ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Sycrest 5 mg sublingual tablets
2.
Each sublingual tablet contains 5 mg asenapine (as maleate).
For a full list of excipients, see section 6.1.
3.
Sublingual tablet
Round, white to off-white, sublingual tablets debossed with “5” on one side.
4.
Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar I
disorder in adults
Posology
Manic episode
The 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 population
The safety and efficacy of Sycrest in children aged below 18 years have not been established. Limited
safety data with Sycrest are available in adolescent patients. A pharmacokinetic study was performed
in adolescent patients. Currently available data are described in section 5.2 but no recommendation on
a posology can be made.
Elderly patients
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.
Renally impaired patients
No 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 patients
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
2
7-fold increase in asenapine exposure was observed. Thus, Sycrest is not recommended in patients
with severe hepatic impairment.
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 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).
Hypersensitivity to the active substance or to any of the excipients.
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).
3
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
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 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 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.
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 medicines to affect Sycrest
4
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 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 medicines
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.
To ensure optimal absorption, eating and drinking should be avoided for 10 minutes after
administration.
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).
Sycrest should not be used during pregnancy unless clearly necessary 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. It is recommended that women receiving Sycrest should not
breast-feed.
5
Fertility
No impairment of fertility has been observed in nonclinical studies (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. Asenapine
may cause somnolence and sedation. Therefore, patients should be cautioned about operating
machinery, including motor vehicles, until they are reasonably certain that Sycrest therapy does not
affect them adversely.
The most frequently reported adverse drug reactions during treatment with asenapine were
somnolence and anxiety. The incidences of the Adverse Drug Reactions (ADRs) associated with
asenapine therapy are tabulated below. The table is based on adverse event reporting from clinical
trials.
All ADRs are listed by system organ class and frequency; very common (≥1/10), common (
≥
1/100 to
1/10,000 to <1/1,000). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
≥
1/1,000 to <1/100) and rare (
≥
System organ
class
Very
common
Common
Uncommon
Rare
Blood and
lymphatic
disorders
Neutropenia
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
Neuroleptic
malignant
syndrome
Eye disorders
Accommodation
disorder
Cardiac
disorders
Sinus bradycardia
Bundle branch
block
Electrocardiogram
QT prolonged
Vascular
disorders
Orthostatic
hypotension
Hypotension
Respiratory,
thoracic and
mediastinal
disorders
Pulmonary
embolism
Gastrointestinal
disorders
Hypoaesthesia
oral
Swollen tongue
Dysphagia
Glossodynia
Paraesthesia oral
6
<1/10), uncommon (
Hepatobiliary
disorders
Alanine
aminotransferase
increased
Musculoskeletal
and connective
tissue disorders
Muscle rigidity
Rhabdomyolysis
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.
Weight increase
In the combined short-term and long-term schizophrenia and bipolar mania trials, 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.
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.
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.
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
7
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
medicines should be administered. Close medical supervision and monitoring should continue until the
patient recovers.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, antipsychotics, ATC code: N05AH05
Mechanism of action
The 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
Clinical efficacy in bipolar I disorder
The 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 population
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 schizophrenia and bipolar I disorder
(see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
8
Absorption
Following 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).
Distribution
Asenapine 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.
Biotransformation
Asenapine 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).
Elimination
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 %) 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-linearity
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 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
Hepatically impaired patients
The 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).
Renally impaired patients
The 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.
Elderly
9
In elderly patients (between 65 and 85 years of age), exposure to asenapine is approximately 30 %
higher than in younger adults.
Paediatric population (Adolescents)
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.
Gender
A population pharmacokinetic analysis indicated that there is no evidence of gender-related
differences in the pharmacokinetics of asenapine.
Race
In a population pharmacokinetic analysis, no clinical relevant effects of race on the pharmacokinetics
of asenapine were found.
Smoking
A 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.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology. Repeat-dose toxicity studies in rat and dog showed mainly dose-limiting
pharmacological effects, such as sedation. Furthermore, prolactin-mediated effects on mammary
glands and oestrus cycle disturbances were observed. In dogs high oral doses resulted in
hepatotoxicity that was not observed after chronic intravenous administration. Asenapine has some
affinity to melanin-containing tissues. However, when tested
in vitro
it was devoid of phototoxicity. In
addition, histopathological examination of the eyes from dogs treated chronically with asenapine did
not reveal any signs of ocular toxicity, demonstrating the absence of a phototoxic hazard. Asenapine
was not genotoxic in a battery of tests. In subcutaneous carcinogenicity studies in rats and mice, no
increases in tumour incidences were observed. Effects in non-clinical studies were observed only at
exposures considered sufficiently in excess of the maximum human exposure indicating little
relevance to clinical use.
Asenapine did not impair fertility in rats and was not teratogenic in rat and rabbit. Embryotoxicity was
found in reproduction toxicology studies using rats and rabbits. Asenapine caused mild maternal
toxicity and slight retardation of foetal skeletal development. Following oral administration to
pregnant rabbits during the period of organogenesis, asenapine adversely affected body weight at the
high dose of 15 mg.kg
-1
twice daily. At this dose foetal body weight decreased. When asenapine was
administered intravenously to pregnant rabbits, no signs of embryotoxicity were observed. In rats,
embryofoetal toxicity (increased post-implantation loss, decreased foetal weights, and delayed
ossification) was observed following oral or intravenous administration during organogenesis or
throughout gestation. Increased neonatal mortality was observed among the offspring of female rats
treated during gestation and lactation. From a cross-fostering study it was concluded that asenapine
induced peri- and postnatal losses are caused by impairment of the pups rather than altered nursing
behaviour of the dams.
6.
6.1 List of excipients
Gelatin
Mannitol (E421)
6.2 Incompatibilities
10
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
Peelable aluminium/aluminium blisters in cartons of 20, 60 or 100 sublingual tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands
8.
EU/1/10/640/001
EU/1/10/640/002
EU/1/10/640/003
9.
Date of first authorisation: 1 September 2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
11
1.
Sycrest 10 mg sublingual tablets
2.
Each sublingual tablet contains 10 mg asenapine (as maleate).
For a full list of excipients, see section 6.1.
3.
Sublingual tablet
Round, white to off-white, sublingual tablets debossed with ”10” on one side.
4.
Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar I
disorder in adults
Posology
Manic episode
The 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 population
The safety and efficacy of Sycrest in children aged below 18 years have not been established. Limited
safety data with Sycrest are available in adolescent patients. A pharmacokinetic study was performed
in adolescent patients. Currently available data are described in section 5.2 but no recommendation on
a posology can be made.
Elderly patients
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.
Renally impaired patients
No 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 patients
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
12
7-fold increase in asenapine exposure was observed. Thus, Sycrest is not recommended in patients
with severe hepatic impairment.
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 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).
Hypersensitivity to the active substance or to any of the excipients.
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).
13
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
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 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 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.
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 medicines to affect Sycrest
14
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 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 medicines
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.
To ensure optimal absorption, eating and drinking should be avoided for 10 minutes after
administration.
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).
Sycrest should not be used during pregnancy unless clearly necessary 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. It is recommended that women receiving Sycrest should not
breast-feed.
15
Fertility
No impairment of fertility has been observed in nonclinical studies (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. Asenapine
may cause somnolence and sedation. Therefore, patients should be cautioned about operating
machinery, including motor vehicles, until they are reasonably certain that Sycrest therapy does not
affect them adversely.
The most frequently reported adverse drug reactions during treatment with asenapine were
somnolence and anxiety. The incidences of the Adverse Drug Reactions (ADRs) associated with
asenapine therapy are tabulated below. The table is based on adverse event reporting from clinical
trials.
All ADRs are listed by system organ class and frequency; very common (≥1/10), common (
≥
1/100 to
1/10,000 to <1/1,000). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
≥
1/1,000 to <1/100) and rare (
≥
System organ
class
Very
common
Common
Uncommon
Rare
Blood and
lymphatic
disorders
Neutropenia
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
Neuroleptic
malignant
syndrome
Eye disorders
Accommodation
disorder
Cardiac
disorders
Sinus bradycardia
Bundle branch
block
Electrocardiogram
QT prolonged
Vascular
disorders
Orthostatic
hypotension
Hypotension
Respiratory,
thoracic and
mediastinal
disorders
Pulmonary
embolism
Gastrointestinal
disorders
Hypoaesthesia
oral
Swollen tongue
Dysphagia
Glossodynia
Paraesthesia oral
16
<1/10), uncommon (
Hepatobiliary
disorders
Alanine
aminotransferase
increased
Musculoskeletal
and connective
tissue disorders
Muscle rigidity
Rhabdomyolysis
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.
Weight increase
In the combined short-term and long-term schizophrenia and bipolar mania trials, 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.
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.
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.
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
17
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
medicines should be administered. Close medical supervision and monitoring should continue until the
patient recovers.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, antipsychotics, ATC code: N05AH05
Mechanism of action
The 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
Clinical efficacy in bipolar I disorder
The 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 population
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 schizophrenia and bipolar I disorder
(see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
18
Absorption
Following 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).
Distribution
Asenapine 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.
Biotransformation
Asenapine 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).
Elimination
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 %) 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-linearity
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 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
Hepatically impaired patients
The 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).
Renally impaired patients
The 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.
Elderly
19
In elderly patients (between 65 and 85 years of age), exposure to asenapine is approximately 30 %
higher than in younger adults.
Paediatric population (Adolescents)
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.
Gender
A population pharmacokinetic analysis indicated that there is no evidence of gender-related
differences in the pharmacokinetics of asenapine.
Race
In a population pharmacokinetic analysis, no clinical relevant effects of race on the pharmacokinetics
of asenapine were found.
Smoking
A 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.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology. Repeat-dose toxicity studies in rat and dog showed mainly dose-limiting
pharmacological effects, such as sedation. Furthermore, prolactin-mediated effects on mammary
glands and oestrus cycle disturbances were observed. In dogs high oral doses resulted in
hepatotoxicity that was not observed after chronic intravenous administration. Asenapine has some
affinity to melanin-containing tissues. However, when tested
in vitro
it was devoid of phototoxicity. In
addition, histopathological examination of the eyes from dogs treated chronically with asenapine did
not reveal any signs of ocular toxicity, demonstrating the absence of a phototoxic hazard. Asenapine
was not genotoxic in a battery of tests. In subcutaneous carcinogenicity studies in rats and mice, no
increases in tumour incidences were observed. Effects in non-clinical studies were observed only at
exposures considered sufficiently in excess of the maximum human exposure indicating little
relevance to clinical use.
Asenapine did not impair fertility in rats and was not teratogenic in rat and rabbit. Embryotoxicity was
found in reproduction toxicology studies using rats and rabbits. Asenapine caused mild maternal
toxicity and slight retardation of foetal skeletal development. Following oral administration to
pregnant rabbits during the period of organogenesis, asenapine adversely affected body weight at the
high dose of 15 mg.kg
-1
twice daily. At this dose foetal body weight decreased. When asenapine was
administered intravenously to pregnant rabbits, no signs of embryotoxicity were observed. In rats,
embryofoetal toxicity (increased post-implantation loss, decreased foetal weights, and delayed
ossification) was observed following oral or intravenous administration during organogenesis or
throughout gestation. Increased neonatal mortality was observed among the offspring of female rats
treated during gestation and lactation. From a cross-fostering study it was concluded that asenapine
induced peri- and postnatal losses are caused by impairment of the pups rather than altered nursing
behaviour of the dams.
6.
6.1 List of excipients
Gelatin
Mannitol (E421)
6.2 Incompatibilities
20
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
Peelable aluminium/aluminium blisters in cartons of 20, 60 or 100 sublingual tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands
8.
EU/1/10/640/004
EU/1/10/640/005
EU/1/10/640/006
9.
Date of first authorisation: 1 September 2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
21
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR
BATCH RELEASE
22
B. CONDITIONS OF THE MARKETING AUTHORISATION
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Organon (Ireland) Ltd.
Drynam Road, Swords, Co. Dublin
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version INT00137451 of the Risk Management Plan (RMP)
presented in Module 1.8.2. of the Marketing Authorisation application and any subsequent updates of
the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
23
ANNEX III
LABELLING AND PACKAGE LEAFLET
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (5 mg)
1.
Sycrest 5 mg sublingual tablets
asenapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sublingual tablet contains 5 mg asenapine (as maleate).
3.
LIST OF EXCIPIENTS
4.
20 sublingual tablets
60 sublingual tablets
100 sublingual tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Sublingual use
Peelable blister. Do not crush, chew or swallow.
Keep the tablet under your tongue until it dissolves.
Do not eat or drink for 10 minutes after taking the tablet.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
26
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
N.V. Organon
Kloosterstraat 6
NL- 5349 AB Oss
The Netherlands
EU/1/10/640/001 20 sublingual tablets
EU/1/10/640/002 60 sublingual tablets
EU/1/10/640/003 100 sublingual tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
sycrest 5 mg
27
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER (5 mg)
1.
Sycrest 5 mg sublingual tablets
asenapine
2.
N.V. Organon
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (10 mg)
1.
Sycrest 10 mg sublingual tablets
asenapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sublingual tablet contains 10 mg asenapine (as maleate).
3.
LIST OF EXCIPIENTS
4.
20 sublingual tablets
60 sublingual tablets
100 sublingual tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Sublingual use
Peelable blister. Do not crush, chew or swallow.
Keep the tablet under your tongue until it dissolves.
Do not eat or drink for 10 minutes after taking the tablet.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
29
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
N.V. Organon
Kloosterstraat 6
NL- 5349 AB Oss
The Netherlands
EU/1/10/640/004 20 sublingual tablets
EU/1/10/640/005 60 sublingual tablets
EU/1/10/640/006 100 sublingual tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
sycrest 10 mg
30
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER (10 mg)
1.
Sycrest 10 mg sublingual tablets
asenapine
2.
N.V. Organon
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
31
B. PACKAGE LEAFLET
32
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sycrest 5 mg sublingual tablets
Sycrest 10 mg sublingual tablets
asenapine
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Sycrest is and what it is used for
2.
Before you take Sycrest
3.
How to take Sycrest
4.
How to store Sycrest
6.
Further information
1.
WHAT SYCREST IS AND WHAT IT IS USED FOR
Sycrest belongs to a group of medicines called antipsychotics and is used to treat moderate to severe
manic episodes associated with bipolar I disorder. Antipsychotic medicines affect the chemicals that
allow communication between nerve cells (neurotransmitters). Illnesses that affect the brain, such as
bipolar I disorder, may be due to certain chemicals in the brain, such as dopamine and serotonin, being
out of balance and these imbalances may cause some of the symptoms you may be experiencing.
Exactly how Sycrest works is unknown, however, it is believed to adjust the balance of these
chemicals.
Manic episodes associated with bipolar I disorder is a condition with symptoms such as feeling “high”,
having excessive amounts of energy, needing much less sleep than usual, talking very quickly with
racing ideas and sometimes severe irritability.
2.
BEFORE YOU TAKE SYCREST
Do not take Sycrest
If you are allergic (hypersensitive) to asenapine or any of the other ingredients (listed in section 6
Further information).
Take special care with Sycrest
Sycrest has not been studied in elderly patients with dementia. However, elderly patients with
dementia, who are treated with other similar types of medicine, may have an increased risk of stroke or
death. Sycrest is not approved for the treatment of elderly patients with dementia and is not
recommended for use in this particular group of patients.
Sycrest may cause low blood pressure. In the early stages of treatment, some people may faint,
especially when getting up from a lying or sitting position. This will usually pass on its own but if it
does not, tell your doctor. Your dose may need to be adjusted.
Sycrest may cause weight gain.
Tell your doctor immediately if you experience
33
-
Keep this leaflet. You may need to read it again.
5.
Possible side effects
−
involuntary rhythmic movements of the tongue, mouth and face. Withdrawal of Sycrest may be
needed.
−
fever, severe muscle stiffness, sweating or a lowered level of consciousness (a disorder called
“neuroleptic malignant syndrome”). Immediate medical treatment may be needed.
Check with your doctor or pharmacist before taking Sycrest:
−
if you have ever been diagnosed with a condition whose symptoms include high body
temperature and muscle stiffness (also known as Neuroleptic Malignant Syndrome).
−
if you have ever experienced abnormal movements of the tongue or face (tardive dyskinesia).
You should be aware that both of these conditions may be caused by this type of medicine.
−
if you have a heart disease or a treatment for heart disease that makes you prone to low blood
pressure
−
if you are diabetic or prone to diabetes
−
you have Parkinson’s disease or dementia
−
if you have epilepsy (seizures)
−
if you experience any difficulty in swallowing (dysphagia)
−
if you have severe liver problems. If you do, you should not take Sycrest
−
if you have difficulty controlling core body temperature
−
if you have thoughts of suicide
Be sure to tell your doctor if you meet any of these conditions as he/she may want to adjust your dose
or monitor you for a while. Also contact your doctor immediately if any of these conditions develops
or worsens while using Sycrest.
Children and adolescents
Use of Sycrest below the age of 18 years is not recommended due to lack of information on whether it
is safe and effective in this age group.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Some medicines may reduce the effect of
Sycrest.
If you are taking other medicines, Sycrest should be taken last.
You should tell your doctor if you are taking antidepressant medicines (specifically fluvoxamine,
paroxetine or fluoxetine), as it may be necessary to change your Sycrest or antidepressant medicine
dose.
You should tell your doctor if you are taking medicines for Parkinson’s disease (such as levodopa), as
Sycrest may make them less effective.
Since Sycrest works primarily in the brain, interference from other medicines (or alcohol) that work in
the brain could occur due to an additive effect on brain function.
Since Sycrest can lower blood pressure, care should be taken when Sycrest is taken with other
medicines that lower blood pressure.
Taking Sycrest with food and drink
Do not eat or drink for 10 minutes after taking the tablet.
You should avoid drinking alcohol when taking Sycrest.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
34
Do not take Sycrest while you are pregnant, unless your doctor tells you so. If you are taking Sycrest
and you become pregnant or you plan to get pregnant, ask your doctor as soon as possible whether you
may continue taking Sycrest.
Do not breast-feed when taking Sycrest.
Driving and using machines
Sycrest may affect your concentration or alertness. Make sure these abilities are not affected before
you drive or operate machinery.
3.
HOW TO TAKE SYCREST
Always take Sycrest exactly as your doctor or pharmacist has told you. Sycrest is not advised if you
are unable to take the tablet as described below.You should check with your doctor or pharmacist if
you are not sure. If you are unable to take Sycrest as is described below, the treatment may not be
effective for you.
The usual dose is a tablet of 5 mg or 10 mg two times a day. One dose should be taken in the morning
and one dose should be taken in the evening.
Instructions for use
-
Do not remove a tablet from the blister until ready to take it.
-
Do not push the tablet through the blister. Do not cut or tear the blister.
-
Peel back the colored tab (Figure 1).
-
Gently remove the tablet (Figure 2). Do not crush the tablet.
-
To ensure optimal absorption, place the tablet under the tongue and wait until it dissolves
completely (Figure 3). The tablet will dissolve in saliva within seconds.
-
Do not eat or drink for 10 minutes after taking the tablet.
Figure 1
Figure 2
Figure 3
If you take more Sycrest than you should
If you take too much Sycrest, contact a doctor straight away. Take the medicine pack with you. In case
of overdose you may feel sleepy or tired, or have abnormal body movements, problems with standing
and walking, feel dizzy due to low blood pressure and feel agitated and confused.
If you forget to take Sycrest
Do not take a double dose to make up for a forgotten dose. If you miss one dose, take your next dose
as usual. If you miss two or more doses, contact your doctor.
If you stop taking Sycrest
If you stop taking Sycrest, you will lose the effects of this medicine. You should not stop taking this
medicine, unless your doctor tells you as your symptoms may return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
35
-
Use dry hands when touching the tablet.
-
Do not swallow or chew on the tablet.
Like all medicines, Sycrest can cause side effects, although not everybody gets them.
Very common side effects
(affects more than 1 user in 10)
-
anxiety
-
sleepiness
Common side effects
(affects 1 to 10 users in 100)
-
weight gain
-
increased appetite
-
slow or sustained muscle contractions
-
involuntary muscle contractions
-
slow movements, tremor
-
sedation
-
dizziness
-
change in taste
-
numb feeling of the tongue or in the mouth
-
muscle tightness
-
fatigue
-
increase in the level of liver proteins
Uncommon side effects
(affects 1 to 10 users in 1,000)
-
high blood sugar
-
convulsion
-
abnormal muscle movements: a collection of symptoms known as extrapyramidal symptoms
(EPS) which may include one or more of the following: abnormal movements of muscles,
tongue, or jaw, slow or sustained muscle contractions, muscle spasms, tremor (shaking),
abnormal movements of the eyes, involuntary muscle contractions, slow movements, or
restlessness
-
speech problems
-
abnormal slow heartbeat
-
middle heart block
-
abnormal electrocardiogram (prolongation of the QT interval)
-
low blood pressure upon standing
-
low blood pressure
-
tingling of the tongue or in the mouth
-
swollen or painful tongue
-
difficulty in swallowing
-
sexual dysfunction
-
lack of regular menstrual periods
Rare side effects
(affects 1 to 10 users in 10,000)
-
changes in the levels of white blood cells
-
neuroleptic malignant syndrome (confusion, reduced or loss of consciousness, high fever, and
severe muscle stiffness)
-
difficulties in focusing with the eyes
-
blood clots in blood vessels to the lungs causing chest pain and difficulty in breathing
-
male breast enlargement
-
leakage of milk or fluid from the breast
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE SYCREST
36
-
restlessness
-
fainting episode
-
muscle disease presenting as unexplained aches and pains
Keep out of the reach and sight of children.
Do not use Sycrest after the expiry date which is stated on the blister and on the carton. The expiry
date refers to the last day of that month.
Store in the original package in order to protect from light and moisture.
This medicinal product does not require any special temperature storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Sycrest contains
–
The active substance is asenapine. Each Sycrest tablet contains either 5 mg or 10 mg of the
active substance. The exact amount is shown on your Sycrest tablet pack.
–
The other ingredients are gelatin and mannitol (E421).
What Sycrest looks like and contents of the pack
The 5 mg sublingual tablets are round white to off-white tablets marked with “5” on one side.
The 10 mg sublingual tablets are round white to off-white tablets marked with “10” on one side.
The sublingual tablets are provided in peelable blisters containing 10 tablets each. Packs may contain
20, 60 or 100 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
N.V. Organon
Kloosterstraat 6
NL-5349 AB Oss
The Netherlands
Manufacturer
Organon (Ireland) Ltd.
Drynam Road, Swords
Co. Dublin, Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Lundbeck S.A.
Avenue Molière 225/Molierelaan 225
B-1050 Bruxelles/Brussel
Tél/Tel: +32 2 340 2828
Luxembourg/Luxemburg
Lundbeck S.A.
Avenue Molière 225/Molierelaan 225
B-1050 Bruxelles/Brussel
Tél/Tel: +32 2 340 2828
България
Lundbeck Export A/S Representative Office
EXPO 2000
Vaptzarov Blvd. 55
Sofia 1407
Teл.: +359 2962 4696
Magyarország
Lundbeck Hungária Kft.
Montevideo utca 3/b
H-1037 Budapest
Tel.: +36 1 436 9980
37
Česká republika
Lundbeck Česká republika s.r.o.
Bozděchova 7
CZ-150 00 Praha 5
Tel: +420 225 275 600
Malta
Charles di Girogio Ltd
Triq il-Kanonku Kamenu Pirrota
MT-1114 B’Kara BKR
Tel: +356 25600500
Danmark
Lundbeck Pharma A/S
Dalbergstrøget 5
DL-2630 Taastrup
Tel: + 45 4371 4270
Nederland
Lundbeck B.V.
Plaza Arena, Jupiter Gebouw
Herikerbergweg 100
NL-1101 CM Amsterdam
Tel: +31 20 697 1901
Deutschland
Lundbeck GmbH
Karnapp 25
D-21079 Hamburg
Tel: +49 40 23649 0
Norge
H. Lundbeck AS
Strandveien 15 B
N-1366 Lysaker
Tlf: + 47 91 300 800
Eesti
Lundbeck Eesti A/S
Weizenbergi 29
EE-10150 Tallinn
Tel: + 372 605 9350
Österreich
Dresdner Strasse 82
A-1200 Vienna
Tel: + 43 1 331 070
Ελλάδα
Lundbeck Hellas S.A.
64, Kifisias Avenue
GR-151 25 Marousi, Athens
Τηλ: + 30 210 610 5036
Polska
Lundbeck Poland Sp. z o. o.
ul. Krzywickiego 34
PL-02-078 Warszawa
Tel.: + 48 22 626 9300
España
Lundbeck España S.A.
Av. Diagonal, 605, 9°-1ª
E-08028 Barcelona
Tel: +34 93 494 9620
Portugal
Lundbeck Portugal Lda
Quinta da Fonte
Edifício D. João I – Piso 0 Ala A
P-2770-203 Paço d’Arcos
Tel: +351 21 00 45 900
France
Lundbeck SAS
37-45, quai du Président Roosevelt
F-92445 Issy-les-Moulineaux Cedex
Tél: + 33 1 79 41 29 00
România
Lundbeck România
Str. Ghiocei no.7A, Sector 2
RO-020571 Bucureşti
Tel: +40 21319 88 26
Ireland
Lundbeck (Ireland) Ltd
7 Riverwalk
Citywest Business Campus
IRL - Dublin 24
Tel: +353 1 468 9800
Slovenija
Lundbeck Pharma d.o.o.
Titova cesta 8
SI-2000 Maribor
Tel.: +386 2 229 4500
Ísland
Lundbeck Export útibú á Íslandi
Ármúla 1
IS-270 Reykjavík
Sími: + 354 414 7070
Slovenská republika
Lundbeck Slovensko s.r.o.
Zvolenská 19
SK-821 09 Bratislava 2
Tel: +421 2 5341 4218
38
Italia
Lundbeck Italia S.p.A.
Via G. Fara 35
I-20124 Milan
Tel: +39 02 677 4171
Suomi/Finland
Oy H. Lundbeck Ab
Itäinen Pitkäkatu 4
/ Österlånggatan 4
FIN-20520 Turku
/Åbo
Puh/Tel: + 358 2 276 5000
Κύπρος
Lundbeck Hellas A.E
Θεµ. ∆έρβη-Φλωρίνης
STADYL BUILDING
CY-1066 Λευκωσία
Τηλ.: + 357 22490305
Sverige
H. Lundbeck AB
Box 23
S-250 53 Helsingborg
Tel: + 46 42 25 43 00
Latvija
SIA Lundbeck Latvia
Kleistu iela 24
Rīga, LV 1067
Tel: + 371 6 7 067 884
United Kingdom
Lundbeck Limited
Lundbeck House
Caldecotte Lake Business Park
Caldecotte
Milton Keynes MK7 8LG - UK
Tel: +44 1908 649 966
Lietuva
UAB Lundbeck Lietuva
L. Stuokos-Guceviciaus 9-3
LT 01122 Vilnius
Tel: + 370 5 231 4188
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
39
Source: European Medicines Agency
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