4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

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

Special populations

Elderly

Sycrest 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.

Renal impairment

No dose adjustment is required for patients with renal impairment. There is no experience with asenapine in patients with severe renal impairment who have a creatinine clearance less than 15 mL/min.

Hepatic impairment

No 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.

Paediatric population

A 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. Long term 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 a posology can be made.

Method of administration

The 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 medicinal products, 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).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Elderly patients with dementia-related psychosis

Elderly 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 syndrome

Neuroleptic 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.

Seizures

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 or have conditions associated with seizures.

Suicide

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

Orthostatic hypotension

Asenapine 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 dyskinesia

Medicinal 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.

Hyperprolactinaemia

Increases 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 interval

Clinically 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 mellitus

Hyperglycaemia 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.

Dysphagia

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

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. 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 impairment

Asenapine 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 bodies

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 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.

Falls

Asenapine may cause adverse effects such as somnolence, orthostatic hypotension, dizziness and extrapyramidal symptoms, which may lead to falls and, consequently, fractures or other injuries. Patients at risk for fall should be evaluated prior to prescribing asenapine.

4.5. Interaction with other medicinal products and other forms of interaction

Given the primary effects of asenapine on the central nervous system (CNS) (see section 4.8), caution should be used when it is taken in combination with other centrally acting medicinal products. Patients should 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 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 twice daily 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 medicinal products

Because 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There 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).

Newborn infants 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 newborn infants. Consequently, newborn infants should be monitored carefully.

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

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The most frequently reported adverse drug reactions (ADRs) associated with the use of asenapine in clinical trials were somnolence and anxiety. Serious hypersensitivity reactions have been reported. Other serious ADRs are discussed in more detail in section 4.4.

Tabulated list of adverse reactions

The incidences of the ADRs associated with asenapine therapy are tabulated below. The table is based on 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 be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

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

Psychiatric disorders

Anxiety

Nervous system disorders

Somnolence

Dystonia

Akathisia

Dyskinesia

Parkinsonism

Sedation

Dizziness

Dysgeusia

Syncope

Seizure

Extrapyramidal disorder

Dysarthria

Restless legs syndrome

Neuroleptic malignant 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

Nausea

Salivary hypersecretion

Swollen tongue

Dysphagia

Glossodynia

Paraesthesia oral

Oral mucosal lesions (ulcerations, blistering and inflammation)

Hepatobiliary disorders

Alanine aminotransferase increased

Injury, poisoning and procedural complications

Falls*

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

* See subsection “Falls” below

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 adult trials.

Weight increase

In 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, flexible-dose bipolar mania trials was 6.5 % for asenapine compared to 0.6 % for placebo.

In a 3-week, placebo-controlled, randomised, 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 2.5 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 gain from baseline at Day 21) 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. In the long-term extension trial (50 weeks), a total of 34.8 % of subjects experienced clinically significant weight increase (i.e., ≥ 7 % increase in body weight at endpoint). Overall mean (SD) weight gain at study endpoint was 3.5 (5.76) kg.

Orthostatic hypotension

The incidence of orthostatic hypotension in elderly subjects was 4.1 % compared to 0.3 % in the combined 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), aspartate transferase (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 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 post-marketing reports of serious hypersensitivity reactions in patients treated with asenapine, including anaphylactic/anaphylactoid reactions, angioedema, swollen tongue and swollen throat (pharyngeal oedema).

Paediatric population

Asenapine 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 trials 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, 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) 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Few cases of overdose were reported in the asenapine program. Reported estimated doses were between 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, intraventricular conduction delay).

No specific information is available on the treatment of overdose with Sycrest. There is no specific antidote to Sycrest. The possibility of multiple medicinal product involvement should be considered. Cardiovascular monitoring is necessary to detect possible arrhythmias and management of overdose should concentrate on supportive therapy, maintaining an adequate airway oxygenation and ventilation, and management of symptoms. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and 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, anticholinergic medicinal products should be administered. Close medical supervision and monitoring should continue until the patient recovers.