1. Name Of The Medicinal Product
INVEGA® 1.5 mg prolonged-release tablets
INVEGA®
INVEGA®
INVEGA®
INVEGA®
2. Qualitative And Quantitative Composition
Each prolonged-release tablet contains 1.5 mg of paliperidone.
Each prolonged-release tablet contains 3 mg of paliperidone.
Each prolonged-release tablet contains 6 mg of paliperidone.
Each prolonged-release tablet contains 9 mg of paliperidone.
Each prolonged-release tablet contains 12 mg of paliperidone.
FOR THE 3 mg TABLET:
Excipient: Each tablet contains 13.2 mg lactose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Prolonged-release tablet
1.5 mg: Trilayer capsule-shaped orange brown tablets printed with “PAL 1.5”
3 mg: Trilayer capsule-shaped white tablets printed with “PAL 3”
6 mg: Trilayer capsule-shaped beige tablets printed with “PAL 6”
9 mg: Trilayer capsule-shaped pink tablets printed with “PAL 9”
12 mg:Trilayer capsule-shaped dark-yellow tablets printed with “PAL 12”.
4. Clinical Particulars
4.1 Therapeutic Indications
INVEGA is indicated for the treatment of schizophrenia.
INVEGA is indicated for the treatment of psychotic or manic symptoms of schizoaffective disorder. Effect on depressive symptoms has not been demonstrated.
4.2 Posology And Method Of Administration
Adults
INVEGA is for oral administration. The administration of INVEGA should be standardised in relation to food intake (see section 5.2). The patient should be instructed to always take INVEGA in the fasting state or always take it together with breakfast and not to alternate between administration in the fasting state or in the fed state.
Schizophrenia
The recommended dose of INVEGA for the treatment of schizophrenia is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
Schizoaffective disorder
The recommended dose of INVEGA for the treatment of schizoaffective disorder is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses within the recommended range of 6 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 4 days. Maintenance of effect has not been studied.
INVEGA must be swallowed whole with liquid, and must not be chewed, divided, or crushed. The active substance is contained within a non absorbable shell designed to release the active substance at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.
Patients with renal impairment
For patients with mild renal impairment (creatinine clearance
For patients with moderate to severe renal impairment (creatinine clearance
Elderly
Dosing recommendations for elderly patients with normal renal function (
Paediatric population
Schizophrenia and schizoaffective disorders: There is no relevant use of INVEGA in children aged less than 12 years. The safety and efficacy of INVEGA in children aged 12 to 18 years has not been established: no data are available.
Other special populations
No dose adjustment for INVEGA is recommended based on gender, race, or smoking status. (For pregnant women and breast-feeding mothers, see section 4.6)
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from INVEGA to other antipsychotic medicinal products. Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.
4.3 Contraindications
Hypersensitivity to the active substance, risperidone, or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Patients with schizoaffective disorder treated with paliperidone should be carefully monitored for a potential switch from manic to depressive symptoms.
QT interval
Caution should be exercised when INVEGA is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines thought to prolong the QT interval.
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 paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotics, including INVEGA, should be discontinued.
Tardive dyskinesia
Medicines 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. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including INVEGA, should be considered.
Hyperglycemia
Rare cases of glucose related adverse reactions, e.g., increase in blood glucose, have been reported in clinical trials with INVEGA. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
Orthostatic hypotension
Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.
Based on pooled data from the three, placebo-controlled, 6-week, fixed-dose trials with INVEGA (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA compared with 0.8% of subjects treated with placebo. INVEGA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia).
Seizures
INVEGA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Potential for gastrointestinal obstruction
Because the INVEGA tablet is non-deformable and does not appreciably change shape in the gastrointestinal tract, INVEGA should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines in non-deformable controlled-release formulations. Due to the controlled-release design of the dosage form, INVEGA should only be used in patients who are able to swallow the tablet whole.
Conditions with decreased gastro-intestinal transit time
Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe diarrhoea, may result in a reduced absorption of paliperidone.
Renal impairment
The plasma concentrations of paliperidone are increased in patients with renal impairment and, therefore, dosage adjustment may be required in some patients (see section 4.2 and 5.2). No data are available in patients with a creatinine clearance below 10 ml/min. Paliperidone should not be used in patients with creatinine clearance below 10 ml/min.
Hepatic impairment
No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.
Elderly patients with dementia
INVEGA has not been studied in elderly patients with dementia. The experience from risperidone is considered valid also for paliperidone.
Overall mortality
In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.
Cerebrovascular adverse reactions
An approximately 3-fold increased risk of cerebrovascular adverse reactions have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known. INVEGA should be used with caution in elderly patients with dementia who have risk factors for stroke.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks versus the benefits when prescribing INVEGA 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.
Priapism
Antipsychotic medicinal products (including risperidone) with α-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance priapism has also been reported with paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 3-4 hours.
Body temperature regulation
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing INVEGA to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Venous Thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with INVEGA and preventive measures undertaken.
Antiemetic effect
An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.
Lactose content (pertains only to the 3 mg tablets)
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Caution is advised when prescribing INVEGA with medicines known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine).
Potential for INVEGA to affect other medicines
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicines that are metabolised by cytochrome P-450 isozymes. In vitro studies indicate that paliperidone is not an inducer of CYP1A2 activity.
Given the primary CNS effects of paliperidone (see section 4.8), INVEGA should be used with caution in combination with other centrally acting medicines, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.
Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.
Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential, e.g., other antipsychotics, tricyclics.
Caution is advised if paliperidone is combined with other medicines known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, clozapine, tricyclics or SSRIs, tramadol, mefloquine, etc.).
No interaction study between INVEGA and lithium has been performed, however, a pharmacokinetic interaction is unlikely to occur.
Co-administration of INVEGA 12 mg once daily with divalproex sodium prolonged-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate. Co-administration of INVEGA with divalproex sodium prolonged-release tablets increased the exposure to paliperidone (see below).
Potential for other medicines to affect INVEGA
In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of INVEGA with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone. In vitro studies have shown that paliperidone is a P-glycoprotein (P-gp) substrate.
Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of INVEGA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if necessary. It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer the effect wears off over a similar time period. Other medicinal products or herbals which are inducers, e.g. rifampicin and St John´s wort (Hypericum perforatum) may have similar effects on paliperidone.
Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone, e.g., metoclopramide.
Co-administration of a single dose of INVEGA 12 mg with divalproex sodium prolonged-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for INVEGA should be considered when INVEGA is co-administered with valproate after clinical assessment.
Concomitant use of INVEGA with risperidone
Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.
4.6 Pregnancy And Lactation
There are no adequate data from the use of paliperidone during pregnancy. Paliperidone was not teratogenic in animal studies, but other types of reproductive toxicity were observed (see section 5.3). Neonates exposed to antipsychotics (including paliperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. INVEGA should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.
Paliperidone is excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if therapeutic doses are administered to breast-feeding women. INVEGA should not be used while breast feeding.
4.7 Effects On Ability To Drive And Use Machines
Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to INVEGA is known.
4.8 Undesirable Effects
The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were headache, akathisia, somnolence, dizziness, sedation, tremor, nausea, agitation, constipation, dyspepsia, tachycardia, extrapyramidal disorder, hypertonia, dry mouth, vomiting, weight increased, sinus tachycardia, dystonia, nasopharyngitis, and fatigue.
The ADRs that appeared to be dose-related included weight increased, dyskinesia, extrapyramidal disorder, hypertonia, parkinsonism, tachycardia, salivary hypersecretion, vomiting, dystonia, headache, breast discharge, gynaecomastia, bradycardia, constipation, dyspepsia, stomach discomfort, asthenia, nasopharyngitis, rhinitis, upper respiratory tract infection, back pain, muscle twitching, myalgia, akathisia, bradykinesia, dysarthria, dystonia, somnolence, restlessness, sleep disorder, breast engorgement, breast pain, galactorrhoea, cough, pharyngolaryngeal pain, and orthostatic hypotension.
The following are all ADRs that were reported in clinical trials and postmarketing. The following terms and frequencies are applied: very common (common (uncommon (rare (very rare (< 1/10,000), and not known (cannot be estimated from the available clinical trial data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The data described in this section are derived from the following clinical trial databases in subjects with schizophrenia, schizoaffective disorder, and bipolar disorder:
- 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily.
- 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the other study, 214 subjects received flexible doses of INVEGA (3 mg to 12 mg once daily). Both studies included subjects who received INVEGA either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.
- three double-blind placebo-controlled studies in subjects with bipolar disorder. In these three studies, a total of 1257 subjects were evaluable for safety, of which a total of 739 subjects were treated with INVEGA.
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a Hyperprolactinaemia can in some cases lead to gynaecomastia, menstual disturbances, amenorrhoea, and galactorrhoea.
b Extrapyramidal disorder may occur: Parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, muscle spasms, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor (includes tremor and parkinsonian rest tremor). It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.
In the schizoaffective disorder studies, a greater proportion of subjects in the total INVEGA dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with INVEGA monotherapy.
Elderly
In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen in non-elderly subjects. INVEGA has not been studied in elderly patients with dementia. In clinical trials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidents have been reported (see section 4.4).
Events of particular interest to the class
Extrapyramidal Symptoms (EPS). In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6 mg doses of INVEGA. Dose dependence for EPS was seen with the two higher doses of INVEGA (9 and 12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher rate than placebo in all dose groups without a clear relationship to dose. EPS included a pooled analysis of the following terms: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor.
Weight Gain. In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of
In schizoaffective disorder clinical trials, a higher percentage of INVEGA-treated subjects (5%) had an increase in body weight of
Laboratory Tests: Serum Prolactin. In schizophrenia clinical trials, increases in serum prolactin were observed with INVEGA in 67% of subjects. Adverse events that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, gynaecomastia) were reported overall in 2% of subjects. Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of treatment, but remained above baseline levels at study endpoint.
Class effects
QT prolongation, ventricular arrythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown.
Paliperidone is the active metabolite of risperidone. The safety profile of risperidone may be pertinent.
4.9 Overdose
In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in association with overdose. In the case of acute overdosage, the possibility of multiple medicinal product involvement should be considered.
Consideration should be given to the prolonged-release nature of the product when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacologic group: Psycholeptics, other antipsychotics ATC code: N05AX13
INVEGA contains a racemic mixture of (+)- and (-)-paliperidone.
Mechanism of Action
Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alfa1-adrenergic receptors and blocks, to a lesser extent, H1-histaminergic and alfa2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.
Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions to a lesser extent than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.
Pharmacodynamic Effects
Clinical Efficacy
Schizophrenia
The efficacy of INVEGA in the treatment of schizophrenia was established in three multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA doses, which varied across the three studies, ranged from 3 to 15 mg once daily. The primary efficacy endpoint was defined as a decrease in total Positive and Negative Syndrome Scale (PANSS) scores as shown in the following table. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. All tested doses of INVEGA separated from placebo on day 4 (p<0.05). Predefined secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression – Severity (CGI-S) scale. In all three studies, INVEGA was superior to placebo on PSP and CGI-S. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score
Schizophrenia Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End Point- LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set
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Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the PANSS was used. A 15 mg dose was also included in Study R076477-SCH-305, but results are not presented since this is above the maximum recommended daily dose of 12 mg.
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