Paliperidone

Given the primary CNS effects of paliperidone, 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.

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.).

For patients with mild renal impairment (creatinine clearance ≥50 to <80 mL/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 10 to <50 mL/min), the recommended initial dose of paliperidone is 3 mg every other day, which may be increased to 3 mg once daily after clinical reassessment.

As paliperidone has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

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.

Co-administration of paliperidone 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 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 12 mg with divalproex sodium prolonged-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 paliperidone should be considered when paliperidone is co-administered with valproate after clinical assessment.

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.

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.

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.

Conditions leading to shorter gastrointestinal transit time, e.g. diseases associated with chronic severe diarrhoea, may result in a reduced absorption of orally taken paliperidone.

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.

Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation.

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).

Paliperidone for injection should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Exacerbation of pre-existing diabetes has been reported during treatment with paliperidone. Patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Paliperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injected paliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, but other types of reproductive toxicity were seen. Neonates exposed to 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.

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.

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to paliperidone is known.

Oral administration

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.

^a Refer to ‘Hyperprolactinaemia’ below.
^b Refer to ‘Extrapyramidal symptoms’ below.
^c Not observed in paliperidone clinical studies but observed in post-marketing environment with paliperidone
^d In placebo-controlled pivotal trials, diabetes mellitus was reported in 0.05% in paliperidone-treated subjects compared to a rate of 0% in placebo group. Overall incidence from all clinical trials was 0.14% in all paliperidone-treated subjects
^e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation irregular, oligomenorrhoea

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 6 mg doses of paliperidone. Dose dependence for EPS was seen with the two higher doses of paliperidone (9 and 12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher rate than placebo in all dose groups without a clear relationship to dose.

EPS included a pooled analysis of the following terms: 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 3 mg and 6 mg compared with placebo, and a higher incidence of weight gain for paliperidone 9 mg and 12 mg 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, the increase in body weight of ≥7% was 3% in the lower-dose (3-6 mg) group, 7% in the higher-dose (9-12 mg) 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.

Paediatric population

Summary of the safety profile

In one short-term and two longer-term studies with paliperidone prolonged-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.

IV administration

Summary of the safety profile

The adverse drug reactions (ADRs) most frequently reported in clinical trials were insomnia, headache, anxiety, upper respiratory tract infection, injection site reaction, parkinsonism, weight increased, akathisia, agitation, sedation/somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhoea, fatigue, and dystonia. Of these, akathisia and sedation/somnolence appeared to be dose-related.

Tabulated list of adverse reactions

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 (≥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).

^a The frequency of these adverse reactions is qualified as “not known” because they were not observed in paliperidone palmitate clinical trials. They were either derived from spontaneous post-marketing reports and frequency cannot be determined, or they were derived from risperidone (any formulation) or oral paliperidone clinical trials data and/or post-marketing reports.
^b Refer to ‘Hyperprolactinaemia’ below.
^c Refer to ‘Extrapyramidal symptoms’ below.
^d In placebo-controlled trials, diabetes mellitus was reported in 0.32% in paliperidone-treated subjects compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65% in all paliperidone palmitate-treated subjects
^e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation delayed, menstruation irregular, oligomenorrhoea

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.

Description of selected adverse reactions

Anaphylactic reaction

Rarely, cases of anaphylactic reaction after injection with paliperidone have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Injection site reactions

The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies with paliperidone. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

Extrapyramidal symptoms (EPS)

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, glabellar reflex abnormal, and 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 the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase ≥7% showed a dose-related trend, with a 5% incidence rate in the placebo group compared with rates of 6%, 8% and 13% in the paliperidone 25 mg, 100 mg, and 150 mg groups, respectively.

During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of paliperidone-treated subjects met this criterion (weight gain of ≥7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was + 0.7 (4.79) kg.

Hyperprolactinaemia

In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received paliperidone. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in <1% of subjects.

Class effects

QT prolongation, ventricular arrhythmias (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 medicinal products (frequency unknown).