PALMEUX Prolonged-release suspension for injection Ref.[50171] Active ingredients: Paliperidone

Source: Health Products Regulatory Authority (IE)  Revision Year: 2022  Publisher: Amdipharm Limited, Temple Chambers, 3 Burlington Road, Dublin 4, Ireland

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Use in patients who are in an acutely agitated or severely psychotic state

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

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 medicinal products 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, paliperidone should be discontinued.

Tardive dyskinesia/extrapyramidal symptoms

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. 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 Palmeux. 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 Palmeux 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 Palmeux and have their WBC followed until recovery.

Hypersensitivity reactions

Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidone have been rarely reported during post-marketing experience (see sections 4.1 and 4.8). If hypersensitivity reactions occur, discontinue use of Palmeux; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve (see sections 4.3 and 4.8).

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes including diabetic coma and ketoacidosis, have been reported during treatment with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with Palmeux 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 Palmeux use. Weight should be monitored regularly.

Use in patients with prolactin-dependent tumours

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.

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 oral paliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo. Palmeux 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

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

Renal impairment

The plasma concentrations of paliperidone are increased in patients with renal impairment and therefore, dose adjustment is recommended in patients with mild renal impairment. Palmeux is not recommended in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) (see sections 4.2 and 5.2).

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

Palmeux has not been studied in elderly patients with dementia. Palmeux should be used with caution in elderly patients with dementia with risk factors for stroke.

The experience from risperidone cited below 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 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.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing Palmeux 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 alpha-adrenergic blocking effects have been reported to induce priapism. During post-marketing surveillance, priapism has also been reported with oral 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 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 Palmeux 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.

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 Palmeux and preventative 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 medicinal products or of conditions such as intestinal obstruction, Reye’s syndrome and brain tumour.

Administration

Care must be taken to avoid inadvertent injection of Palmeux into a blood vessel.

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as Palmeux (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.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

Caution is advised when prescribing Palmeux 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 other antipsychotics and some antimalarials (e.g. mefloquine). This list is indicative and not exhaustive.

Potential for Palmeux to affect other medicines

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P-450 isozymes.

Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), Palmeux 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 Palmeux is administered with other therapeutic agents 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 Palmeux and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.

Potential for other medicines to affect Palmeux

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 Palmeux should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of Palmeux should be re-evaluated and decreased if necessary.

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 Palmeux intramuscular injection. This interaction has not been studied with Palmeux.

Concomitant use of Palmeux with risperidone or with oral paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when Palmeux is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of Palmeux with other antipsychotics is limited.

Concomitant use of Palmeux 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).

4.6. Fertility, pregnancy and lactation

Pregnancy

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. Palmeux should not be used during pregnancy unless clearly necessary.

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. Palmeux 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, 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 Palmeux is known.

4.8. Undesirable effects

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).

System Organ
Class
Adverse Drug Reaction
Frequency
Very commonCommon 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
eye infection,
acarodermatitis,
subcutaneous
abscess
 
Blood and
lymphatic
system disorders
  white blood cell count
decreased,
thrombocytopenia,
anaemia
neutropenia,
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
diabetic coma,
head titubation
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
 tachycardiaatrioventricular block,
conduction disorder,
electrocardiogram QT
prolonged, postural
orthostatic tachycardia
syndrome, bradycardia,
electrocardiogram
abnormal, palpitations
atrial fibrillation,
sinus
arrhythmia
 
Vascular
disorders
 hypertension hypotension, orthostatic
hypotension
venous
thrombosis,
flushing
pulmonary
embolism,
ischaemia
Respiratory,
thoracic and
mediastinal
disorders
 cough, nasal
congestion
dyspnoea, respiratory tract
congestion, wheezing,
pharyngolaryngeal pain,
epistaxis
sleep apnoea
syndrome,
pulmonary
congestion,
rales
hyperventilation,
pneumonia
aspiration,
dysphonia
Gastrointestinal
disorders
 abdominal pain,
vomiting, nausea,
constipation,
diarrhoea, dyspepsia,
toothache
abdominal discomfort,
gastroenteritis, dysphagia,
dry mouth, flatulence
pancreatitis,
swollen tongue,
faecal
incontinence,
faecaloma,
cheilitis
intestinal
obstruction,
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,
dandruff
Stevens-Johnson
syndrome/toxic
epidermal
necrolysis,
angioedema,
skin
discolouration,
seborrhoeic
dermatitis
Musculoskeletal
and connective
tissue disorders
 musculoskeletal pain,
back pain, arthralgia
blood creatine
phosphokinase increased,
muscle spasms, joint
stiffness, muscular
weakness, neck pain
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,
galactorrhoea
erectile dysfunction,
ejaculation disorder,
menstrual disordere,
gynaecomastia, sexual
dysfunction, breast pain
breast
discomfort,
breast
engorgement,
breast
enlargement,
vaginal
discharge
priapism
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 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 Palmeux-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 injection have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.4).

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 injection. 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 is 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 injection 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 injection-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 injection. 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal 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: HPRA Pharmacovigilance Website: www.hpra.ie.

6.2. Incompatibilities

This medicinal product must not be mixed with other medicinal products.

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