Invega 3 Mg/6 Mg/9 Mg/12 Mg Tablets

INVEGA (paliperidone) is indicated for the treatment of schizophrenia. INVEGA has not been studied in patients unresponsive to risperidone.

INVEGA (paliperidone) is indicated for the treatment of schizophrenia in adolescents 12 u2013 17 years of age.

INVEGA (paliperidone) is indicated for the treatment of schizoaffective disorder as monotherapy and in combination with antidepressants and/or mood stabilisers in adults. Efficacy beyond 6 weeks has not been demonstrated.

Schizophrenia

Adults (u2265 18 years of age)

The recommended dose of INVEGA 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.

Adolescents (12 u2013 17 years of age)

The recommended dose of INVEGA for the treatment of schizophrenia in adolescents 12 u2013 17 years of age is 3 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from a higher dose of 6 mg to 12 mg/day. Dose increases should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days.

Schizoaffective Disorder

Adults (u2265 18 years of age)

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 lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses. 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. There is no experience of treating schizoaffective disorder for more than 6 weeks.

Special populations

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 (see section 4.4).

Patients with renal impairment

For patients with mild renal impairment (creatinine clearance u2265 50 to < 80 m l /min), the recommended initial dose is 3 mg once daily. The dose may be increased to 6 mg once daily based on clinical response and tolerability.

For patients with moderate to severe renal impairment (creatinine clearance u2265 10 to < 50 m l /min), the recommended dose of INVEGA is 3 mg every other day which may then be increased to 3 mg once daily after clinical assessment. As INVEGA has not been studied in patients with creatinine clearance below 10 m l /min, use is not recommended in such patients (see section 4.4).

Elderly

Dosing recommendations for elderly patients with normal renal function (u2265 80 m l /min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments are required according to their renal function status (see u201cPatients with Renal impairmentu201d above). INVEGA should be used with caution in elderly patients with dementia with risk factors for stroke (see section 4.4).

Adolescents and children

Safety and effectiveness of INVEGA for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of INVEGA for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.

Switching to other antipsychotic medicinal products

There are no systematically collected data to specifically address switching patients from INVEGA to other antipsychotic medicinal products.

Method of administration

INVEGA is for oral administration and can be administered with or without food. The administration of INVEGA should be standardised in relation to food intake. 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 (see section 5.2). INVEGA must be swallowed whole with the aid of adequate amounts of liquids, 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.

Hypersensitivity to the active substance (paliperidone), risperidone, or to any of the excipients listed in section 6.1.

Severe renal impairment (CrCL < 10 m l /min) (see section 4.4)

Decreased gastro-intestinal transit time (see section 4.4)

Dementia or Parkinsonu2019s disease (see section 4.4)

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 a history of dysrhythmias, in patients with congenital long QT syndrome, and in concomitant use with medicines known 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 antipsychotics, including INVEGA. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, INVEGA should be discontinued.

Tardive Dyskinesia/extrapyramidal symptoms

Medicines with dopamine receptor antagonistic properties such as INVEGA 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 INVEGA, should be considered.

Extrapyramidal symptoms and psychostimulants

Caution is warranted in patients receiving both psychostimulants (e.g methylphenidate) and paliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see section 4.5)

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with INVEGA. Patients with an established diagnosis of diabetes mellitus who are started on INVEGA should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with INVEGA should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with INVEGA should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when INVEGA was discontinued: however, some patients required continuation of anti-diabetic treatment despite discontinuation of INVEGA.

Weight gain

Significant weight gain has been reported. Monitoring weight gain is advisable when INVEGA is being used. Patients may be advised to refrain from overeating in view of the possibility of weight gain.

Orthostatic hypotension

INVEGA (paliperidone) may induce orthostatic hypotension based on its alpha-blocking activity. Based on pooled data from 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 a patient to hypotension (e.g. dehydration, hypovolaemia and treatment with antihypertensive medications).

Seizures

INVEGA should be used cautiously in patients with a history of seizures or other conditions that 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 pre-existing gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines with a non-absorbable shell.

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 INVEGA (see section 4.3).

Renal impairment

The plasma concentrations of INVEGA are increased in patients with renal impairment. Dosage adjustment may be required (see section 4.2 and section 5.2). No data are available in patients with a creatinine clearance below 10 m l /min. INVEGA should not be used in patients with creatinine clearance below 10 m l /min.

Hepatic impairment

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if INVEGA is used in such patients.

Elderly

In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen in non-elderly subjects.

Elderly patients with Dementia

INVEGA has not been studied in elderly patients with dementia.

Overall Mortality

In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other antipsychotic medicines, 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 events (CAE)

In placebo-controlled trials in elderly patients with dementia, treated with some atypical antipsychotic medicines, including risperidone, aripiprazole and olanzapine, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities, compared to placebo. INVEGA should be used with caution in elderly patients with dementia who have risk factors for stroke.

Leukopenia, neutropenia, and agranulocytosis

Events of leukopenia, neutropenia and agranulocytosis have been reported with INVEGA. Agranulocytosis has been reported during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a medicine-induced leukopenia/neutropenia should be monitored during therapy and discontinuation of INVEGA should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with significant neutropenia (absolute neutrophil count < 1 X 10 9 /L) should discontinue INVEGA and have their WBC followed until recovery.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with INVEGA. 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.

Parkinsonu2019s disease and Dementia with Lewy bodies

INVEGA has not been studied in patients with Parkinsonu2019s Disease or Dementia with Lewy Bodies (DLB) (see section 4.3). These groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics such as INVEGA. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Medicines with alpha-adrenergic blocking effects, including INVEGA, have been reported to induce priapism. Priapism has been reported with INVEGA during post-marketing surveillance (See section 4.8: Post-marketing Data). Patients should be informed to seek urgent medical care in case priapism has not resolved within 3-4 hours.

Body temperature regulation

Disruption of the bodyu2019s ability to reduce core body temperature has been attributed to antipsychotic medicines. 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.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with INVEGA. This effect, although not demonstrated in humans may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reyeu2019s syndrome, and brain tumour.

Class effects

QT prolongation, ventricular dysrythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and Torsade de pointes may occur with antipsychotics including INVEGA.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including INVEGA. IFIS may increase the risk of eye complications during and after the operation. Current or past use of INVEGA should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping INVEGA prior to cataract surgery has not been established and must be weighed against the risk of stopping INVEGA therapy.

Paediatric population

The sedative effect of INVEGA should be closely monitored in this population. A change in the time of administration of INVEGA may improve the impact of sedation on the patient. Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation in adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects. During treatment with INVEGA regular examinations for extrapyramidal symptoms and other movement disorders should also be conducted.

For specific posology recommendations in paediatric population see section 4.2

Events of particular interest to the class

Laboratory Tests: Serum Prolactin

In clinical trials, median increases in serum prolactin were observed with INVEGA in 67 % of subjects. Potentially prolactin-related adverse events (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.

Lactose content (pertains only to the 3 mg INVEGA tablets)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take INVEGA.

Caution is advised when prescribing INVEGA with medicines known to prolong the QT interval, e.g. class IA antidysrhythmics (e.g., quinidine, disopyramide) and class III antidysrhythmics (e.g., amiodarone, sotalol), some antihistamines, some other antipsychotics and some antimalarials (e.g., mefloquine).

Potential for INVEGA to affect other medicines

INVEGA (paliperidone) is not expected to cause clinically important pharmacokinetic interactions with medicines that are metabolised by cytochrome P-450 isozymes. Formal interaction studies have not been performed.

INVEGA should be used with caution in combination with other centrally acting medicines e.g. anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.

INVEGA may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, 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 INVEGA is combined with other medicines known to lower the seizure threshold (i.e. phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Co-administration of INVEGA at steady-state (12 mg once daily) with divalproex sodium extended-release tablets (500 mg to 2 000 mg once daily) did not affect the steady-state pharmacokinetics of valproate. (See below for effect of divalproex sodium on INVEGA).

Potential for other medicines to affect INVEGA

In vitro studies indicate that CYP2D6 and CYP3A4 may be 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 INVEGA.

Medicinal products affecting gastrointestinal transit time may affect the absorption of INVEGA, e.g. metoclopramide.

Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37 % in the mean steady-state C max 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 drug 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 Johnu00b4s wort (Hypericum perforatum) may have similar effects on paliperidone.

Co-administration of a single dose of INVEGA 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50 % in the C max 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.

Concomitant use of INVEGA with psychostimulants

The combined use of psychostimulants (e.g methylphenidate) with paliperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Pregnancy

The safety of INVEGA for use during human pregnancy has not been established. A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. Paliperidone, the active metabolite of risperidone, was not specifically evaluated in this study. The risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was elevated compared to no antipsychotic exposure (relative risk=1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies.

Neonates exposed to antipsychotic medicines (including INVEGA) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include 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.

Breastfeeding

INVEGA is excreted in human breast milk. Therefore, women receiving INVEGA should not breastfeed.

INVEGA can have 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.

Clinical Trial Data

Adults

Summary of the safety profile

The adverse drug reactions (ADRs) most frequently reported in clinical trials with adults were headache, insomnia, sedation/somnolence, parkinsonism, akathisia, tachycardia, tremor, dystonia, upper respiratory tract infection, anxiety, dizziness, increased weight, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhoea, dry mouth, toothache, musculoskeletal pain, hypertension, asthenia, back pain, prolonged electrocardiogram QT, and cough.

The ADRs that appeared to be dose-related included headache, sedation/somnolence, parkinsonism, akathisia, tachycardia, dystonia, dizziness, tremor, upper respiratory tract infection, dyspepsia, and musculoskeletal pain.

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.

Tabulated list of adverse reactions in Clinical Studies

The following are all ADRs that were reported with paliperidone by frequency category estimated from paliperidone palmitate clinical trials. The following terms and frequencies are applied: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

Summary of Adverse Reactions in Clinical Studies

Expected signs and symptoms are those resulting from an exaggeration of the known pharmacological effects of INVEGA, i.e. drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Tosade de pointes and ventricular fibrillation have been reported. In the case of acute overdosage, the possibility of multiple drug involvement should be considered.

Treatment is supportive and symptomatic. Consideration should be given to the prolonged-release nature of the product when assessing treatment needs and recovery. There is no antidote to INVEGA. 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 dysrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures. Administration of activated charcoal together with a laxative should be considered. Close supervision and monitoring should continue until the patient recovers.