Active ingredients: Asenapine (asenapine maleate)
Sycrest 5 mg sublingual tablets
Sycrest 10 mg sublingual tablets
Why is Sycrest used? What is it for?
Sycrest contains the active substance asenapine. This medicine belongs to a group of medicines called antipsychotics. Sycrest is used for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Antipsychotic medicines affect the chemicals that allow nerve cells (neurotransmitters) to communicate. Diseases affecting the brain, such as bipolar I disorder, can be due to an imbalance of certain chemicals in the brain, such as dopamine and serotonin, which can cause some of the symptoms you suffer from. The precise mechanism of how this medicine works is unknown, however it is believed to regulate the balance of these chemicals.
Manic episodes associated with bipolar I disorder represent a condition with symptoms such as "feeling high", having an "excessive amount of energy, needing less sleep than usual, speaking very quickly with flight of ideas and sometimes irritability. serious.
Contraindications When Sycrest should not be used
Do not take Sycrest
If you are allergic to asenapine or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Sycrest
Talk to your doctor, pharmacist or nurse before taking Sycrest.
Sycrest has not been studied in elderly patients with dementia. However, elderly patients with dementia who are treated with other similar types of medicines may be at an increased risk of developing stroke or death.
Sycrest is not approved for the treatment of elderly patients with dementia and is not recommended for use in this particular patient group. Sycrest can cause low blood pressure. In the early stages of treatment, some people may faint, especially when taking the position. standing upright after lying down or sitting up. This usually goes away on its own, if not, tell your doctor. Your dose may need to be adjusted.
Tell your doctor right away if they occur
- involuntary rhythmic movements of the tongue, mouth and face. Sycrest may need to be stopped.
- fever, severe muscle stiffness, sweating or a reduced level of consciousness (a disorder called 'neuroleptic malignant syndrome'). Immediate medical treatment may be required.
Check with your doctor or pharmacist before taking Sycrest:
- if you have ever been diagnosed with a condition whose symptoms include high temperature and muscle stiffness (also known as neuroleptic malignant syndrome)
- if you have ever had abnormal movements of the tongue or face (tardive dyskinesia). You should be aware that both of these conditions can be caused by this type of medicine.
- if you have heart disease or are being treated for heart disease which predisposes you to low blood pressure
- if you are diabetic or predisposed to diabetes
- if you have Parkinson's disease or dementia
- if you have epilepsy (fits)
- if you have difficulty swallowing (dysphagia)
- if you have severe liver problems. In this case, do not take Sycrest
- if you have difficulty keeping your core body temperature under control
- if you have suicidal thoughts
- if you have elevated levels of prolactin in the blood (hyperprolactinaemia)
Be sure to tell your doctor if any of these apply to you, as they may prefer to adjust your dose or monitor you for a while. Contact your doctor immediately if any of these conditions develop or worsen while using Sycrest.
Children and adolescents
Sycrest is not recommended for use in patients under 18 years of age.
Interactions Which drugs or foods may change the effect of Sycrest
Other medicines and Sycrest
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Some medicines can reduce or increase 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 and fluoxetine), as the dose of Sycrest or the antidepressant medicine may need to be adjusted.
You should tell your doctor if you are taking medicines for Parkinson's disease (such as levodopa), as this medicine may make them less effective.
Since Sycrest acts primarily on the brain, there may be interference from other medicines (or alcohol) that act on the brain, due to an additional effect on brain function.
Since Sycrest can lower blood pressure, care should be taken when taking Sycrest with other medicines that lower blood pressure.
Sycrest with food, drink and alcohol
Do not drink or eat for 10 minutes after taking this medicine. You should avoid drinking alcohol while taking this medicine.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant or are planning to become pregnant, ask your doctor or pharmacist for advice before using this medicine.
Do not take Sycrest if you are pregnant unless your doctor tells you to. If you are taking this medicine and become pregnant or plan to become pregnant, ask your doctor as soon as possible if you can continue taking Sycrest.
The following symptoms may occur in newborn babies of mothers who have used Sycrest in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in feeding. you have any of these symptoms you may need to contact your doctor.
Do not breastfeed when taking Sycrest.
Driving and using machines
Sycrest can cause drowsiness or sedation. Therefore, make sure your concentration and attention are not affected before driving vehicles or using machines.
Dose, Method and Time of Administration How to use Sycrest: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is one 5 mg or 10 mg sublingual tablet twice a day. One dose should be taken in the morning and one dose should be taken in the evening.
Instructions for Use
Sycrest is for sublingual use.
Sycrest is not recommended if you are unable to take the tablet as described below. If you are unable to take this medicine as described below, the treatment may not be effective for you.
- Do not remove the sublingual tablet from the blister until you are ready to take it.
- When touching the tablet, your hands should be dry.
- Do not push the tablet through the blister. Do not cut or tear the blister.
- Detach 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 has completely dissolved (figure 3). The tablet will dissolve with saliva within seconds.
- Do not swallow or chew the tablet.
- Do not drink or eat for 10 minutes after taking the tablet.
Overdose What to do if you have taken too much Sycrest
If you take more Sycrest than you should
If you take too much Sycrest, contact a doctor immediately. Take the medicine pack with you. In case of an overdose you may feel sleepy or tired, or have abnormal body movements, problems 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 a dose, just take the next dose as usual. If you miss two or more doses, contact your doctor or pharmacist.
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 to, as your symptoms may return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Sycrest
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects have been reported with this medicine. Contact your doctor immediately if you experience any of the following symptoms:
- allergic reactions (these usually include a mix of effects such as difficulty in breathing or swallowing, swelling of the face, lips, tongue or throat, rash, itching and increased heart rate)
- sudden rise in body temperature, with sweating, fast heart rate, severe muscle stiffness, confusion and blood pressure fluctuations which can lead to coma
- convulsions, fits or seizures
- fainting
Tell your doctor immediately if you have:
- signs of increased blood sugar levels such as excessive thirst, hunger or excessive urination, weakness or worsening of diabetes
- worm-like movements of the tongue or other uncontrolled movements of the tongue, mouth, cheeks, or jaw that can spread to the arms and legs
Other side effects reported with this medicine include:
Very common side effects (may affect more than 1 in 10 people)
- anxiety
- numbness
Common side effects (may affect up to 1 in 10 people)
- weight gain
- increased appetite
- slow or sustained muscle contractions
- restlessness
- involuntary muscle contractions
- slow movements, tremor
- sedation
- dizziness
- nausea
- change in taste
- feeling of numbness in the tongue or mouth
- increased salivation (loss of saliva)
- muscle stiffness
- fatigue
- increased level of liver enzymes
Uncommon side effects (may affect up to 1 in 100 people)
- abnormal muscle movements: a set of symptoms known as extrapyramidal symptoms (EPS) which may include one or more of the following symptoms: abnormal movements of the muscles, tongue or jaw, slow or sustained muscle contractions, muscle spasms, tremor (shaking), abnormal eye movements, involuntary muscle twitching, slow movements, or restlessness
- uncomfortable sensations in the legs (also called restless legs syndrome)
- speech problems
- abnormal, slow or fast heartbeat
- branch heart block
- abnormal electrocardiogram (QT prolongation)
- low blood pressure when standing
- low blood pressure
- tingling of the tongue or in the mouth
- swollen or painful tongue
- difficulty swallowing
- ulcers, soreness, redness, swelling and blisters inside the mouth
- sexual dysfunction
- lack of regular menstrual cycles
Rare side effects (may affect up to 1 in 1,000 people)
- changes in white blood cell levels
- difficulty focusing with eyesight
- blood clots in the blood vessels to the lungs causing chest pain and difficulty in breathing
- muscle disorders presenting as unexplained continuous aches and sharp pains
- increase in the size of the male breast
- loss of milk or fluid from the breast
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton. The expiry date refers to the last day of the month.
Store this medicine in the original package in order to protect the medicine from light and moisture.
This medicinal product does not require any special storage temperatures.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Sycrest contains
- The active ingredient is asenapine.
- Each Sycrest 5 mg sublingual tablet contains 5 mg of asenapine.
- Each Sycrest 10 mg sublingual tablet contains 10 mg of asenapine.
- The exact contents are indicated on the packaging of Sycrest tablets.
- The other ingredients are gelatin and mannitol (E421).
Sycrest looks like and contents of the pack
The 5 mg sublingual tablets are round, white to off-white, marked "5" on one side.
The 10 mg sublingual tablets are round, white to off-white, marked "10" on one side.
The sublingual tablets are supplied in peelable foil blisters each containing 10 tablets. The packs contain 20, 60 or 100 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SYCREST 10 MG SUBLINGUAL TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sublingual tablet contains 10 mg of asenapine (as maleate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Sublingual tablet.
White to off-white, round, sublingual tablets, debossed with "10" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults.
04.2 Posology and method of administration
Dosage
Manic episode
The recommended starting dose of Sycrest is 10 mg twice daily, as monotherapy. 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 only after clinical evaluation. For combination therapy, a starting dose of 5 mg twice daily is recommended. Based on the clinical response and tolerability of the individual patient, the dose may be increased to 10 mg twice daily.
Learn more about special patient populations
Pediatric population
The safety and efficacy of Sycrest in children below 18 years of age have not been established. Limited safety data are available with the use of Sycrest in adolescent patients. A pharmacokinetic study was performed in adolescent patients. Currently available data are described in section 5.2 but do not allow for any recommendation on a posology.
Elderly patients
Sycrest should be used with caution in the elderly. Limited efficacy data are available in patients 65 years of age and older. Available pharmacokinetic data are described in section 5.2.
Patients with renal impairment
No dosage adjustment is required for patients with renal impairment.There is no experience with asenapine in patients with severe renal impairment with creatinine clearance below 15 ml / min.
Patients with hepatic impairment
No dosage adjustment is required for patients with mild hepatic impairment. The possibility of elevated plasma levels of asenapine cannot be excluded in some patients with moderate hepatic impairment (Child-Pugh Class B) and caution is advised. In subjects with severe hepatic impairment (Child-Pugh Class C), a 7-fold increase in asenapine exposure was observed. Therefore, 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. When touching the tablet, your hands should be dry. The tablet should not be pushed through the package. The package should not be cut or torn. Pull the tab. remove the colored tablet gently.The tablet must not be crushed.
To ensure optimal absorption, Sycrest sublingual tablet should be placed under the tongue so that it dissolves completely. The tablet will dissolve with saliva within seconds. Sycrest sublingual tablets should not be chewed or swallowed. Avoid drinking and eating for 10 minutes after administration.
When used in combination with other medicines, Sycrest should be taken last.
Sycrest treatment is not recommended in patients unable to comply with this method of administration, as the bioavailability of asenapine when ingested is low (
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Elderly patients with psychosis associated with dementia
Elderly patients with psychosis associated with dementia who are treated with antipsychotic drugs are at increased risk of dying.
Sycrest is not approved for the treatment of patients with dementia-associated psychosis and is not recommended for use in this particular patient group.
Neuroleptic malignant syndrome
The onset of Neuroleptic Malignant Syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic instability, altered state of consciousness and elevated levels of serum creatine phosphokinase, has been reported with the administration of antipsychotic drugs, including asenapine. clinical reports, myoglobinuria (rhabdomyolysis) and acute renal failure are reported.
If a patient develops signs and symptoms suggestive of NMS, Sycrest administration should be discontinued.
Convulsions
In clinical studies, cases of convulsions have been reported from time to time during treatment with asenapine. Therefore, in patients with a history of seizure disorder or other conditions associated with seizures, Sycrest should be used with caution.
Suicide
The possibility of a suicide attempt is part of psychotic pathology and bipolar disorder. Therefore, careful monitoring of high-risk patients is required during treatment.
Orthostatic hypotension
Asenapine may induce orthostatic hypotension and syncope, especially at the start of treatment, possibly due to its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for orthostatic hypotension (see section 4.8). In clinical studies, cases of syncope have occasionally been reported during treatment with Sycrest. Sycrest should be administered with caution in elderly patients and in patients with known cardiovascular disease (eg, heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disorders, or conditions that predispose the patient to hypotension (eg, dehydration and hypovolemia).
Tardive dyskinesia
Medicinal products with anti-dopaminergic properties have been associated with the "induction of tardive dyskinesia, characterized by rhythmic involuntary movements, predominantly of the tongue and / or face. In clinical trials, cases of tardive dyskinesia have occasionally been reported during treatment with asenapine. L" Onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. Should signs and symptoms of tardive dyskinesia occur in a patient treated with Sycrest, the possibility of discontinuing treatment should be considered.
Hyperprolactinemia
Increases in prolactin levels have been observed in some patients taking Sycrest. In clinical studies, few adverse reactions related to the abnormal prolactin levels reported were observed.
QT interval
Clinically relevant prolongation of the QT interval does not appear to be associated with asenapine. Caution should be exercised when prescribing Sycrest to patients with known cardiovascular disease or a family history of QT interval prolongation and in combination with other medicinal products that are thought to prolong. the QT interval.
Hyperglycemia and diabetes mellitus
Hyperglycaemia or exacerbation of pre-existing diabetes has occasionally been reported during treatment with asenapine. Evaluation of the relationship between the use of atypical antipsychotics and abnormal glucose values is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia or bipolar disorder and by the "increased incidence of diabetes mellitus in the population. General It is recommended that diabetic patients and those with risk factors for developing diabetes mellitus be placed under adequate clinical monitoring.
Dysphagia
Dysmotility and esophageal aspiration have been associated with antipsychotic treatment. A few cases of dysphagia have been reported sporadically in patients treated with Sycrest.
Body thermoregulation
The alteration of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Clinical studies concluded that clinically relevant changes in body temperature do not appear to be associated with the use of asenapine. Special care is advised when prescribing Sycrest to patients who may be exposed to conditions that may contribute to an increase in body temperature. for example intense physical exercise, exposure to extreme heat, concomitant therapy with anticholinergic drugs or in patients prone to dehydration.
Patients with severe hepatic impairment
Exposure to asenapine was increased 7-fold in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Sycrest is not recommended in these patients.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks and benefits of prescribing antipsychotic drugs, including Sycrest, to patients with Parkinson's disease or dementia with Lewy bodies (DLB), as both groups may be at increased risk for Neuroleptic Malignant Syndrome, as well as having increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, dullness, postural instability with frequent falls, in addition to extrapyramidal symptoms.
04.5 Interactions with other medicinal products and other forms of interaction
Based on the primary central nervous system (CNS) effects of asenapine (see section 4.8), the medicinal product should be administered with caution in combination with other centrally acting medicinal products. Patients should be advised not to consume alcohol while being treated with Sycrest.
Potential for other medicines to affect Sycrest
Asenapine is eliminated primarily by direct glucuronidation of UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (mainly CYP1A2). The potential effects of inhibitors and an activator of several of these enzyme cycles on the pharmacokinetics of asenapine were investigated, specifically , fluvoxamine (CYP1A2 inhibitor), paroxetine (CYP2D6 inhibitor), imipramine (CYP1A2 / 2C19 / 3A4 inhibitor), cimetidine (CYP3A4 / 2D6 / 1A2 inhibitor), carbamazepine (CYP3A4 / 1A2 inhibitor), "UGT). With the exception of fluvoxamine, none of the interacting medicinal products resulted in clinically relevant alterations in the pharmacokinetics of asenapine.
During concomitant administration with a single 5 mg dose of asenapine, 25 mg fluvoxamine twice daily resulted in a 29% increase in asenapine AUC. The full therapeutic dose of fluvoxamine is suspected to produce a greater increase in concentrations. Concomitant administration of asenapine and fluvoxamine should therefore be undertaken with caution.
Potential for Sycrest to affect other medicines
Due to its α1-adrenergic antagonism with the potential to induce orthostatic hypotension (see section 4.4), Sycrest may potentiate the effects of some antihypertensive agents.
Asenapine may antagonize the effect of levodopa and dopamine agonists. If this combination is deemed necessary, the lowest effective dose of each treatment should be prescribed.
Studies in vitro indicate that asenapine weakly inhibits CYP2D6. Clinical drug interaction studies on the effects of CYP2D6 inhibition by asenapine showed the following results:
- After concomitant administration of dextromethorphan and asenapine in healthy subjects, the dextrorphan / dextromethorphan ratio (DX / DM) was measured as a marker of CYP2D6 activity. Indicative of a CYP2D6 inhibition, treatment with a dose of asenapine from 5 mg twice daily generated a fractional drop in the DX / DM ratio, down to 0.43. In the same study, treatment with a 20 mg dose of paroxetine per day reduced the DX / DM ratio to 0.032.
- In a separate study, concomitant 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 substrate of CYP2D6).
- Concomitant administration of a single 20 mg dose of paroxetine (a substrate and inhibitor of CYP2D6) during treatment with a 5 mg twice daily dose of asenapine in 15 healthy male subjects resulted in an almost double increase of exposure to paroxetine.
Asenapine in vivo appears to be at best a weak inhibitor of CYP2D6. However, asenapine may enhance the inhibitory effects of paroxetine on its metabolism.
Sycrest should therefore be administered with caution in combination with other medicinal products which are both substrates and inhibitors of CYP2D6.
To ensure optimal absorption, avoid drinking and eating for 10 minutes following administration.
04.6 Pregnancy and lactation
Pregnancy
There are insufficient data on the use of Sycrest in pregnant women. Asenapine did not show any teratogenic effects in animal studies. Animal studies have shown maternal and embryo toxicity (see section 5.3).
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 restlessness, hypertonia, hypotonia, tremor, somnolence, difficulty breathing, or feeding disturbances in neonates. Therefore, neonates should be monitored closely.
Sycrest should not be used in pregnancy unless strictly necessary and only if the potential benefit outweighs the potential risk to the fetus.
Feeding time
Asenapine was excreted in the milk of lactating rats. It is not known whether asenapine or its metabolites are excreted in human milk. Women taking Sycrest are recommended not to breastfeed.
Fertility
No impairment of fertility was observed in non-clinical studies (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. Asenapine may cause somnolence and sedation. Therefore, patients should be cautious about operating machines or driving vehicles until it is reasonably certain that treatment with Sycrest no longer has any negative effects.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse drug reactions during asenapine treatment were somnolence and anxiety.
Table of adverse reactions
The incidence of adverse drug reactions (ADRs) associated with asenapine treatment is shown in the table below. The table is based on adverse events 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,
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Therefore the frequency of these adverse events is defined as “not known”.
Description of selected adverse reactions
Extrapyramidal symptoms (SEP)
In clinical trials, the incidence of extrapyramidal symptoms in patients treated with asenapine was higher than in placebo (15.4% vs 11.0%).
From the short-term (6-week) studies in schizophrenia, there appears to be a dose-response relationship for akathisia in patients treated with asenapine and for parkinsonism there was a tendency to increase with higher doses.
Weight gain
In the associated short- and long-term clinical studies in schizophrenia and bipolar mania, the mean weight change for asenapine was 0.8 kg. The proportion of subjects with clinically significant weight gain (≥7% weight gain from baseline to assessment) in short-term schizophrenia clinical trials was 5.3% for asenapine versus 2.3% for placebo. The proportion of subjects with clinically significant weight gain (≥7% weight gain from baseline to assessment) in short-term bipolar mania clinical trials was 6.5% for asenapine versus 0.6% for placebo.
Orthostatic hypotension
The incidence of orthostatic hypotension in elderly subjects was 4.1% compared to 0.3% in the combined population of the phase 2/3 studies.
Liver enzymes
Transient and asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartate transferase (AST) have been observed commonly, particularly in early treatment.
Other results
Cerebrovascular events have been reported in patients treated with asenapine but there is no evidence of a higher than expected incidence in adults between 18 and 65 years of age.
Asenapine has anesthetic properties. Oral hypoesthesia and oral paraesthesia can occur directly after administration and usually resolves within 1 hour.
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with asenapine, including anaphylactic / anaphylactoid reactions, angioedema, swelling of the tongue and swelling of the throat (pharyngeal edema).
04.9 Overdose
Cases of overdose have been reported in the asenapine therapy program. The estimated doses reported ranged from 15 to 400 mg. In most cases it was unclear whether asenapine was taken sublingually. Drug-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 Sycrest overdose. There is no specific antidote to Sycrest. The possibility that multiple medicinal products have been taken should be considered.Cardiovascular monitoring should be performed for arrhythmias, and management of overdose should focus on supportive care, maintaining adequate airway oxygenation and ventilation, and managing symptoms. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and / or sympathomimetic agents (do not use epinephrine and dopamine, as beta-stimulations can worsen hypotension in a situation of Sycrest-induced alpha-adrenergic blockade). severe extra-pyramidal drugs, anticholinergic medicinal products should be administered.Continue close monitoring and clinical supervision until the patient is recovered.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: psycholeptics, antipsychotics.
ATC code: N05AH05.
Mechanism of action
As with other medicinal products effective for bipolar disorder, the mechanism of action of asenapine is not fully understood. However, based on the pharmacology of the receptors, the efficacy of asenapine is believed to be mediated by a "combination of" antagonist activity of D2 and 5-HT2A receptors. Actions at other receptors, such as, for example, 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 manic or mixed episode of bipolar I disorder as defined by DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) with or without psychotic manifestations was evaluated in two 3-week, randomized, double-blind, placebo- and active substance (olanzapine) monotherapy-controlled studies involving 488 and 489 patients, respectively. All patients met the diagnostic criteria for bipolar I disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), current manic episode (DSM-IV 296.4x), or mixed (DSM-IV) 296.6x) and had a questionnaire score ≥20 Young Mania Rating Scale (Y-MRS) allo screening and baseline. Rapid cycle patients were excluded from these studies. Asenapine demonstrated "superior efficacy to placebo in reducing manic symptoms over 3 weeks". Point estimates [95% CI] for change from baseline to "endpoint in the YMRS using the 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 registration studies were studied in a further 9-week extension of the study. In this study, maintenance of the effect during the episode was demonstrated after 12 weeks of treatment. randomized.
In a 12-week, placebo-controlled clinical study involving 326 patients with a manic or mixed episode of bipolar I disorder, with or without psychotic features, results partially non-responder to lithium or valproate alone for 2 weeks at therapeutic serum levels, the addition of asenapine as adjunct therapy was found to be superior in efficacy to lithium or valproate given alone at week 3 (point estimates [95% CI] for change from baseline all "endpoint in YMRS using the 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.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with asenapine in one or more subsets of the pediatric population in bipolar I disorder (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Absorption
Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations within 0.5 - 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Absolute bioavailability of asenapine when swallowed is poor (water several minutes (2 or 5) after administration of asenapine resulted in a reduction in asenapine exposure (19% and 10%, respectively). Therefore, drinking and eating should be avoided. within 10 minutes following administration (see section 4.2).
Distribution
Asenapine is rapidly distributed and has a large volume of distribution (approximately 1,700 l), which indicates extensive extravascular distribution. Asenapine is extensively bound to plasma proteins (95%), including albumin and α1-acid glycoprotein.
Biotransformation
Asenapine is extensively metabolised. Direct glucuronidation (mediated by UGT1A4) and oxidation via cytochrome P450 (mainly CYP1A2, with participation of 2D6 and 3 ° 4) and demethylation are the major metabolic pathways of asenapine. In one study in vivo conducted in humans, with radioactive isotope-labeled asenapine, the predominant drug-related entity in plasma was asenapine N + -glucuronide; others included N-dysmethylasenapine, N-dysmethylasenapine, N-carbamoyl glucuronide, and unmodified asenapine in small amounts. Sycrest's activity is mainly due to the parent compound.
Asenapine is a weak inhibitor of CYP2D6. Asenapine does not induce any induction of CYP1A2 or CYP3A4 activity in human hepatocyte cultures. Concomitant administration of asenapine with known inhibitors, activators or substrates of these metabolic pathways has been studied in numerous clinical drug-drug interaction studies (see section 4.5).
Elimination
Asenapine is a compound with clearance high, which after intravenous administration is 52 l / h. In a mass balance study, most of the radioactive dose was excreted in the urine (approximately 50%) and faeces (approximately 40%), with only a small amount excreted in the faeces (5-16%) as unchanged compound. After a rapid initial 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 (double increase) results in less linear (1.7-fold) increases in the extent of exposure and maximal concentration. The less than proportional increase in Cmax and AUC with administration of one dose may be attributed to limitations in the absorption capacity of the oral mucosa after sublingual administration.
During the administration of the double daily dosage, the steady-state it is obtained in 3 days. Overall, the pharmacokinetics of asenapine allo steady-state it is similar to that of the single dose.
Pharmacokinetic properties in special populations
Hepatic impairment
The pharmacokinetics of asenapine were similar between patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment and those with normal hepatic function. In subjects with severe hepatic impairment (Child-Pugh Class C), a 7-fold increase in asenapine exposure was observed (see section 4.2).
Renal impairment
The pharmacokinetics of asenapine following a single 5 mg dose were similar between patients with varying degrees of renal impairment and those with normal renal function.
There is no experience with asenapine in patients with severe renal impairment with creatinine clearance below 15 ml / min.
Senior citizens
In elderly patients (aged 65 to 85 years), exposure to asenapine is approximately 30% higher than in young adults.
Pediatric population (Adolescents)
At a daily dose of 5 mg twice daily, the pharmacokinetics of asenapine in adolescent patients (aged 12-17 years) are similar to that seen in adults. In adolescents, the 10 mg twice daily dose resulted in no increase in exposure compared to the 5 mg twice daily dose.
Sex
Population pharmacokinetic analysis indicated that there is no evidence of sex-related differences in the pharmacokinetics of asenapine.
Race
Population pharmacokinetic analysis indicated that no relevant clinical effects of race on the pharmacokinetics of asenapine were identified.
Smoke
A "population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, has no effect on clearance by asenapina. In a dedicated study, smoking during administration of a 5 mg sublingual dose had no effect on the pharmacokinetics of asenapine.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies on pharmacological safety. Repeated dose toxicity studies conducted in rats and dogs showed mainly dose-limiting pharmacological effects, such as sedation. In addition, prolactin-mediated effects on mammary glands and oestrus cycle disturbances were observed. In dogs, high doses administered orally resulted in hepatotoxicity, which was not observed after chronic intravenous administration. Asenapine has a certain affinity for melanin-containing tissues. However, how much has been tested in vitro, was found to be free from phototoxicity. Furthermore, histopathological examination of the eyes of dogs treated chronically with asenapine did not reveal any signs of ocular toxicity, demonstrating the absence of a phototoxic hazard. Asenapine showed no genotoxicity in a series of tests. In subcutaneous carcinogenicity studies conducted in rats and mice, no increase in the incidence of tumors was observed. Effects in non-clinical studies were observed only at exposures deemed sufficiently in excess of the maximum human exposure, indicating poor exposure. relevance to clinical use.
Asenapine did not impair fertility in rats and did not show any teratogenic effects in rats and rabbits. Embryotoxicity was found in rats and rabbits in reproductive toxicology studies. Asenapine caused mild maternal toxicity and mild retardation of fetal skeletal development. After oral administration to pregnant rabbits during the period of organogenesis, asenapine has negatively affected weight, with a high dose of 15 mg.kg-1 twice a day. At this dose, the animal's fetal weight decreased. When asenapine was administered intravenously to pregnant rabbits, no signs of embryotoxicity were observed. In rats, embryo-fetal toxicity (increased post-implantation loss, decreased fetal weight and delayed ossification) has been observed after oral or intravenous administration, during organogenesis or gestation. An increase in neonatal mortality was observed among the offspring of female rats treated during gestation and lactation. From a type study cross-fostering it was concluded that asenapine-induced peri- and postnatal deaths are caused by a deficiency of the infants rather than by the altered breastfeeding behavior of the mothers.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Jelly
Mannitol (E421)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect from light and moisture.
This medicinal product does not require any special storage temperatures.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / aluminum blister with removable foil in cartons of 20, 60 or 100 sublingual tablets per carton.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/640/004
040761049
EU / 1/10/640/005
040761052
EU / 1/10/640/006
040761064
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 1 September 2010
10.0 DATE OF REVISION OF THE TEXT
02/2013
