapine may cause somnolence and sedation. Therefore, patients should be cautioned about drivingand using machines until they are reasonably certain that Sycrest therapy does not affect themadversely.

The most frequently reported adverse drug reactions (ADRs) associated with the use of asenapine inclinical trials were somnolence and anxiety. Serious hypersensitivity reactions have been reported.

Other serious ADRs are discussed in more detail in section 4.4.

The incidences of the ADRs associated with asenapine therapy are tabulated below. The table is basedon adverse reactions reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common ( 1/100 to< 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000) and not known (cannot beestimated from the available data). Within each frequency grouping, ADRs are presented in order ofdecreasing seriousness.

System organ Very Common Uncommon Rare Notclass common known

Blood and Neutropenialymphaticdisorders

Immune system Allergicdisorders reactions

Metabolism Weight Hyperglycaemiand nutrition increased adisorders Increasedappetite

Psychiatric Anxietydisorders

System organ Very Common Uncommon Rare Notclass common known

Nervous Somnolenc Dystonia Syncope Neurolepticsystem e Akathisia Seizure malignantdisorders Dyskinesia Extrapyramidal syndrome

Parkinsonism disorder

Sedation Dysarthria

Dizziness Restless legs

Dysgeusia syndrome

Eye disorders Accommodation disorder

Cardiac Sinusdisorders bradycardia

Bundle branchblock

Electrocardio-gram QTprolonged

Sinustachycardia

Vascular Orthostaticdisorders hypotension

Respiratory, Pulmonarythoracic and embolismmediastinaldisorders

Gastrointestinal Hypoaesthesia Swollen tonguedisorders oral Dysphagia

Nausea Glossodynia

Salivary Paraesthesiahypersecretion oral

Oral mucosallesions(ulcerations,blistering andinflammation)

Hepatobiliary Alaninedisorders aminotransferase increased

Injury, Falls*poisoning andproceduralcomplications

Musculoskeleta Muscle rigidity Rhabdomyolysil and sconnectivetissue disorders

Pregnancy, Drugpuerperium and withdrawaperinatal lconditions syndromeneonatal(see 4.6)

System organ Very Common Uncommon Rare Notclass common known

Reproductive Sexual Gynaecomastiasystem and dysfunction Galactorrhoeabreast disorders Amenorrhoea

General Fatiguedisorders andadministrationsite conditions

* See subsection “Falls” below

Extrapyramidal Symptoms (EPS)

In clinical trials, the incidence of extrapyramidal symptoms in asenapine-treated patients was higherthan placebo (15.4 % vs 11.0 %).

From the short-term (6 weeks) schizophrenia trials there appears to be a dose-response relationship forakathisia in patients treated with asenapine, and for parkinsonism there was an increasing trend withhigher doses.

Based on a small pharmacokinetic study, paediatric patients appeared to be more sensitive to dystoniawith initial dosing with asenapine when a gradual up-titration schedule was not followed (seesection 5.2). The incidence of dystonia in paediatric clinical trials using a gradual up-titration wassimilar to that seen in adult trials.

Weight increase

In the combined short-term and long-term schizophrenia and bipolar mania trials in adults, the meanchange in body weight for asenapine was 0.8 kg. The proportion of subjects with clinically significantweight gain (≥ 7 % weight gain from baseline at endpoint) in the short-term schizophrenia trials was5.3 % for asenapine compared to 2.3 % for placebo. The proportion of subjects with clinicallysignificant weight gain (≥ 7 % weight gain from baseline at endpoint) in the short-term, flexible-dosebipolar mania trials was 6.5 % for asenapine compared to 0.6 % for placebo.

In a 3-week, placebo-controlled, randomized, fixed-dose efficacy and safety trial in paediatric patients10 to 17 years of age with bipolar I disorder, the mean change from baseline to endpoint in weight forplacebo and asenapine 2.5 mg, 5 mg, and 10 mg twice daily, was 0.48, 1.72, 1.62, and 1.44 kg,respectively. The proportion of subjects with clinically significant weight gain (≥ 7 % weight gainfrom baseline at Day 21) was 14.1 % for asenapine 2.5 mg twice daily, 8.9 % for asenapine 5 mgtwice daily, and 9.2 % for asenapine 10 mg twice daily, compared to 1.1 % for placebo. In thelong-term extension trial (50 weeks), a total of 34.8 % of subjects experienced clinically significantweight increase (i.e., ≥ 7 % increase in body weight at endpoint). Overall mean (SD) weight gain atstudy endpoint was 3.5 (5.76) kg.

The incidence of orthostatic hypotension in elderly subjects was 4.1 % compared to 0.3 % in thecombined phase 2/3 trial population.

Falls

Falls may occur as a result of one or more adverse events such as the following: Somnolence,

Orthostatic hypotension, Dizziness, Extrapyramidal symptoms.

Hepatic enzymes

Transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartatetransferase (AST) have been seen commonly, especially in early treatment.

Other findings

Cerebrovascular events have been reported in patients treated with asenapine but there is no evidenceof any excess incidence over what is expected in adults between 18 and 65 years of age.

Asenapine has anaesthetic properties. Oral hypoaesthesia and oral paraesthesia may occur directlyafter administration and usually resolves within 1 hour.

There have been post-marketing reports of serious hypersensitivity reactions in patients treated withasenapine, including anaphylactic/anaphylactoid reactions, angioedema, swollen tongue and swollenthroat (pharyngeal oedema).

Asenapine is not indicated for the treatment of children and adolescent patients below 18 years (seesection 4.2).

The clinically relevant adverse experiences identified in the paediatric bipolar and schizophrenia trialswere similar to those observed in adult bipolar and schizophrenia trials.

The most common adverse reactions (≥ 5 % and at least twice the rate of placebo) reported inpaediatric patients with bipolar I disorder were somnolence, sedation, dizziness, dysgeusia,hypoaesthesia oral, paraesthesia oral, nausea, increased appetite, fatigue, and weight increased (see

Weight increase above).

The most common adverse reactions (proportion of patients  5 % and at least twice placebo) reportedin paediatric patients with schizophrenia were somnolence, sedation, akathisia, dizziness, andhypoaesthesia oral. There was a statistically significant higher incidence of patients with ≥ 7 % weightgain (from baseline to endpoint) compared to placebo (3.1 %) for Sycrest 2.5 mg twice daily (9.5 %)and Sycrest 5 mg twice daily (13.1 %).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Few cases of overdose were reported in the asenapine program. Reported estimated doses werebetween 15 and 400 mg. In most cases it was not clear if asenapine had been taken sublingually.

Treatment-related adverse reactions included agitation and confusion, akathisia, orofacial dystonia,sedation, and asymptomatic ECG findings (bradycardia, supraventricular complexes, intraventricularconduction delay).

No specific information is available on the treatment of overdose with Sycrest. There is no specificantidote to Sycrest. The possibility of multiple medicinal product involvement should be considered.

Cardiovascular monitoring is necessary to detect possible arrhythmias and management of overdoseshould concentrate on supportive therapy, maintaining an adequate airway oxygenation andventilation, and management of symptoms. Hypotension and circulatory collapse should be treatedwith appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrineand dopamine should not be used, since beta stimulations may worsen hypotension in the setting of

Sycrest-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergicmedicinal products should be administered. Close medical supervision and monitoring should continueuntil the patient recovers.

Pharmacotherapeutic group: Psycholeptics, antipsychotics, ATC code: N05AH05

The mechanism of action of asenapine is not fully understood. However, based on its receptorpharmacology, it is proposed that the efficacy of asenapine is mediated through a combination ofantagonist activity at D2 and 5-HT2A receptors. Actions at other receptors e.g., 5-HT1A, 5-HT1B,5-HT2C, 5-HT6, 5-HT7, D3, and α2-adrenergic receptors, may also contribute to the clinical effects ofasenapine.

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5,5-HT6, and 5-HT7 receptors, dopamine D2, D3, D4, and D1 receptors, α1 and α2-adrenergicreceptors, and histamine H1 receptors, and moderate affinity for H2 receptors. In in vitro assaysasenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity formuscarinic cholinergic receptors.

Clinical efficacy in bipolar I disorder

The efficacy of asenapine in the treatment of a DSM-IV manic or mixed episode of bipolar I disorderwith or without psychotic features was evaluated in two similarly designed 3-week, randomized,double-blind, flexible-dose, placebo- and active controlled (olanzapine) monotherapy trials involving488 and 489 patients, respectively. All patients met the Diagnostic and Statistical Manual of Mental

Disorders, 4th Edition (DSM-IV) diagnostic criteria for bipolar I disorder, current episode manic(DSM-IV 296.4x), or mixed (DSM-IV 296.6x) and had a Young Mania Rating Scale (Y-MRS) scoreof ≥ 20 at screening and baseline. Patients with rapid cycling were excluded from these studies.

Asenapine demonstrated superior efficacy to placebo in the reduction of manic symptoms over3 weeks. Point estimates [95 % CI] for the change from baseline to endpoint in YMRS using LOCFanalysis in the two studies were as follows:

- 11.5 [-13.0, -10.0] for asenapine vs -7.8 [-10.0, -5.6] for placebo and

- 10.8 [-12.3, -9.3] for asenapine vs -5.5 [-7.5, -3.5] for placebo.

A statistically significant difference between asenapine and placebo was seen as early as day 2.

Patients from the two pivotal 3 week trials were studied for a further 9 weeks an extension trial.

Maintenance of effect during the episode after 12 weeks of randomised treatment was demonstrated inthis trial.

In one double-blind, fixed-dose, parallel-group, 3-week placebo controlled trial in subjects withbipolar I disorder experiencing an acute manic or mixed episode involving 367 patients of which 126received placebo, 122 received asenapine 5 mg twice daily (BID), and 119 received asenapine 10 mg

BID, the primary efficacy hypothesis was met. Both asenapine doses (5 mg BID and 10 mg BID) weresuperior to placebo and showed statistically significant improvement in change from baseline in

Y-MRS total score at Day 21 compared with placebo. Based upon a LOCF analysis including allpatients treated, the difference in least squares (LS) mean change from baseline to Day 21 in the

Y-MRS total score between asenapine 5 mg BID and placebo was -3.1 points (95 % CI [-5.7, -0.5];p-value = 0.0183). The difference in LS mean change from baseline to Day 21 in the Y-MRS totalscore between asenapine 10 mg BID and placebo was -3.0 points (95 % CI [-5.6, -0.4];p-value = 0.0244). A statistically significant difference between asenapine and placebo was seen asearly as day 2. In this short-term, fixed-dose controlled trial there was no evidence of added benefitwith a 10 mg twice daily dose compared to 5 mg twice daily.

In a 12-week, placebo-controlled trial involving 326 patients with a manic or mixed episode of bipolar

I disorder, with or without psychotic features, who were partially non-responsive to lithium orvalproate monotherapy for 2 weeks at therapeutic serum levels, the addition of asenapine as adjunctivetherapy resulted in superior efficacy to lithium or valproate monotherapy at week 3 (point estimates[95 % CI] for the change from baseline to endpoint in YMRS using LOCF analysis were -10.3 [-11.9,

- 8.8] for asenapine and -7.9 [-9.4, -6.4] for placebo) and at week 12 (-12.7 [-14.5, -10.9] for asenapineand -9.3 [-11.8, -7.6] for placebo) in the reduction of manic symptoms.

Asenapine is not indicated for the treatment of children and adolescent patients below 18 years (seesection 4.2).

The safety and efficacy of Sycrest was evaluated in 403 paediatric patients with bipolar I disorder whoparticipated in a single, 3-week, placebo-controlled, double-blind trial, of whom 302 patients received

Sycrest at fixed doses ranging from 2.5 mg to 10 mg twice daily. Study results showed statisticallysignificant superiority for all three Sycrest doses in improving the Young Mania Rating Scale (YMRS)total score as measured by the change from baseline to Day 21, as compared with placebo. Long termefficacy could not be established in a 50-week, uncontrolled, open-label extension trial. The clinicallyrelevant adverse reactions identified in the paediatric trials were generally similar to those observed inthe adult trials. However, adverse effects of treatment on weight gain and on plasma lipid profileappeared to be greater than effects observed in the adult trials.

Efficacy of Sycrest was not demonstrated in an 8-week, placebo-controlled, double-blind, randomized,fixed-dose trial in 306 adolescent patients aged 12-17 years with schizophrenia at doses of 2.5 and5 mg twice daily.

Paediatric studies with Sycrest were performed using flavoured sublingual tablets. The European

Medicines Agency has deferred the obligation to submit the results of studies with Sycrest in one ormore subsets of the paediatric population in bipolar I disorder (see section 4.2 for information onpaediatric use).

Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrationsoccurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is35 %. The absolute bioavailability of asenapine when swallowed is low (< 2 % with an oral tabletformulation). The intake of water several (2 or 5) minutes after asenapine administration resulted indecreased (19 % and 10 %, respectively) asenapine exposure. Therefore, eating and drinking should beavoided for 10 minutes after administration (see section 4.2).

Asenapine is rapidly distributed and has a large volume of distribution (approximately 20-25 L/kg),indicating extensive extravascular distribution. Asenapine is highly bound (95 %) to plasma proteins,including albumin and α1-acid glycoprotein.

Asenapine is extensively metabolized. Direct glucuronidation (mediated by UGT1A4) and cytochrome

P450 (primarily CYP1A2, with contributions of 2D6 and 3A4) mediated oxidation and demethylationare the primary metabolic pathways for asenapine. In an in vivo study in humans with radio-labelledasenapine, the predominant drug-related entity in plasma was asenapine N+-glucuronide; othersincluded N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchangedasenapine in smaller amounts. Sycrest activity is primarily due to the parent compound.

Asenapine is a weak inhibitor of CYP2D6. Asenapine does not cause induction of CYP1A2 or

CYP3A4 activities in cultured human hepatocytes. Co-administration of asenapine with knowninhibitors, inducers or substrates of these metabolic pathways has been studied in a number ofdrug-drug interaction studies (see section 4.5).

Asenapine is a high clearance compound, with a clearance after intravenous administration of 52 L/h.

In a mass balance study, the majority of the radioactive dose was recovered in urine (about 50 %) andfaeces (about 40 %), with only a small amount excreted in faeces (5-16 %) as unchanged compound.

Following an initial more rapid distribution phase, the terminal half-life of asenapine is approximately24 h.

Increasing the dose from 5 to 10 mg twice daily (a two-fold increase) results in less than linear(1.7 times) increases in both the extent of exposure and maximum concentration. The less thanproportional increase of Cmax and AUC with dose may be attributed to limitations in the absorptioncapacity from the oral mucosa following sublingual administration.

During twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapinepharmacokinetics are similar to single-dose pharmacokinetics.

The pharmacokinetics of asenapine were similar among subjects with mild (Child-Pugh A) ormoderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function. In subjectswith severe hepatic impairment (Child-Pugh C), a 7-fold increase in asenapine exposure was observed(see section 4.2).

The pharmacokinetics of asenapine following a single dose of 5 mg asenapine were similar amongsubjects with varying degrees of renal impairment and subjects with normal renal function.

There is no experience with asenapine in severe renal impairment patients with a creatinine clearanceless than 15 mL/min.

In elderly patients (between 65 and 85 years of age), exposure to asenapine is approximately 30 %higher than in younger adults.

Paediatric population (children and adolescents)

In a PK study using unflavoured sublingual tablets, at the 5 mg twice daily dose level, asenapinepharmacokinetics in adolescent patients (12 to 17 years of age, inclusive) are similar to those observedin adults. In adolescents, the 10 mg twice daily dose did not result in increased exposure compared to5 mg twice daily.

In a second PK study using flavoured sublingual tablets, the 10 mg twice daily dose in a paediatricpopulation (10 to 17 years of age, inclusive) resulted in an approximate dose-proportional increase inasenapine exposure compared to 5 mg twice daily.

A population pharmacokinetic analysis indicated that there is no evidence of gender-relateddifferences in the pharmacokinetics of asenapine.

In a population pharmacokinetic analysis, no clinical relevant effects of race on the pharmacokineticsof asenapine were found.

A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, has no effecton the clearance of asenapine. In a dedicated study, concomitant smoking during administration of asingle 5 mg sublingual dose had no effect on the pharmacokinetics of asenapine.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology. Repeat-dose toxicity studies in rat and dog showed mainly dose-limitingpharmacological effects, such as sedation. Furthermore, prolactin-mediated effects on mammaryglands and oestrus cycle disturbances were observed. In dogs high oral doses resulted inhepatotoxicity that was not observed after chronic intravenous administration. Asenapine has someaffinity to melanin-containing tissues. However, when tested in vitro it was devoid of phototoxicity. Inaddition, histopathological examination of the eyes from dogs treated chronically with asenapine didnot reveal any signs of ocular toxicity, demonstrating the absence of a phototoxic hazard. Asenapinewas not genotoxic in a battery of tests. In subcutaneous carcinogenicity studies in rats and mice, noincreases in tumour incidences were observed. Effects in non-clinical studies were observed only atexposures considered sufficiently in excess of the maximum human exposure indicating littlerelevance to clinical use.

Asenapine did not impair fertility in rats and was not teratogenic in rat and rabbit. Embryotoxicity wasfound in reproduction toxicology studies using rats and rabbits. Asenapine caused mild maternaltoxicity and slight retardation of foetal skeletal development. Following oral administration topregnant rabbits during the period of organogenesis, asenapine adversely affected body weight at thehigh dose of 15 mg.kg-1 twice daily. At this dose foetal body weight decreased. When asenapine wasadministered intravenously to pregnant rabbits, no signs of embryotoxicity were observed. In rats,embryofoetal toxicity (increased post-implantation loss, decreased foetal weights, and delayedossification) was observed following oral or intravenous administration during organogenesis orthroughout gestation. Increased neonatal mortality was observed among the offspring of female ratstreated during gestation and lactation. From a cross-fostering study it was concluded that asenapineinduced peri- and postnatal losses are caused by impairment of the pups rather than altered nursingbehaviour of the dams.

Gelatin

Mannitol (E421)

Not applicable.

3 years

Store in the original package in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

Peelable aluminium/aluminium blisters in cartons of 20, 60 or 100 sublingual tablets per carton.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands

EU/1/10/640/001

EU/1/10/640/002

EU/1/10/640/003

Date of first authorisation: 01 September 2010

Date of latest renewal: 05 May 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.