Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Hypersensitivity to the active substance, to risperidone or to any of the excipients listed in section 6.1.
BYANNLI should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
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 medicinal products thought to prolong the QT interval.
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, paliperidone should be discontinued. Consideration should be given to the long-acting nature of BYANNLI.
Medicinal products 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. Consideration should be given to the long-acting nature of BYANNLI.
Caution is warranted in patients receiving both, psychostimulants (e.g., methylphenidate) and paliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medicinal products. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).
Events of leucopenia, neutropenia, and agranulocytosis have been reported with paliperidone. Patients with a history of a clinically significant low white blood cell (WBC) count or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of BYANNLI 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 × 109/L) should discontinue BYANNLI and have their WBC followed until recovery. Consideration should be given to the long-acting nature of BYANNLI. Hypersensitivity reactions Hypersensitivity reactions can occur even in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.8).
Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes, including diabetic coma and ketoacidosis, have been reported with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with BYANNLI 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.
Significant weight change has been reported with BYANNLI use. Weight should be monitored regularly (see section 4.8).
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 a pre-existing tumour that may be prolactin-dependent.
Paliperidone may induce orthostatic hypotension in some patients based on its alpha-adrenergic blocking activity. BYANNLI 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 hypovolaemia).
BYANNLI should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
The plasma concentrations of paliperidone are increased in patients with renal impairment. Patients with mild renal impairment (creatinine clearance ≥50 mL/min to ≤80 mL/min) who are stabilised on either 1-monthly paliperidone palmitate injectable or 3-monthly paliperidone palmitate injectable may be transitioned to BYANNLI (see section 4.2). The 1 000 mg dose of BYANNLI is not recommended for patients with mild renal impairment. BYANNLI is not recommended in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) (see sections 4.2 and 5.2).
No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.
BYANNLI has not been studied in elderly patients with dementia. BYANNLI is not recommended to treat elderly patients with dementia due to increased risk of overall mortality and cerebrovascular adverse reactions.
The experience from risperidone cited below is considered valid also for paliperidone.
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.
An approximately 3-fold increased risk of cerebrovascular adverse reactions has 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.
Physicians should weigh the risks versus the benefits when prescribing BYANNLI to patients with Parkinson’s disease or DLB since both groups may be at increased risk of NMS 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.
Antipsychotic medicinal products (including paliperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 4 hours.
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing BYANNLI 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 medicinal products with anticholinergic activity or being subject to dehydration.
Cases of 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 BYANNLI and preventative measures undertaken.
An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdose with certain medicinal products or of conditions such as intestinal obstruction, Reye’s syndrome and brain tumour.
Care must be taken to avoid inadvertent injection of BYANNLI into a blood vessel.
IFIS has been observed during cataract surgery in patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as BYANNLI (see section 4.8).
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicinal products 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially sodium-free.
Caution is advised when prescribing BYANNLI with medicinal products 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 antibiotics (e.g., fluoroquinolones), some other antipsychotics and some antimalarials (e.g., mefloquine). This list is indicative and not exhaustive.
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P450 isozymes.
Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), BYANNLI should be used with caution in combination with other centrally acting medicinal products, 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 BYANNLI is administered with other medicinal products that have this potential, e.g., other antipsychotics, tricyclics.
Caution is advised if paliperidone is combined with other medicinal products known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).
Co-administration of oral paliperidone prolonged-release tablets at steady-state (12 mg once daily) with divalproex sodium prolonged-release tablets (500 mg to 2 000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.
No interaction study between BYANNLI and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.
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 oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.
Co-administration of oral paliperidone prolonged-release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of BYANNLI should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of BYANNLI should be re-evaluated and decreased if necessary. Consideration should be given to the long-acting nature of BYANNLI.
Co-administration of a single dose of an oral paliperidone prolonged-release tablet 12 mg with divalproex sodium prolonged-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged-release tablets and BYANNLI gluteal intramuscular injection. This interaction has not been studied with BYANNLI.
Since paliperidone is the major active metabolite of risperidone, caution should be exercised when BYANNLI is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of BYANNLI with other antipsychotics is limited.
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).
Plasma exposure to paliperidone after a single dose of BYANNLI is expected to remain for up to 4 years (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. BYANNLI should only be used in women planning to become pregnant if clearly necessary.
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 (see section 5.3). 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 has been detected in plasma up to 18 months after a single dose of the 3-monthly paliperidone palmitate injectable. Plasma exposure to paliperidone after a single dose of BYANNLI is expected to remain for up to 4 years (see section 5.2). Maternal exposure to BYANNLI before and during pregnancy may lead to adverse reactions in the newborn child. BYANNLI should not be used during pregnancy unless clearly necessary.
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. Since a single dose of BYANNLI is expected to remain for up to 4 years in plasma (see section 5.2), breast-fed infants may be at risk even from BYANNLI administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 4 years with BYANNLI should not breast feed.
There were no relevant effects observed in the non-clinical studies.
Paliperidone has minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to BYANNLI is known.
The most frequently observed adverse reactions reported in ≥ 5% of patients in the randomised double-blind active controlled clinical trial of BYANNLI were upper respiratory tract infection, injection site reaction, weight increased, headache and Parkinsonism.
The following are all adverse reactions 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
| System Organ Class | Adverse reactions | |||||
|---|---|---|---|---|---|---|
| Frequency | ||||||
| Very common | Common | Uncommon | Rare | Not knowna | ||
| Infections and infestations | upper respiratory tract infection, urinary tract infection, influenza | pneumonia, bronchitis, respiratory tract infection, sinusitis, cystitis, ear infection, tonsillitis, onychomycosis, cellulitis subcutaneous abscess | eye infection, acarodermatitis | |||
| Blood and lymphatic system disorders | white blood cell count decreased, anaemia | neutropenia, thrombocytopenia, eosinophil count increased | agranulocytosis | |||
| Immune system disorders | hypersensitivity | anaphylactic reaction | ||||
| Endocrine disorders | hyperprolactinaemiab | inappropriate antidiuretic hormone secretion, glucose urine present | ||||
| Metabolism and nutrition disorders | hyperglycaemia, weight increased, weight decreased, decreased appetite | diabetes mellitusd, hyperinsulinaemia, increased appetite, anorexia, blood triglycerides increased, blood cholesterol increased | diabetic ketoacidosis, hypoglycaemia, polydipsia | water intoxication | ||
| Psychiatric disorders | insomniae | agitation, depression, anxiety | sleep disorder, mania, libido decreased, nervousness, nightmare | catatonia, confusional state, somnambulism, blunted affect, anorgasmia | sleep-related eating disorder | |
| Nervous system disorders | parkinsonismc, akathisiac, sedation/ somnolence, dystoniac, dizziness, dyskinesiac, tremor, headache | tardive dyskinesia, syncope, psychomotor hyperactivity, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia | neuroleptic malignant syndrome, cerebral ischaemia, unresponsive to stimuli, loss of consciousness, depressed level of consciousness, convulsione, balance disorder, coordination abnormal, head titubation | diabetic coma | ||
| Eye disorders | vision blurred, conjunctivitis, dry eye | glaucoma, eye movement disorder, eye rolling, photophobia, lacrimation increased, ocular hyperaemia | floppy iris syndrome (intraoperative) | |||
| Ear and labyrinth disorders | vertigo, tinnitus, ear pain | |||||
| Cardiac disorders | tachycardia | atrioventricular block, conduction disorder, electrocardiogram QT prolonged, postural orthostatic tachycardia syndrome, bradycardia, electrocardiogram abnormal, palpitations | atrial fibrillation, sinus arrhythmia | |||
| Vascular disorders | hypertension | hypotension, orthostatic hypotension | pulmonary embolism, venous thrombosis, flushing | ischaemia | ||
| Respiratory, thoracic and mediastinal disorders | cough, nasal congestion | dyspnoea, pharyngolaryngeal pain, epistaxis | sleep apnoea syndrome, pulmonary congestion, respiratory tract congestion, rales, wheezing | hyperventilation, pneumonia aspiration, dysphonia | ||
| Gastrointestinal disorders | abdominal pain, vomiting, nausea, constipation, diarrhoea, dyspepsia, toothache | abdominal discomfort, gastroenteritis, dysphagia, dry mouth, flatulence | pancreatitis, intestinal obstruction, swollen tongue, faecal incontinence, faecaloma, cheilitis | ileus | ||
| Hepatobiliary disorders | transaminases increased | gamma- glutamyltransferase increased, hepatic enzyme increased | jaundice | |||
| Skin and subcutaneous tissue disorders | urticaria, pruritus, rash, alopecia, eczema, dry skin, erythema, acne | drug eruption, hyperkeratosis, seborrhoeic dermatitis, dandruff | Stevens-Johnson syndrome/toxic epidermal necrolysis, angioedema, skin discolouration | |||
| Musculoskeletal and connective tissue disorders | musculoskeletal pain, back pain, arthralgia | blood creatine phosphokinase increased, muscle spasms, joint stiffness, muscular weakness | rhabdomyolysis, joint swelling | posture abnormal | ||
| Renal and urinary disorders | urinary incontinence, pollakiuria, dysuria | urinary retention | ||||
| Pregnancy, puerperium and perinatal conditions | drug withdrawal syndrome neonatal (see section 4.6) | |||||
| Reproductive system and breast disorders | amenorrhoea | erectile dysfunction, ejaculation disorder, menstrual disordere, gynaecomastia, galactorrhoea, sexual dysfunction, breast pain | priapism,breast discomfort, breast engorgement, breast enlargement, vaginal discharge | |||
| General disorders and administration site conditions | pyrexia, asthenia, fatigue, injection site reaction | face oedema, oedemae, body temperature increased, gait abnormal, chest pain, chest discomfort, malaise, induration | hypothermia, chills, thirst, drug withdrawal syndrome, injection site abscess, injection site cellulitis, injection site cyst, injection site haematoma | body temperature decreased, injection site necrosis, injection site ulcer | ||
| Injury, poisoning and procedural complications | fall | |||||
a The frequency of 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 subjects treated with 1-monthly paliperidone palmitate injectable compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65% in all subjects treated 1-monthly paliperidone palmitate injectable.
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.
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.
Rarely, cases of anaphylactic reaction after injection with 1-monthly paliperidone palmitate injectable have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.4).
In the clinical trial of BYANNLI, 10.7% of subjects reported injection site related adverse reaction (4.5% in subjects treated with the comparator 3-monthly paliperidone palmitate injectable). None of these events were serious or led to discontinuation. Based on the investigators' clinical ratings, induration, redness, and swelling were absent or mild in ≥ 95% of the assessments. Subject-rated injection site pain based on a visual analogue scale was low and decreased in intensity over time.
In the clinical trial of BYANNLI, akathisia, dyskinesia, dystonia, parkinsonism, and tremor were reported in 3.6%, 1.5%, 0.6%, 5.0%, and 0.2% of subjects, respectively. EPS included a pooled analysis of the following terms: parkinsonism (includes extrapyramidal disorder, extrapyramidal symptoms, on and off phenomenon, Parkinson’s disease, parkinsonian crisis, 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 (includes dyskinesia, chorea, movement disorder, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, cervical spasm, emprosthotonus, oculogyric crisis, oromandibular dystonia, risus sardonicus, tetany, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor (includes tremor, action tremor).
In the 12-month clinical trial of BYANNLI, the number of subjects with abnormal weight percent change from double-blind baseline to double-blind end point is presented in the table below. The overall mean weight change from double-blind baseline to double-blind end point was +0.10 kg for the BYANNLI group and +0.96 kg for the 3-monthly paliperidone palmitate group. In subjects 18-25 years of age, mean (SD) weight change of -0.65 (4.955) kg was observed for the BYANNLI group and +4.33 (7.112) kg in the 3-monthly paliperidone palmitate group. For overweight subjects (BMI 25 to <30), mean weight change of -0.53 kg in the BYANNLI group and +1.15 kg in the 3-monthly paliperidone palmitate group was observed.
Number of patients with abnormal weight percent change from (double-blind) baseline to end point:
| Weight percent change | PP3M1 (N=219) | BYANNLI (N=473) |
|---|---|---|
| Decrease ≥7% | 15 (6.8%) | 43 (9.1%) |
| Increase ≥7% | 29 (13.2%) | 50 (10.6%) |
1 PP3M – 3-monthly paliperidone palmitate injectable
In the 12-month clinical trial of BYANNLI, the mean (SD) change from double-blind baseline in prolactin levels was -2.19 (13.61) µg/L for males and -4.83 (34.39) µg/L for females in the 6-monthly paliperidone palmitate group and in the 3-monthly paliperidone palmitate group it was 1.56 (19.08)◦µg/L for males and 9.03 (40.94) µg/L for females. During the double-blind phase, 3 females (4.3%) in the 3-monthly paliperidone palmitate group and 5 females (3.3%) in the 6-monthly paliperidone palmitate group experienced amenorrhoea.
QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics.
Cases of VTE, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown).
Reporting suspected adverse reactions after authorisation of the medical product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products.
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