- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
Manic episodeThe recommended starting dose of Sycrest as monotherapy is 10 mg twice daily. One dose should be taken in the morning and one dose should be taken in the evening. The dose can be reduced to 5 mg twice daily according to clinical assessment. For combination therapy a starting dose of 5 mg twice daily is recommended. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily.
Additional information on special populations
Paediatric populationA pharmacokinetic study and a short term efficacy and safety study were performed in a paediatric population (ages 10-17 years) with manic or mixed episodes associated with bipolar I disorder. The long term safety of Sycrest in children aged below 18 years has not been established. Limited safety data with Sycrest are available in paediatric patients.Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Older peopleSycrest should be used with care in the elderly. Limited data on efficacy in patients 65 years of age and older are available. Available pharmacokinetic data are described in section 5.2.
Renally impaired patientsNo dose adjustment is required for patients with renal impairment. There is no experience with asenapine in severe renal impairment patients with a creatinine clearance less than 15 ml/min.
Hepatic impaired patientsNo dose adjustment is required for patients with mild hepatic impairment. The possibility of elevated asenapine 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), a 7-fold increase in asenapine exposure was observed. Thus, Sycrest is not recommended in patients with severe hepatic impairment.
Method of administrationThe tablet should not be removed from the blister until ready to take it. Dry hands should be used when touching the tablet. The tablet should not be pushed through the tablet pack. The tablet pack should not be cut or torn. The coloured tab should be peeled back and the tablet should be removed gently. The tablet should not be crushed.To ensure optimal absorption, the Sycrest sublingual tablet should be placed under the tongue and allowed to dissolve completely. The tablet will dissolve in saliva within seconds. Sycrest sublingual tablets should not be chewed or swallowed. Eating and drinking should be avoided for 10 minutes after administration.When used in combination with other medication, Sycrest should be taken last.Treatment with Sycrest is not advised in patients who are unable to comply with this method of administration, as the bioavailability of asenapine when swallowed is low (<2 % with an oral tablet formulation).
Elderly patients with dementia-related psychosisElderly patients with dementia-related psychosis treated with antipsychotic substances are at an increased risk of death.Sycrest is not approved for the treatment of patients with dementia-related psychosis and is not recommended for use in this particular group of patients.
Neuroleptic malignant syndromeNeuroleptic malignant syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including asenapine. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS Sycrest must be discontinued.
SeizuresIn 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 or have conditions associated with seizures.
SuicideThe possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder and close supervision of high-risk patients should accompany treatment.
Orthostatic hypotensionAsenapine may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for experiencing orthostatic hypotension (see section 4.8). In clinical trials, cases of syncope were occasionally reported during treatment with Sycrest. Sycrest should be used with caution in elderly patients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia).
Tardive dyskinesiaMedicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported during treatment with asenapine. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Sycrest, discontinuation of treatment should be considered.
HyperprolactinaemiaIncreases in prolactin levels were observed in some patients with Sycrest. In clinical trials, there were few adverse reactions related to abnormal prolactin levels reported.
QT intervalClinically relevant QT prolongation does not appear to be associated with asenapine. Caution should be exercised when Sycrest is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.
Hyperglycaemia and diabetes mellitusHyperglycaemia or exacerbation of pre-existing diabetes has occasionally been reported during treatment with asenapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia or bipolar disorder and the increasing incidence of diabetes mellitus in the general population. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
DysphagiaEsophageal dysmotility and aspiration have been associated with antipsychotic treatment. Cases of dysphagia were occasionally reported in patients treated with Sycrest.
Body temperature regulationDisruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. From the clinical trials, it is concluded that clinically relevant body temperature dysregulation does not appear to be associated with asenapine. Appropriate care is advised when prescribing Sycrest for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity or being subject to dehydration.
Patients with severe hepatic impairmentAsenapine exposure is increased 7-fold in patients with severe hepatic impairment (Child-Pugh C). Therefore, Sycrest is not recommended in such patients.
Parkinson's disease and dementia with Lewy bodiesPhysicians should weigh the risks versus the benefits when prescribing antipsychotic medicinal products, including Sycrest, to patients with Parkinson's disease or dementia with Lewy Bodies (DLB) since both groups may be at increased risk of neuroleptic malignant syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Potential for other medicines to affect SycrestAsenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and an inducer of several of these enzyme pathways on asenapine pharmacokinetics were studied, specifically fluvoxamine (CYP1A2 inhibitor), paroxetine (CYP2D6 inhibitor), imipramine (CYP1A2/2C19/3A4 inhibitor), cimetidine (CYP3A4/2D6/1A2 inhibitor), carbamazepine (CYP3A4/1A2 inducer) and valproate (UGT inhibitor). Except for fluvoxamine, none of the interacting medicinal products resulted in clinically relevant alterations in asenapine pharmacokinetics. During combined administration with a single dose of asenapine 5 mg, fluvoxamine 25 mg BID resulted in a 29 % increase in asenapine AUC. The full therapeutic dose of fluvoxamine would be expected 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 medicinesBecause of its α1-adrenergic antagonism with potential for inducing orthostatic hypotension (see section 4.4), Sycrest may enhance the effects of certain antihypertensive agents.Asenapine may antagonise the effect of levodopa and dopamine agonists. If this combination is deemed necessary, the lowest effective dose of each treatment should be prescribed. In vitro studies indicate that asenapine weakly inhibits CYP2D6. Clinical drug interaction studies investigating the effects of CYP2D6 inhibition by asenapine showed the following results:− Following co-administration of dextromethorphan and asenapine in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in a fractional decrease in DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily 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-mg dose 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 an almost 2-fold increase in paroxetine exposure. In vivo asenapine appears to be at most a weak inhibitor of CYP2D6. However, asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.Therefore, Sycrest should be co-administered cautiously with medicinal products that are both substrates and inhibitors for CYP2D6.To ensure optimal absorption, eating and drinking should be avoided for 10 minutes after administration.
PregnancyThere are no adequate data from the use of Sycrest in pregnant women. Asenapine was not teratogenic in animal studies. Maternal and embryo toxic effects were found in animal studies (see section 5.3). Neonates exposed to antipsychotics (including Sycrest) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder in neonates. Consequently, newborns should be monitored carefully. Sycrest should not be used during pregnancy unless clearly necessary and only if the potential benefit outweighs the potential risk to the foetus.
Breast-feedingAsenapine was excreted in milk of rats during lactation. It is not known whether asenapine or its metabolites are excreted in human milk. It is recommended that women receiving Sycrest should not breast-feed.
FertilityNo impairment of fertility has been observed in nonclinical studies (see section 5.3).
|System organ class||Very common||Common||Uncommon||Rare||Not known|
|Blood and lymphatic disorders||Neutropenia|
|Immune system disorders||Allergic reactions|
|Metabolism and nutrition disorders||Weight increased Increased appetite||Hyperglycaemia|
|Nervous system disorders||Somnolence||Dystonia Akathisia Dyskinesia Parkinsonism Sedation Dizziness Dysgeusia||Syncope Seizure Extrapyramidal disorder Dysarthria||Neuroleptic malignant syndrome||Restless legs syndrome|
|Eye disorders||Accommodation disorder|
|Cardiac disorders||Sinus bradycardia Bundle branch block Electrocardiogram QT prolonged Sinus tachycardia|
|Vascular disorders||Orthostatic hypotension Hypotension|
|Respiratory, thoracic and mediastinal disorders||Pulmonary embolism|
|Gastrointestinal disorders||Hypoaesthesia oral||Swollen tongue Dysphagia Glossodynia Paraesthesia oral||Nausea Oral mucosal lesions (ulcerations, blistering and inflammation) Salivary hypersecretion|
|Hepatobiliary disorders||Alanine aminotransferase increased|
|Musculoskeletal and connective tissue disorders||Muscle rigidity||Rhabdomyolysis|
|Pregnancy, puerperium and perinatal conditions||Drug withdrawal syndrome neonatal (see 4.6)|
|Reproductive system and breast disorders||Sexual dysfunction Amenorrhoea||Gynaecomastia Galactorrhoea|
|General disorders and administration site conditions||Fatigue|
Description of selected adverse reactions
Extrapyramidal Symptoms (EPS)In clinical trials, the incidence of extrapyramidal symptoms in asenapine-treated patients was higher than placebo (15.4 % vs 11.0 %).From the short-term (6 weeks) schizophrenia trials there appears to be a dose-response relationship for akathisia in patients treated with asenapine, and for parkinsonism there was an increasing trend with higher doses.Based on a small pharmacokinetic study, paediatric patients appeared to be more sensitive to dystonia with initial dosing with asenapine when a gradual up-titration schedule was not followed (see section 5.2). The incidence of dystonia in paediatric clinical trials using a gradual up-titration was similar to that seen in adults trials..
Weight increaseIn the combined short-term and long-term schizophrenia and bipolar mania trials in adults, the mean change in body weight for asenapine was 0.8 kg. The proportion of subjects with clinically significant weight gain (≥ 7 % weight gain from baseline at endpoint) in the short-term schizophrenia trials was 5.3 % for asenapine compared to 2.3 % for placebo. The proportion of subjects with clinically significant weight gain (≥ 7 % weight gain from baseline at endpoint) in the short-term bipolar 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 patients 10 to 17 years of age with bipolar I disorder, the mean change from baseline to endpoint in weight for placebo and asenapine 2.5mg, 5mg, 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 gain from baseline at endpoint) was 14.1 % for asenapine 2.5 mg twice daily, 8.9 % for asenapine 5 mg twice daily, and 9.2 % for asenapine 10 mg twice daily, compared to 1.1 % for placebo.
Orthostatic hypotensionThe incidence of orthostatic hypotension in elderly subjects was 4.1 % compared to 0.3 % in the combined phase 2/3 trial population.
Hepatic enzymesTransient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartate transferase (AST) have been seen commonly, especially in early treatment.
Other findingsCerebrovascular events have been reported in patients treated with asenapine but there is no evidence of 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 directly after administration and usually resolves within 1 hour.There have been postmarketing reports of serious hypersensitivity reactions in patients treated with asenapine, including anaphylactic/anaphylactoid reactions, angioedema, swollen tongue and swollen throat (pharyngeal oedema).
Paediatric populationAsenapine is not indicated for the treatment of children and adolescent patients below 18 years (see section 4.2).The clinically relevant adverse experiences identified in the paediatric bipolar and schizophrenia trails were 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 in paediatric patients with bipolar I disorder were somnolence, sedation, dizziness, disgeusia, hypoaesthesia oral, paraesthesia oral, nausea, increased appetite, fatigue, and weight increased.The most common adverse reactions (proportion of patients ≥5 % and at least twice placebo) reported in paediatric patients with schizophrenia were somnolence, sedation, akathisia, dizziness, and hypoaesthesia oral. There was a statistically significant higher incidence of patients with ≥7 % weight gain (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 of suspected adverse reactions.Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mechanism of actionThe mechanism of action of asenapine, as with other medicinal products having efficacy in bipolar disorder, is not fully understood. However, based on its receptor pharmacology, it is proposed that the efficacy of asenapine is mediated through a combination of antagonist 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 of asenapine.
Clinical efficacy in bipolar I disorderThe efficacy of asenapine in the treatment of a DSM-IV manic or mixed episode of bipolar I disorder with or without psychotic features was evaluated in two similarly designed 3-week, randomized, double-blind, placebo- and active controlled (olanzapine) monotherapy trials involving 488 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) score of ≥ 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 over 3 weeks. Point estimates [95 % CI] for the change from baseline to endpoint in YMRS using LOCF analysis 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 in this trial. 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 or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of asenapine as adjunctive therapy 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-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 asenapine and -9.3 [-11.8, -7.6] for placebo) in the reduction of manic symptoms.
Paediatric populationAsenapine is not indicated for the treatment of children and adolescent patients below 18 years (see section 4.2).The safety and efficacy of Sycrest was evaluated in 403 paediatric patients with bipolar I disorder who participated 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 statistically significant 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. However, the clinical relevance of the efficacy findings has not been established. No long term data are available with regard to the efficacy and the safety of asenapine in this population.Efficacy of Sycrest was not demonstrated in an 8-week, placebo, double-blind, randomized, fixed-dose trial in 306 adolescent patients aged 12-17 years with schizophrenia at doses 2.5 mg and 5 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 asenapine in one or more subsets of the paediatric population in bipolar I disorder (see section 4.2 for information on paediatric use).
AbsorptionFollowing sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35 %. The absolute bioavailability of asenapine when swallowed is low (<2 % with an oral tablet formulation). The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased (19 % and 10 %, respectively) asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration (see section 4.2).
DistributionAsenapine is rapidly distributed and has a large volume of distribution (approximately 1700 l), indicating extensive extravascular distribution. Asenapine is highly bound (95 %) to plasma proteins, including albumin and α1-acid glycoprotein.
BiotransformationAsenapine is extensively metabolized. Direct glucuronidation (mediated by UGT1A4) and cytochrome P450 (primarily CYP1A2, with contributions of 2D6 and 3A4) mediated oxidation and demethylation are the primary metabolic pathways for asenapine. In an in vivo study in humans with radio-labelled asenapine, the predominant drug-related entity in plasma was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine 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 known inhibitors, inducers or substrates of these metabolic pathways has been studied in a number of drug-drug interaction studies (see section 4.5).
EliminationAsenapine 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 %) and faeces (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 approximately 24 h.
Linearity/non-linearityIncreasing 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 than proportional increase of Cmax and AUC with dose may be attributed to limitations in the absorption capacity from the oral mucosa following sublingual administration.During twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.
Pharmacokinetics in special populations
Hepatic impairmentThe pharmacokinetics of asenapine were similar among subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function. In subjects with severe hepatic impairment (Child-Pugh C), a 7-fold increase in asenapine exposure was observed (see section 4.2).
Renal impairementThe pharmacokinetics of asenapine following a single dose of 5 mg asenapine were similar among subjects 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 clearance less than 15 ml/min.
Older peopleIn 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, asenapine pharmacokinetics in adolescent patients (12 to 17 years of age, inclusive) are similar to those observed in adults. In adolescents, the 10 mg twice daily dose did not result in increased exposure compared to 5 mg twice daily.In a second PK study using flavoured sublingual tablets, at the 5mg and 10mg twice daily dose level, asenapine pharmacokinetics in a paediatric population (10 to 17 years of age, inclusive) are similar to those observed in adults. The 10 mg twice daily dose resulted in an approximate dose-proportional increase in asenapine exposure compared to 5 mg twice daily.
GenderA population pharmacokinetic analysis indicated that there is no evidence of gender-related differences in the pharmacokinetics of asenapine.
RaceIn a population pharmacokinetic analysis, no clinical relevant effects of race on the pharmacokinetics of asenapine were found.
SmokingA population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, has no effect on the clearance of asenapine. In a dedicated study, concomitant smoking during administration of a single 5 mg sublingual dose had no effect on the pharmacokinetics of asenapine.
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