Paliperidone 3mg extended-release tablets 

1. Name of the medicinal product

Paliperidone 3mg extended-release tablets Taj Pharma
Paliperidone 6mg extended-release tablets Taj Pharma
Paliperidone 9mg extended-release tablets Taj Pharma
Paliperidone 12mg extended-release tablets Taj Pharma

2. Qualitative and quantitative composition

Each extended-release tablet contains
Paliperidone                                    3mg
Excipients                                          q.s

Each extended-release tablet contains
Paliperidone                                    6mg
Excipients                                          q.s

Each extended-release tablet contains
Paliperidone                                    9mg
Excipients                                          q.s

Each extended-release tablet contains
Paliperidone                                    12mg
Excipients                                          q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Extended-release tablet

4. Clinical particulars

4.1 Therapeutic indications

Paliperidone  is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and older.

Paliperidone  is indicated for the treatment of schizoaffective disorder in adults.

4.2 Posology and method of administration

Posology

Schizophrenia (adults)

The recommended dose of  paliperidone for the treatment of schizophrenia in adults is 6mg 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 3mg to 12mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3mg/day are recommended and generally should occur at intervals of more than 5 days.

Schizoaffective disorder (adults)

The recommended dose of  paliperidone for the treatment of schizoaffective disorder in adults is 6mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses within the recommended range of 6mg to 12mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3mg/day are recommended and generally should occur at intervals of more than 4 days.

Switching to other antipsychotic medicinal products

There are no systematically collected data to specifically address switching patients from paliperidone 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.

Elderly

Dosing recommendations for elderly patients with normal renal function (≥ 80 mL/min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal impairment below). paliperidone should be used with caution in elderly patients with dementia with risk factors for stroke (see section 4.4). Safety and efficacy of paliperidone in patients > 65 years of age with schizoaffective disorder have not been studied.

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. As paliperidone has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

Renal impairment

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

For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 to < 50 mL/min), the recommended initial dose of Paliperidone is 3mg every other day, which may be increased to 3mg once daily after clinical reassessment. As paliperidone has not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients.

Paediatric population

Schizophrenia: The recommended starting dose of  paliperidone for the treatment of schizophrenia in adolescents 15 years and older is 3mg once daily, administered in the morning.

Adolescents weighing < 51 kg: the maximum recommended daily dose of paliperidone is 6mg.

Adolescents weighing ≥ 51 kg: the maximum recommended daily dose of paliperidone is 12mg.

Dosage adjustment, if indicated, should occur only after clinical reassessment based on the individual need of the patient. When dose increases are indicated, increments of 3mg/day are recommended and generally should occur at intervals of 5 days or more. The safety and efficacy of paliperidone in the treatment of schizophrenia in adolescents between 12 and 14 years old has not been established. Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made. There is no relevant use of Paliperidone in children aged less than 12 years.

Schizoaffective disorder: The safety and efficacy of Paliperidone in the treatment of schizoaffective disorder in patients aged 12 to 17 years has not been studied or established. There is no relevant use of Paliperidone in children aged less than 12 years.

Other special populations

No dose adjustment for Paliperidone is recommended based on gender, race, or smoking status.

Method of administration

Paliperidone is for oral administration. It 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.

The administration of Paliperidone should be standardised in relation to food intake (see section 5.2). The patient should be instructed to always take PALIPERIDONE 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.

4.3 Contraindications

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

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 Paliperidone 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 Paliperidone, should be discontinued.

Tardive dyskinesia/extrapyramidal symptoms

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 Paliperidone, should be considered.

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 stimulant treatment is recommended (see section 4.5).

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents, including Paliperidone. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Paliperidone 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 severe neutropenia (absolute neutrophil count < 1 x 10⁹/L) should discontinue Paliperidone and have their WBC followed until recovery.

Hyperglycemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with paliperidone. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including Paliperidone, should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Weight gain

Significant weight gain has been reported with Paliperidone use. Weight should be monitored regularly.

Hyperprolactinaemia

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Paliperidone should be used with caution in patients with possible prolactin-dependent tumours.

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 Paliperidone (3, 6, 9, and 12mg), orthostatic hypotension was reported by 2.5% of subjects treated with Paliperidone compared with 0.8% of subjects treated with placebo. Paliperidone 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

PALIPERIDONE 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 Paliperidone tablet is non-deformable and does not appreciably change shape in the

gastrointestinal tract, Paliperidone 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, Paliperidone 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 sections 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

Paliperidone 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. Paliperidone 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 Paliperidone 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 post-marketing 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 Paliperidone 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 Paliperidone 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.

Paediatric population

The sedative effect of Paliperidone should be closely monitored in this population. A change in the time of administration of Paliperidone may improve the impact of sedation on the patient.

Because of the potential effects of prolonged hyperprolactinemia 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 Paliperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.

For specific posology recommendations in the paediatric population see section 4.2.

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha 1a-adrenergic antagonist effect, such as Paliperidone (see section 4.8).

IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Excipients

Lactose content (pertains only to the 3mg tablets)

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

Sodium content

This medicinal product contains less than 1 mmol sodium (23mg) per tablet, i.e., essentially sodium-free.

4.5 Interaction with other medicinal products and other forms of interaction

Caution is advised when prescribing Paliperidone 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 Paliperidone 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), Paliperidone 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 Paliperidone 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 Paliperidone and lithium has been performed, however, a pharmacokinetic interaction is unlikely to occur.

Co-administration of Paliperidone 12mg once daily with divalproex sodium extended-release tablets (500mg to 2,000mg once daily) did not affect the steady-state pharmacokinetics of valproate. Co-administration of Paliperidone with divalproex sodium extended-release tablets increased the exposure to paliperidone (see below).

Potential for other medicines to affect Paliperidone

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 Paliperidone 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 Paliperidone once daily with carbamazepine 200mg 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 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 Paliperidone should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of Paliperidone 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 Paliperidone 12mg with divalproex sodium extended-release tablets (two 500mg tablets once daily) resulted in an increase of approximately 50% in the C_max and AUC of paliperidone. Dosage reduction for Paliperidone should be considered when Paliperidone is co-administered with valproate after clinical assessment.

Concomitant use of Paliperidone with risperidone

Concomitant use of Paliperidone 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 Paliperidone with psychostimulants

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

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

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. Paliperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

Breast-feeding

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. Paliperidone should not be used while breast feeding.

Fertility

There were no relevant effects observed in the non-clinical studies.

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 Paliperidone is known.

4.8 Undesirable effects

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, weight increased, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhoea, dry mouth, toothache, musculoskeletal pain, hypertension, asthenia, back pain, electrocardiogram QT prolonged, 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 Paliperidone dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with Paliperidone monotherapy.

Tabulated list of adverse reactions

The following are all the ADRs that were reported in clinical trials and post-marketing experience with paliperidone by frequency category estimated from Paliperidone clinical trials in adults. The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Undesirable effects noted with risperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reactions have been noted with the use of risperdone products and can be expected to occur with Paliperidone.

Psychiatric disorders: sleep-related eating disorder

Nervous system disorders: cerebrovascular disorder

Eye disorders: floppy iris syndrome (intraoperative)

Respiratory, thoracic and mediastinal disorders: rales

Description of selected adverse reactions

Extrapyramidal symptoms (EPS)

In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6mg doses of Paliperidone. Dose dependence for EPS was seen with the two higher doses of Paliperidone (9 and 12mg). 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: 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, parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, 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. It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.

Weight gain

In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for Paliperidone 3mg and 6mg compared with placebo, and a higher incidence of weight gain for Paliperidone 9mg and 12mg compared with placebo.

In schizoaffective disorder clinical trials, a higher percentage of Paliperidone-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined two dose groups (see section 5.1), the increase in body weight of ≥ 7% was 3% in the lower-dose (3-6mg) group, 7% in the higher-dose (9-12mg) group, and 1% in the placebo group.

Hyperprolactinaemia

In schizophrenia clinical trials, increases in serum prolactin were observed with Paliperidone in 67% of subjects. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, 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.

Elderly

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

Paediatric population

Summary of the safety profile

In one short-term and two longer-term studies with paliperidone extended-release tablets conducted in adolescents 12 years and older with schizophrenia, the overall safety profile was similar to that seen in adults. In the pooled adolescent schizophrenia population (12 years and older, N = 545) exposed to Paliperidone, the frequency and type of undesirable effects were similar to those in adults except for the following ADRs that were reported more frequently in adolescents receiving Paliperidone than adults receiving Paliperidone (and more frequently than placebo): sedation/somnolence, parkinsonism, weight increase, upper respiratory tract infection, akathisia, and tremor were reported very commonly (≥ 1/10) in adolescents; abdominal pain, galactorrhoea, gynaecomastia, acne, dysarthria, gastroenteritis, epistaxis, ear infection, blood triglyceride increased, and vertigo were reported commonly (≥ 1/100, < 1/10) in adolescents.

Extrapyramidal Symptoms (EPS)

In the short-term, placebo-controlled, fixed-dose adolescent study, the incidence of EPS was higher than placebo for all doses of Paliperidone with an increased frequency of EPS at higher doses. Across all adolescent studies, EPS was more common in adolescents than in adults for each Paliperidone dose.

Weight gain

In the short-term, placebo-controlled, fixed-dose adolescent study, a higher percentage of Paliperidone-treated subjects (6-19% depending on dose) had an increase in body weight of ≥ 7% compared to placebo-treated subjects (2%). There was no clear dose relationship. In the long-term 2-year study, the subjects who were exposed to Paliperidone during both the double-blind and open-label studies reported a modest weight gain (4.9 kg).

In adolescents, weight gain should be assessed against that expected with normal growth.

Prolactin

In the up to 2-year, open-label treatment study of Paliperidone in adolescents with schizophrenia, incidence of elevated serum prolactin levels occurred in 48% of females and 60% of males. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 9.3% of subjects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important

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 extended-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. 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 Paliperidone 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.

Clinical efficacy

Schizophrenia

The efficacy of Paliperidone 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. Paliperidone doses, which varied across the three studies, ranged from 3 to 15mg 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, disorganised thoughts, uncontrolled hostility/excitement, and anxiety/depression. All tested doses of Paliperidone 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, Paliperidone 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 ≥ 30%) as a secondary endpoint.

In a long-term trial designed to assess the maintenance of effect, Paliperidone was significantly more effective than placebo in maintaining symptom control and delaying relapse of schizophrenia. After having been treated for an acute episode for 6 weeks and stabilised for an additional 8 weeks with Paliperidone (doses ranging from 3 to 15mg once daily) patients were then randomised in a double-blind manner to either continue on Paliperidone or on placebo until they experienced a relapse in schizophrenia symptoms. The trial was stopped early for efficacy reasons by showing a significantly longer time to relapse in patients treated with Paliperidone compared to placebo (p=0.0053).

Schizoaffective disorder

The efficacy of Paliperidone in the acute treatment of psychotic or manic symptoms of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale (YMRS) and/or Hamilton Rating Scale 21 for Depression (HAM-D 21). The population included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of Paliperidone (3-12mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of Paliperidone: 6mg with the option to reduce to 3mg (n = 105) or 12mg with the option to reduce to 9mg (n = 98) once daily. Both studies included subjects who received PaliperidonE either as monotherapy or in combination with mood stabilisers and/or antidepressants. Dosing was in the morning without regard to meals. Efficacy was evaluated using the PANSS.

The Paliperidone group in the flexible-dose study (dosed between 3 and 12mg/day, mean modal dose of 8.6mg/day) and the higher dose group of Paliperidone in the 2 dose-level study (12mg/day with option to reduce to 9mg/day) were each superior to placebo in the PANSS at 6 weeks. In the lower dose group of the 2 dose-level study (6mg/day with option to reduce to 3mg/day), Paliperidone was not significantly different from placebo as measured by the PANSS. Only few subjects received the 3mg dose in both studies and efficacy of this dose could not be established. Statistically superior improvements in manic symptoms as measured by YMRS (secondary efficacy scale) were observed in patients from the flexible-dose study and the Paliperidone higher dose in the second study.

Taking the results of both studies together (pooled study-data), Paliperidone improved the psychotic and manic symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or in combination with mood stabilisers and/or antidepressants. However, overall the magnitude of effect in regard to PANSS and YMRS observed on monotherapy was larger than that observed with concomitant antidepressants and/or mood stabilisers. Moreover, in the pooled population, Paliperidone was not efficacious in patients concomitantly receiving mood stabiliser and antidepressants in regard to the psychotic symptoms, but this population was small (30 responders in the paliperidone group and 20 responders in the placebo group). Additionally, in study SCA-3001 in the ITT population the effect on psychotic symptoms measured by PANSS was clearly less pronounced and not reaching statistical significance for patients receiving concomitantly mood stabilisers and/or antidepressants. An effect of Paliperidone on depressive symptoms was not demonstrated in these studies, but has been demonstrated in a long-term study with the long-acting injectable formulation of paliperidone (described further down in this section).

An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score ≥ 30% and CGI-C Score ≤ 2) as a secondary endpoint.

In a long-term trial designed to assess the maintenance of effect, the long-acting injectable formulation of paliperidone was significantly more effective than placebo in maintaining symptom control and delaying relapse of psychotic, manic, and depressive symptoms of schizoaffective disorder. After having been successfully treated for an acute psychotic or mood episode for 13 weeks and stabilised for an additional 12 weeks with the long-acting injectable formulation of paliperidone (doses ranging from 50 to 150mg) patients were then randomised to a 15-month double-blind relapse prevention period of the study to either continue on the long-acting injectable formulation of paliperidone or on placebo until they experienced a relapse of schizoaffective symptoms. The study showed a significantly longer time to relapse in patients treated with the long-acting injectable formulation of paliperidone compared to placebo (p < 0.001).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Paliperidone in all subsets of the paediatric population in the treatment of schizoaffective disorders. See section 4.2 for information on paediatric use.

The efficacy of PALIPERIDONE in the treatment of schizophrenia in adolescents between 12 and 14 years old has not been established.

The efficacy of Paliperidone in adolescent subjects with schizophrenia (Paliperidone N = 149, placebo N = 51) was studied in a randomised, double-blind, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1.5mg/day to 12mg/day. Subjects were 12-17 years of age and met DSM-IV criteria for schizophrenia. Efficacy was evaluated using PANSS. This study demonstrated the efficacy of Paliperidone of the medium dose group in adolescent subjects with schizophrenia. Secondary by dose analysis demonstrated the efficacy of 3mg, 6mg, and 12mg dose given once daily.

Efficacy of Paliperidone over a flexible dose range of 3mg/day to 9mg/day in adolescent subjects (12 years and older) with schizophrenia (Paliperidone N = 112, aripiprazole N = 114) was also evaluated in a randomised, double-blind, active-controlled study that included an 8-week, double-blind acute phase and an 18-week, double-blind maintenance phase. The changes in PANSS total scores from baseline to week 8 and week 26 were numerically similar between the Paliperidone and aripiprazole treatment groups. In addition, the difference in the percentage of patients demonstrating ≥ 20% improvement in PANSS total score at week 26 between the two treatment groups was numerically similar.

5.2 Pharmacokinetic properties

The pharmacokinetics of paliperidone following Paliperidone administration are dose proportional within the available dose range.

Absorption

Following a single dose, Paliperidone exhibits a gradual ascending release rate, allowing the plasma concentrations of paliperidone to steadily rise to reach peak plasma concentration (C_max) approximately 24 hours after dosing. With once-daily dosing of PALIPERIDONE, steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects.

Paliperidone is the active metabolite of risperidone. The release characteristics of Paliperidone result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone (fluctuation index 38% versus 125%).

The absolute oral bioavailability of paliperidone following Paliperidone administration is 28% (90% CI of 23%-33%).

Administration of paliperidone extended-release tablets with a standard high-fat/high-caloric meal increases C_max and AUC of paliperidone by up to 50-60% compared with administration in the fasting state.

Distribution

Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. The plasma protein binding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin.

Biotransformation and elimination

One week following administration of a single oral dose of 1mg immediate-release ¹⁴C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolised by the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the faeces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of Paliperidone between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. The terminal elimination half-life of paliperidone is about 23 hours.

In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Hepatic impairment

Paliperidone is not extensively metabolised in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment

Elimination of paliperidone decreased with decreasing renal function. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (Creatinine Clearance [CrCl] = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min), and 71% in severe (CrCl = < 30 mL/min) renal impairment. The mean terminal elimination half-life of paliperidone was 24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).

Elderly

Data from a pharmacokinetic study in elderly subjects (≥ 65 years of age, n = 26) indicated that the apparent steady-state clearance of paliperidone following Paliperidone administration was 20% lower compared to that of adult subjects (18-45 years of age, n = 28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction of age-related decreases in CrCl.

Adolescents

Paliperidone systemic exposure in adolescent subjects (15 years and older) was comparable to that in adults. In adolescents weighing < 51 kg, a 23% higher exposure was observed than in adolescents weighing ≥ 51 kg. Age alone did not influence the paliperidone exposure.

Race

Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following PALIPERIDONE administration.

Gender

The apparent clearance of paliperidone following Paliperidone administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and creatinine clearance between men and women.

Smoking status

Based on in vitro studies utilising human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. A population pharmacokinetic analysis showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is unlikely to be of clinical relevance, though.

5.3 Preclinical safety data

Repeat-dose toxicity studies of paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. Paliperidone was not teratogenic in rat and rabbit. In rat reproduction studies using risperidone, which is extensively converted to paliperidone in rats and humans, a reduction was observed in the birth weight and survival of the offspring. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. Paliperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.

In a 7-week juvenile toxicity study in rats administered oral doses of paliperidone up to 2.5mg/kg/day, corresponding to an exposure approximately equal to the clinical exposure based on AUC, no effects on growth, sexual maturation and reproductive performance were observed. Paliperidone did not impair the neurobehavioural development in males at doses up to 2.5mg/kg/day. At 2.5mg/kg/day in females, an effect on learning and memory was observed. This effect was not observed after discontinuation of treatment. In a 40-week juvenile toxicity study in dogs with oral doses of risperidone (which is extensively converted to paliperidone) up to 5mg/kg/day, effects on sexual maturation, long bone growth and femur mineral density were observed from 3 times the clinical exposure based on AUC.

6. Pharmaceutical particulars

6.1 List of excipients

Core

Polyethylene oxide Sodium chloride

Povidone, Stearic acid, Butyl hydroxytoluene , Ferric oxide, Polyethylene oxide, Ferric oxide, Hydroxyethyl cellulose, Polyethylene glycol, Cellulose acetate

Overcoat

Hypromellose, Titanium dioxide, Lactose monohydrate, Triacetin

Carnauba wax

Printing ink

Iron oxide, Propylene glycol, Hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Bottles: Do not store above 30°C. Keep the bottle tightly closed in order to protect from moisture.

Blisters: Do not store above 30°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Bottles:

White high-density polyethylene (HDPE) bottle with induction sealing and polypropylene child-resistant closure. Each bottle contains two 1 g dessicant silica gel (silicone dioxide) pouches (pouch is food approved polyethylene).

Pack sizes of 30 and 350 extended-release tablets.

Blisters:

Polyvinyl chloride (PVC) laminated with polychloro-trifluoroethylene (PCTFE)/aluminium push-through layer.

Pack sizes of 14, 28, 30, 49, 56, and 98 extended-release tablets.

Or

White polyvinyl chloride (PVC) laminated with polychloro-trifluoroethylene (PCTFE)/aluminium push-through layer.

Pack sizes of 14, 28, 30, 49, 56, and 98 extended-release tablets.

Or

Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-through child-resistant blister.

Pack sizes of 14, 28, 49, 56, and 98 extended-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Manufactured By:
   Taj Pharmaceuticals Ltd.
   at: Plot. No. 220, Mahagujarat
   Industrial Estate, At & Post-Moraiya,
   Tal-Sanand, Dist- Ahmedabad Gujarat (India)

Paliperidone 3mg/6mg/9mg/12mg extended-release tablets

Package leaflet: Information for the user

Paliperidone 3mg extended-release tablets Taj Pharma
Paliperidone 6mg extended-release tablets Taj Pharma
Paliperidone 9mg extended-release tablets Taj Pharma
Paliperidone 12mg extended-release tablets Taj Pharma 

Paliperidone

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor, pharmacist or
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet:

1. What Paliperidone is and what it is used for
2. What you need to know before you take Paliperidone
3. How to take Paliperidone
4. Possible side effects
5. How to store Paliperidone
6. Contents of the pack and other information

1.             What Paliperidone is and what it is used for

Paliperidone contains the active substance paliperidone which belongs to the class of antipsychotic medicines.

Paliperidone is used to treat schizophrenia in adults and in adolescents aged 15 years and older.

Schizophrenia is a disorder with symptoms such as hearing things, seeing or sensing things that are not there, mistaken beliefs, unusual suspiciousness, becoming withdrawn, incoherent speech, and behaviour and emotional flatness. People with this disorder may also feel depressed, anxious, guilty, or tense.

Paliperidone is also used to treat schizoaffective disorder in adults.

Schizoaffective disorder is a mental condition in which a person experiences a combination of schizophrenia symptoms (as listed above) in addition to mood disorder symptoms (feeling very high, feeling sad, feeling agitated, distracted, sleeplessness, talkativeness, losing interest in everyday activities, sleeping too much or too little, eating too much or too little, and recurrent thoughts of suicide).

Paliperidone can help alleviate the symptoms of your disease and stop your symptoms from coming back.

What you need to know before you take Paliperidone

Do not take Paliperidone

• if you are allergic to paliperidone, risperidone, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Paliperidone.

• Patients with schizoaffective disorder treated with this medicine should be carefully monitored for a potential switch from manic to depressive
• This medicine has not been studied in elderly patients with dementia. However, elderly patients with dementia, who are treated with other similar types of medicine, may have an increased risk of stroke or death. (see section 4, possible side effects).
• if you have Parkinson’s disease or
• 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 experienced abnormal movements of the tongue or face (Tardive Dyskinesia).
  • You should be aware that both of these conditions may be caused by this type of medicine.
• if you know that you have had low levels of white blood cells in the past (which may or may not have been caused by other medicines).
• if you are diabetic or prone to
• if you have heart disease or heart disease treatment that makes you prone to low blood
• if you have
• if you have a swallowing, stomach or intestinal disorder that reduces your ability to swallow or pass foods by normal bowel
• if you have diseases associated with
• if you have kidney
• if you have liver
• if you have prolonged and/or painful erection.
• if you have difficulty controlling core body temperature or
• if you have an abnormally high level of the hormone prolactin in your blood or if you have a possible prolactin-dependent tumour.
• if you or someone else in your family has a history of blood clots, as antipsychotics have been associated with formation of blood

If you have any of these conditions, please talk to your doctor as he/she may want to adjust your dose or monitor you for a while.

As dangerously low numbers of a certain type of white blood cell needed to fight infection in your blood has been seen very rarely with patients taking Paliperidone, your doctor may check your white blood cell counts.

Paliperidone may cause you to gain weight. Significant weight gain may adversely affect your health. Your doctor should regularly measure your body weight.

As diabetes mellitus or worsening of pre-existing diabetes mellitus have been seen with patients taking Paliperidone, your doctor should check for signs of high blood sugar. In patients with pre-existing diabetes mellitus blood glucose should be monitored regularly.

During an operation on the eye for cloudiness of the lens (cataract), the pupil (the black circle in the middle of your eye) may not increase in size as needed. Also, the iris (the coloured part of the eye) may become floppy during surgery and that may lead to eye damage. If you are planning to have an operation on your eye, make sure you tell your eye doctor that you are taking this medicine.

Children and adolescents

Paliperidone is not for use in children and adolescents under 15 years for the treatment of schizophrenia.
Paliperidone is not for use in children and adolescents who are under 18 years for the treatment of schizoaffective disorder.
This is because it is not known if Paliperidone is safe or effective in these age groups.

Other medicines and Paliperidone

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines. Abnormalities of electrical function in the heart may occur when this medicine is taken with certain heart medicines that control heart rhythm, or some other types of medicines such as antihistamines, antimalarials, or other antipsychotics.

Since this medicine works primarily in the brain, interference from other medicines (or alcohol) that work in the brain could occur due to additive effect on brain function.

Since this medicine can lower blood pressure, care should be taken when this medicine is taken with other medicines that lower blood pressure.

This medicine can reduce the effect of medicines against Parkinson’s disease and restless legs syndrome (e.g., levodopa).

The effects of this medicine may be affected if you are taking medicines that affect the speed of movement in the gut (e.g., metoclopramide).

Dosage reduction for this medicine should be considered when this medicine is co-administered with valproate.

The use of oral risperidone together with this medicine is not recommended as the combination of the two medicines may lead to increased side effects.

Paliperidone should be used with caution with medicines that increase the activity of the central nervous system (psychostimulants such as methylphenidate).

Paliperidone with alcohol

Alcohol should be avoided when taking this medicine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not take this medicine during pregnancy unless this has been discussed with your doctor. The following symptoms may occur in newborn babies of mothers that have used paliperidone in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor.

You should not breastfeed when taking this medicine.

Driving and using machines

Dizziness and vision problems may occur during treatment with this medicine (see section 4, possible side effects). This should be considered in cases where full alertness is required, e.g., when driving a car or handling machines.

The 3mg tablet of Paliperidone contains lactose

The 3mg tablet of this medicine contains lactose, a type of sugar. If you have been told by a doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Paliperidone contains sodium

This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially ‘sodium-free’.

2.             How to take Paliperidone

Take this medicine exactly as the doctor, pharmacist or nurse has told you to.

Use in adults

The recommended dose in adults is 6mg once a day taken in the morning. The dose may be increased or decreased by your doctor within the dose range of 3mg to 12mg once a day for schizophrenia or

6mg to 12mg once a day for schizoaffective disorder. This depends on how well the medicine works for you.

Use in adolescents

The recommended starting dose for treating schizophrenia in adolescents 15 years and older is 3mg once a day taken in the morning.

For adolescents weighing 51 kg or more the dose may be increased within the range of 6mg to 12mg once a day.

For adolescents weighing less than 51 kg the dose may be increased to 6mg once a day.

Your doctor will decide how much to give you. The amount you take depends on how well the medicine works for you.

How and when to take Paliperidone

This medicine must be taken by mouth, swallowed whole with water or other liquids. It must not be chewed, broken, or crushed.

This medicine should be taken every morning with breakfast or without breakfast, but in the same way every day. Do not alternate between taking this medicine with breakfast one day and without having breakfast the next day.

The active ingredient, paliperidone, dissolves once swallowed and the tablet shell is passed out of the body as waste.

Patients with kidney problems

Your doctor may adjust your dose of this medicine based upon your kidney function.

Elderly

Your doctor may reduce your dose of medicine if your kidney function is reduced.

If you take more Paliperidone than you should

Contact your doctor right away. You may experience sleepiness, tiredness, abnormal body movements, problems with standing and walking, dizziness from low blood pressure, and abnormal heart beats.

If you forget to take Paliperidone

Do not take a double dose to make up for a forgotten dose. If you miss one dose, take your next dose on the day following the missed dose. If you miss two or more doses, contact your doctor.

If you stop Paliperidone

Do not stop taking this medicine since you will lose the effects of the medicine. You should not stop this medicine unless told to do so by your doctor as your symptoms may return.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

3.         Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if you:

• experience blood clots in the veins, especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty breathing. If you notice any of these symptoms seek medical advice
• have dementia and experience a sudden change in your mental state or sudden weakness or numbness of your face, arms or legs, especially on one side, or slurred speech, even for a short period of time. These may be signs of a
• experience fever, muscle stiffness, sweating or a lowered level of consciousness (a disorder called “Neuroleptic Malignant Syndrome”). Immediate medical treatment may be
• are a man and experience prolonged or painful erection. This is called priapism. Immediate medical treatment may be
• experience involuntary rhythmic movements of the tongue, mouth and face. Withdrawal of paliperidone may be
• experience a severe allergic reaction characterised by fever, swollen mouth, face, lip or tongue, shortness of breath, itching, skin rash and sometimes drop in blood pressure (amounting to an ‘anaphylactic reaction’).

Very common: may affect more than 1 in 10 people

• difficulty falling or staying asleep
• parkinsonism: This condition may include slow or impaired movement, sensation of stiffness or tightness of the muscles (making your movements jerky), and sometimes even a sensation of movement “freezing up” and then restarting. Other signs of parkinsonism include a slow shuffling walk, a tremor while at rest, increased saliva and/or drooling, and a loss of expression on the
• restlessness
• feeling sleepy or less alert

Common side effects: may affect up to 1 in 10 people

• infection of the chest (bronchitis), common cold symptoms, sinus infection, urinary tract infection, feeling like you have the flu
• weight gain, increased appetite, weight loss, decreased appetite
• elated mood (mania), irritability, depression, anxiety
• dystonia: This is a condition involving slow or sustained involuntary contraction of muscles. While it can involve any part of the body (and may result in abnormal posture), dystonia often involves muscles of the face, including abnormal movements of the eyes, mouth, tongue or
• dizziness
• dyskinesia: This is a condition involving involuntary muscle movements, and can include repetitive, spastic or writhing movements, or
• tremor (shaking)
• blurry vision
• an interruption in conduction between the upper and lower parts of the heart, abnormal electrical conduction of the heart, prolongation of the QT interval from your heart, slow heart rate, rapid heart rate
• low blood pressure upon standing (consequently, some people taking Paliperidone may feel faint, dizzy, or may pass out when they stand up or sit up suddenly), high blood pressure
• sore throat, cough, stuffy nose
• abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhoea, indigestion, dry mouth, toothache
• increased liver transaminases in your blood
• itching, rash
• bone or muscle ache, back pain, joint pain
• loss of menstrual periods
• fever, weakness, fatigue (tiredness).

Uncommon side effects: may affect up to 1 in 100 people

• pneumonia, infection of the breathing passages, bladder infection, ear infection, tonsillitis
• white blood cell count decreased, decrease in platelets (blood cells that help you stop bleeding), anaemia, decrease in red blood cells
• Paliperidone can raise your levels of a hormone called “prolactin” found on a blood test (which may or may not cause symptoms). When symptoms of high prolactin occur, they may include: (in men) breast swelling, difficulty in getting or maintaining erections, or other sexual dysfunction, (in women) breast discomfort, leakage of milk from the breasts, missed menstrual periods, or other problems with your
• diabetes or worsening diabetes, high blood sugar, increased waist size, loss of appetite resulting in malnutrition and low body weight, high blood triglycerides (a fat)
• sleep disorder, confusion, decreased sexual drive, inability to reach orgasm, nervousness, nightmares
• tardive dyskinesia (twitching or jerking movements that you cannot control in your face, tongue, or other parts of your body). Tell your doctor immediately if you experience involuntary rhythmic movements of the tongue, mouth and face. Withdrawal of PALIPERIDONE may be
• convulsion (fits), fainting, a restless urge to move parts of your body, dizziness upon standing, disturbance in attention, problems with speech, loss or abnormal sense of taste, reduced sensation of skin to pain and touch, a sensation of tingling, pricking, or numbness of skin
• oversensitivity of the eyes to light, eye infection or “pink eye”, dry eye
• a sensation of spinning (vertigo), ringing in the ears, ear pain
• irregular heartbeat, abnormal electrical tracing of the heart (electrocardiogram or ECG), a fluttering or pounding feeling in your chest (palpitations)
• low blood pressure
• shortness of breath, wheezing, nosebleeds
• swollen tongue, stomach or intestinal infection, difficulty swallowing, excessive passing of gas or wind
• increased GGT (a liver enzyme called gamma-glutamyltransferase) in your blood, increased liver enzymes in your blood
• hives (or “nettle rash”), hair loss, eczema, acne
• an increase of CPK (creatine phosphokinase) in your blood, an enzyme which is sometimes released with muscle breakdown, muscle spasms, joint stiffness, joint swelling, muscle weakness, neck pain
• incontinence (lack of control) of urine, frequent passing of urine, inability to pass urine, pain when passing urine
• erectile dysfunction, ejaculation disorder
• missed menstrual periods or other problems with your cycle (females), leakage of milk from the breasts, sexual dysfunction, breast pain, breast discomfort
• swelling of the face, mouth, eyes, or lips, swelling of the body, arms or legs
• chills, an increase in body temperature
• a change in the way you walk
• feeling thirsty
• chest pain, chest discomfort, feeling unwell

Rare side effects: may affect up to 1 in 1,000 people

• eye infection, fungal infection of the nails, infection of the skin, skin inflammation caused by mites
• dangerously low numbers of a certain type of white blood cell needed to fight infection in your blood
• decrease in the type of white blood cells that help to protect you against infection, increase in eosinophils (a type of white blood cell) in your blood
• severe allergic reaction characterised by fever, swollen mouth, face, lip or tongue, shortness of breath, itching, skin rash and sometimes drop in blood pressure, allergic reaction
• sugar in the urine
• inappropriate secretion of a hormone that controls urine volume
• life threatening complications of uncontrolled diabetes
• dangerously excessive intake of water, low blood sugar, excessive drinking of water, increased cholesterol in your blood
• sleep walking
• not moving or responding while awake (catatonia)
• lack of emotion
• neuroleptic malignant syndrome (confusion, reduced or loss of consciousness, high fever, and severe muscle stiffness)
• loss of consciousness, balance disorder, abnormal coordination
• blood vessel problems in the brain, coma due to uncontrolled diabetes, unresponsive to stimuli, low level of consciousness, shaking of the head
• glaucoma (increased pressure within the eyeball), increased tears, redness of the eyes, problems with movement of your eyes, eye rolling
• atrial fibrillation (an abnormal heart rhythm), rapid heartbeat upon standing
• blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately
• decreased oxygen in parts of your body (because of decreased blood flow), flushing
• trouble breathing during sleep (sleep apnea), fast, shallow breathing
• pneumonia caused by inhaling food, congestion of breathing passages, voice disorder
• a blockage in the bowels, stool incontinence, very hard stool, lack of bowel muscle movement that causes blockage
• yellowing of the skin and the eyes (jaundice)
• inflammation of the pancreas
• serious allergic reaction with swelling that may involve the throat and lead to difficulty breathing
• thickening of the skin, dry skin, skin redness, skin discolouration, flaky itchy scalp or skin, dandruff
• breakdown of muscle fibers and pain in muscles (rhabdomyolysis), abnormal posture
• priapism (a prolonged penile erection that may require surgical treatment)
• development of breasts in men, enlargement of the glands in your breasts, discharge from the breasts, vaginal discharge
• a delay in menstrual periods, breast enlargement
• very low body temperature, a decrease in body temperature
• symptoms of drug

Not known: frequency cannot be estimated from the available data

• lung congestion
• increased insulin (a hormone that controls blood sugar levels) in your

The following side effects have been seen with the use of another medicine called risperidone that is very similar to paliperidone, so these can also be expected with Paliperidone: sleep-related eating disorder, other types of blood vessel problems in the brain and crackly lung sounds. Eye problems during cataract surgery may also occur. During cataract surgery, a condition called intraoperative floppy iris syndrome (IFIS) can happen if you take or have taken Paliperidone. If you need to have cataract surgery, be sure to tell your eye doctor if you take or have taken this medicine.

Additional side effects in adolescents

Adolescents generally experienced side effects that were similar to those seen in adults except the following side effects were seen more commonly:

• feeling sleepy or less alert
• parkinsonism: This condition may include slow or impaired movement, sensation of stiffness or tightness of the muscles (making your movements jerky), and sometimes even a sensation of movement “freezing up” and then restarting. Other signs of parkinsonism include a slow

shuffling walk, a tremor while at rest, increased saliva and/or drooling, and a loss of expression on the face.

• weight gain
• common cold symptoms
• restlessness
• tremor (shaking)
• stomach pain
• leaking milk from the breasts in girls
• breast swelling in boys
• acne
• problems with speech
• stomach or intestinal infection
• nose bleeds
• ear infection
• high blood triglycerides (a fat)
• sensation of spinning (vertigo).

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.

By reporting side effects you can help provide more information on the safety of this medicine.

4.             How to store Paliperidone

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/bottle and carton after EXP. The expiry date refers to the last day of that month.

Bottles: Do not store above 30°C. Keep the bottle tightly closed in order to protect from moisture. Blisters: Do not store above 30°C. Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

Contents of the pack and other information What Paliperidone contains

The active substance is paliperidone

Each Paliperidone 3mg extended-release tablet contains 3mg of paliperidone.

Each Paliperidone 6mg extended-release tablet contains 6mg of paliperidone.

Each Paliperidone 9mg extended-release tablet contains 9mg of paliperidone.

Each Paliperidone 12mg extended-release tablet contains 12mg of paliperidone.

The other ingredients are:

Coated tablet core:

Polyethylene oxide, Sodium chloride Povidone Stearic acid

Butyl hydroxytoluene

Ferric Oxide (3, 12mg tablet only) Polyethylene Oxide, Ferric Oxide Hydroxyethyl Cellulose Polyethylene glycol  Cellulose acetate

Iron oxide

Colour overcoat:

Hypromellose

Titanium dioxide

Polyethylene glycol, Ferric Oxide (Yellow) Ferric Oxide, Lactose monohydrate, Triacetin Carnauba wax

Printing ink:

Iron oxide (Black), Propylene glycol Hypromellose

What Paliperidone looks like and contents of the pack

Paliperidone extended-release tablets are capsule shaped. All tablets are available in the following pack sizes:

Bottles: The tablets are supplied in a plastic bottle with a child-resistant plastic cap. Each bottle contains either 30 tablets or 350 tablets. Each bottle contains two silica gel pouches which are provided to absorb moisture and keep the tablets dry.

Blisters: The tablets are supplied in blisters packed in cartons of 14, 28, 30, 49, 56, and 98 tablets.

Not all pack sizes may be marketed.

7. Manufactured By:
   Taj Pharmaceuticals Ltd.
   at: Plot. No. 220, Mahagujarat
   Industrial Estate, At & Post-Moraiya,
   Tal-Sanand, Dist- Ahmedabad Gujarat (India)