ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
INVEGA 1.5 mg prolonged-release tablets
2.
Each prolonged-release tablet contains 1.5 mg of paliperidone.
For a full list of excipients, see section 6.1.
3.
Prolonged-release tablet
Trilayer capsule-shaped orange brown tablets
printed with “PAL 1.5”.
4.
4.1
INVEGA is indicated for the treatment of schizophrenia
.
4.2
Adults
INVEGA is for oral administration. The recommended dose of INVEGA is 6 mg once daily,
administered in the morning. The administration of INVEGA should be standardised in relation to
food intake (see section 5.2). The patient should be instructed to always take INVEGA in the fasting
state or always take it together with breakfast and not to alternate between administration in the
fasting state or in the fed state. Initial dose titration is not required. Some patients may benefit from
lower or higher doses within the recommended range of 3 to 12 mg once daily. Dosage adjustment, if
indicated, should occur only after clinical reassessment. When dose increases are indicated,
increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
INVEGA 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.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA
has not been studied in patients with severe hepatic impairment, caution is recommended in such
patients.
Patients with renal impairment
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 INVEGA is 1.5 mg every day, which may be increased to 3 mg once
daily after clinical reassessment. As INVEGA has not been studied in patients with creatinine
clearance below 10 ml/min, use is not recommended in such patients.
2
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 Patients
with Renal Impairment above). INVEGA should be used with caution in elderly patients with
dementia with risk factors for stroke (see section 4.4).
Paediatric population
Safety and efficacy of INVEGA in patients < 18 years of age have not been studied. There is no
experience in children.
Other special populations
No dose adjustment for INVEGA is recommended based on gender, race, or smoking status. (For
pregnant women and breast-feeding mothers, see section 4.6)
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from INVEGA 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.
4.3
Hypersensitivity to the active substance, risperidone, or to any of the excipients.
4.4
QT interval
As with other antipsychotics, caution should be exercised when INVEGA 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 antipsychotics , including 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 INVEGA, should be discontinued.
Tardive dyskinesia
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 INVEGA, should be considered.
Hyperglycemia
Rare cases of glucose related adverse reactions, e.g., increase in blood glucose, have been reported in
clinical trials with INVEGA. As with other antipsychotics, appropriate clinical monitoring is
advisable in diabetic patients and in patients with risk factors for the development of diabetes
mellitus.
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 INVEGA (3,
6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA
3
compared with 0.8% of subjects treated with placebo. INVEGA should be used with caution in
patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia,
conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to
hypotension (e.g., dehydration and hypovolemia).
Seizures
INVEGA 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 INVEGA tablet is non-deformable and does not appreciably change shape in the
gastrointestinal tract, INVEGA 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, INVEGA
should only be used in patients who are able to swallow the tablet whole.
Conditions with decreased gastro-intestinal transit time
Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe
diarrhoea, may result in a reduced absorption of 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 section 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
INVEGA has not been studied in elderly patients with dementia. Hence, until data demonstrate
otherwise 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. INVEGA 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 antipsychotic medicinal
products, including INVEGA, 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
4
include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal
symptoms.
Priapism
Antipsychotic drugs (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
medicines. Appropriate care is advised when prescribing INVEGA to patients who will be
experiencing conditions which may contribute to an elevation in core body temperature, e.g.,
exercising strenuously, exposure to extreme heat, receiving concomitant medication with
anticholinergic activity, or being subject to dehydration.
Venous Thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since
patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk
factors for VTE should be identified before and during treatment with INVEGA and preventive
measures undertaken.
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.
4.5
Caution is advised when prescribing INVEGA 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 INVEGA to affect other medicines
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with
medicines that are metabolised by cytochrome P-450 isozymes.
Given the primary CNS effects of paliperidone (see section 4.8), INVEGA 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 INVEGA 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.).
5
Potential for other medicines to affect INVEGA
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 INVEGA 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 INVEGA 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 INVEGA should be re-evaluated and increased if necessary. Conversely,
on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if
necessary.
It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer
the effect wears off over a similar time period. Other medicinal products or herbals which are
inducers, e.g. rifampicin and St 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.
Concomitant use of INVEGA with risperidone
Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active
metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.
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).
The use of antipsychotics during the last trimester of pregnancy has resulted in long term but
reversible neurological disturbances of extrapyramidal nature in the infant. INVEGA 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. INVEGA should not be used
while breast feeding.
4.7
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 INVEGA is known.
The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were headache,
akathisia, somnolence, sedation, dizziness, extrapyramidal disorder, tachycardia, agitation,
constipation, nausea, tremor, dyspepsia, vomiting, dry mouth, hypertonia, sinus tachycardia, weight
increased, dystonia, and fatigue.
6
The ADRs that appeared to be dose-related in the schizophrenia clinical trials included weight
increased, headache, salivary hypersecretion, vomiting, dyskinesia, akathisia, dystonia,
extrapyramidal disorder, hypertonia, and parkinsonism.
The following are all ADRs that were reported in clinical trials and postmarketing. The following
terms and frequencies are applied:
very common
(≥ 1/10),
common
(≥ 1/100 to < 1/10),
uncommon
(≥
1/1000 to < 1/100),
rare
(≥ 1/10,000 to < 1/1000),
very rare
(< 1/10,000), and
not known
(cannot be
estimated from the available clinical trial data). Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
The frequency category is determined based on the pooled dataset of six placebo-controlled, double-
blind studies in schizophrenia and bipolar disorder. There were a total of 1205 adult subjects with
schizophrenia who participated in three placebo-controlled, 6-week, double-blind clinical trials, of
whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily. In
addition, the pooled dataset includes 1257 adult subjects with bipolar disorder who participated in
three placebo-controlled, double-blind trials, of whom 739 subjects received INVEGA.
7
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
Infections and
infestations
urinary tract
infection
Immune system
disorders
angioedema
anaphylactic
reaction,
hypersensitivity
Endocrine
disorders
hyperprolactinaemia
Metabolism and
nutrition
disorders
weight increased,
increased appetite
hyperglycaemia
Psychiatric
disorders
agitation
nightmare
Nervous system
disorders
headache
dystonia,
extrapyramidal
disorder, akathisia,
tremor, hypertonia,
dizziness, drooling,
sedation,
somnolence ,
syncope, tardive
dyskinesia,
dysarthria,
parkinsonism,
dyskinesia,
dizziness postural.
lethargy
transient ischaemic
attack, grand mal
convulsion,
convulsion,
parkinsonian gait,
cogwheel rigidity
cerebrovascular
accident,
neuroleptic
malignant
syndrome
Eye disorders
vision blurred
oculogyric crisis
Cardiac disorders
sinus tachycardia,
tachycardia, bundle
branch block
atrioventricular
block first degree,
bradycardia, bundle
branch block left,
palpitations,
electrocardiogram
abnormal, sinus
arrhythmia
electrocardiogram
QT prolonged
Vascular
disorders
orthostatic
hypotension
hypotension
ischaemia
Respiratory,
thoracic and
mediastinal
disorders
pharyngolaryngeal
pain, nasal
congestion
pneumonia
aspiration
Gastrointestinal
disorders
vomiting, abdominal
pain upper, stomach
discomfort, nausea,
dyspepsia, dry
mouth, constipation
salivary
hypersecretion,
flatulence
small intestinal
obstruction,
swollen tongue
Skin and
subcutaneous
tissue disorders
pruritus
rash
rash papular
Musculoskeletal,
connective tissue
and bone
disorders
arthralgia, back
pain, pain in
extremity
muscle rigidity,
muscle spasms,
muscle twitching,
musculoskeletal
pain, trismus
torticollis
Renal and urinary
disorders
urinary retention
urinary incontinence
8
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
Reproductive
system and breast
disorders
erectile dysfunction,
galactorrhoea,
amenorrhoea,
retrograde
ejaculation
gynaecomastia,
breast discharge,
menstruation
irregular, breast
tenderness
priapism
General disorders
asthenia, fatigue
oedema, oedema
peripheral
Elderly
In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen
in non-elderly subjects. INVEGA 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).
Events of Particular interest to the class
Extrapyramidal Symptoms (EPS).
In clinical trials, there was no difference observed between placebo
and the 3 and 6 mg doses of INVEGA. Dose dependence for EPS was seen with the two higher doses
of INVEGA (9 and 12 mg). EPS included a pooled analysis of the following terms: dyskinesia,
dystonia, hyperkinesia, Parkinsonism, and tremor.
Weight Gain.
In 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 INVEGA 3 mg and
6 mg compared with placebo, and a higher incidence of weight gain for INVEGA 9 mg and 12 mg
compared with placebo.
Laboratory Tests: Serum Prolactin.
In clinical trials, median increases in serum prolactin were
observed with INVEGA in 67% of subjects. Adverse events that may suggest increase in prolactin
levels (e.g., amenorrhoea, galactorrhoea, gynaecomastia) were reported overall in 2% of subjects.
Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of
treatment, but remained above baseline levels at study endpoint.
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.
4.9
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 prolonged-release nature of the product when assessing
treatment needs and recovery. There is no specific antidote to paliperidone. General supportive
9
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. Gastric lavage (after intubation if the patient is unconscious) and
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.
5.1
Pharmacodynamic properties
Pharmacologic group: other antipsychotics
ATC code: N05AX13
INVEGA 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.
Pharmacodynamic Effects
Clinical Efficacy
The efficacy of INVEGA was established in three multi-centre, placebo-controlled, double-blind, 6-
week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA doses, which varied
across the three studies, ranged from 3 to 15 mg 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. All tested doses of INVEGA 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, INVEGA was superior to placebo on
PSP and CGI-S.
10
Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From
Baseline to End Point- LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-
SCH-305: Intent-to-Treat Analysis Set
Placebo
3 mg
6 mg
9 mg
12 mg
R076477-SCH-303
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=126)
94.1 (10.74)
-4.1 (23.16)
(N=123)
94.3 (10.48)
-17.9 (22.23)
<0.001
-13.7 (2.63)
(N=122)
93.2 (11.90)
-17.2 (20.23)
<0.001
-13.5 (2.63)
(N=129)
94.6 (10.98)
-23.3 (20.12)
<0.001
-18.9 (2.60)
R076477-SCH-304
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=105)
93.6 (11.71)
-8.0 (21.48)
(N=111)
92.3 (11.96)
-15.7 (18.89)
0.006
-7.0 (2.36)
(N=111)
94.1 (11.42)
-17.5 (19.83)
<0.001
-8.5 (2.35)
R076477-SCH-305
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=120)
93.9 (12.66)
-2.8 (20.89)
(N=123)
91.6 (12.19)
-15.0 (19.61)
<0.001
-11.6 (2.35)
(N=123)
93.9 (13.20)
-16.3 (21.81)
<0.001
-12.9 (2.34)
Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine
at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the
PANSS was used.
A 15 mg dose was also included in Study R076477-SCH-305, but results are not
presented since this is above the maximum recommended daily dose of 12 mg.
In a long-term trial designed to assess the maintenance of effect, INVEGA 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 stabilized for an additional 8 weeks with
INVEGA (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind
manner to either continue on INVEGA 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 INVEGA compared to placebo (p=0.0053).
5.2
Pharmacokinetic properties
The pharmacokinetics of paliperidone following INVEGA administration are dose
proportional within the available dose range.
Absorption
Following a single dose, INVEGA exhibits a gradual ascending release rate, allowing the plasma
concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax)
approximately 24 hours after dosing. With once-daily dosing of INVEGA, 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 INVEGA 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 INVEGA administration is 28% (90% CI
of 23%-33%).
Administration of paliperidone prolonged-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.
11
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 1 mg immediate-release
14
C-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 discernable
difference on the apparent clearance of paliperidone after administration of INVEGA 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 metabolized 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 [Cr Cl] =
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 INVEGA 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.
Race
Population pharmacokinetics analysis revealed no evidence of race-related differences in the
pharmacokinetics of paliperidone following INVEGA administration.
Gender
The apparent clearance of paliperidone following INVEGA 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.
12
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.
6.
6.1
List of excipients
For the 1.5 mg tablet:
Coated tablet core:
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Iron oxide (black) (E172)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Colour overcoat:
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400
Ferric oxide (yellow) (E172)
Ferric oxide (red) (E172)
Carnauba wax
Printing ink:
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
13
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 prolonged-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 prolonged-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 prolonged-release tablets.
Or
• Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-through layer.
Pack sizes of 14, 28, 49, 56, and 98 prolonged-release tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
Janssen-Cilag International NV,
Turnhoutseweg 30,
B-2340 Beerse,
Belgium.
8.
EU/1/07/395/077-095
14
9.
Date of first authorisation: 12/01/2009
10.
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA):
http://www.emea.europa.eu/
15
1.
INVEGA 3 mg prolonged-release tablets
2.
Each prolonged-release tablet contains 3 mg of paliperidone.
Excipient: Each tablet contains 13.2 mg lactose.
For a full list of excipients, see section 6.1.
3.
Prolonged-release tablet
Trilayer capsule-shaped white tablets
printed with “PAL 3”
4.
4.1
INVEGA is indicated for the treatment of schizophrenia
.
4.2
Adults
INVEGA is for oral administration. The recommended dose of INVEGA is 6 mg once daily,
administered in the morning. The administration of INVEGA should be standardised in relation to
food intake (see section 5.2). The patient should be instructed to always take INVEGA in the fasting
state or always take it together with breakfast and not to alternate between administration in the
fasting state or in the fed state. Initial dose titration is not required. Some patients may benefit from
lower or higher doses within the recommended range of 3 to 12 mg once daily. Dosage adjustment, if
indicated, should occur only after clinical reassessment. When dose increases are indicated,
increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
INVEGA 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.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA
has not been studied in patients with severe hepatic impairment, caution is recommended in such
patients.
Patients with renal impairment
16
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 INVEGA is 1.5 mg every day, which may be increased to 3 mg once
daily after clinical reassessment. As INVEGA has not been studied in patients with creatinine
clearance below 10 ml/min, use is not recommended in such patients.
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 Patients
with Renal Impairment above). INVEGA should be used with caution in elderly patients with
dementia with risk factors for stroke (see section 4.4).
Paediatric population
Safety and efficacy of INVEGA in patients < 18 years of age have not been studied. There is no
experience in children.
Other special populations
No dose adjustment for INVEGA is recommended based on gender, race, or smoking status. (For
pregnant women and breast-feeding mothers, see section 4.6)
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from INVEGA 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.
4.3
Hypersensitivity to the active substance, risperidone, or to any of the excipients.
4.4
QT interval
As with other antipsychotics, caution should be exercised when INVEGA 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 antipsychotics , including 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 INVEGA, should be discontinued.
Tardive dyskinesia
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 INVEGA, should be considered.
Hyperglycemia
17
Rare cases of glucose related adverse reactions, e.g., increase in blood glucose, have been reported in
clinical trials with INVEGA. As with other antipsychotics, appropriate clinical monitoring is
advisable in diabetic patients and in patients with risk factors for the development of diabetes
mellitus.
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 INVEGA (3,
6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA
compared with 0.8% of subjects treated with placebo. INVEGA should be used with caution in
patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia,
conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to
hypotension (e.g., dehydration and hypovolemia).
Seizures
INVEGA 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 INVEGA tablet is non-deformable and does not appreciably change shape in the
gastrointestinal tract, INVEGA 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, INVEGA
should only be used in patients who are able to swallow the tablet whole.
Conditions with decreased gastro-intestinal transit time
Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe
diarrhoea, may result in a reduced absorption of 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 section 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
INVEGA has not been studied in elderly patients with dementia. Hence, until data demonstrate
otherwise 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
18
increased risk is not known. INVEGA 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 antipsychotic medicinal
products, including INVEGA, 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 drugs (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
medicines. Appropriate care is advised when prescribing INVEGA to patients who will be
experiencing conditions which may contribute to an elevation in core body temperature, e.g.,
exercising strenuously, exposure to extreme heat, receiving concomitant medication with
anticholinergic activity, or being subject to dehydration.
Venous Thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since
patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk
factors for VTE should be identified before and during treatment with INVEGA and preventive
measures undertaken.
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.
Lactose content (pertains only to the 3 mg tablets)
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
4.5
Caution is advised when prescribing INVEGA 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 INVEGA to affect other medicines
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with
medicines that are metabolised by cytochrome P-450 isozymes.
Given the primary CNS effects of paliperidone (see section 4.8), INVEGA should be used with
caution in combination with other centrally acting medicines,
e.g., anxiolytics, most antipsychotics,
hypnotics, opiates, etc. or alcohol.
19
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 INVEGA 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.).
Potential for other medicines to affect INVEGA
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 INVEGA 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 INVEGA 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 INVEGA should be re-evaluated and increased if necessary. Conversely,
on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if
necessary.
It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer
the effect wears off over a similar time period. Other medicinal products or herbals which are
inducers, e.g. rifampicin and St 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.
Concomitant use of INVEGA with risperidone
Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active
metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.
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).
The use of antipsychotics during the last trimester of pregnancy has resulted in long term but
reversible neurological disturbances of extrapyramidal nature in the infant. INVEGA 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. INVEGA should not be used
while breast feeding.
20
4.7
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 INVEGA is known.
The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were headache,
akathisia, somnolence, sedation, dizziness, extrapyramidal disorder, tachycardia, agitation,
constipation, nausea, tremor, dyspepsia, vomiting, dry mouth, hypertonia, sinus tachycardia, weight
increased, dystonia, and fatigue.
The ADRs that appeared to be dose-related in the schizophrenia clinical trials included weight
increased, headache, salivary hypersecretion, vomiting, dyskinesia, akathisia, dystonia,
extrapyramidal disorder, hypertonia, and parkinsonism.
The following are all ADRs that were reported in clinical trials and postmarketing. The following
terms and frequencies are applied:
very common
(≥ 1/10),
common
(≥ 1/100 to < 1/10),
uncommon
(≥
1/1000 to < 1/100),
rare
(≥ 1/10,000 to < 1/1000),
very rare
(< 1/10,000), and
not known
(cannot be
estimated from the available clinical trial data). Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
The frequency category is determined based on the pooled dataset of six placebo-controlled, double-
blind studies in schizophrenia and bipolar disorder. There were a total of 1205 adult subjects with
schizophrenia who participated in three placebo-controlled, 6-week, double-blind clinical trials, of
whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily. In
addition, the pooled dataset includes 1257 adult subjects with bipolar disorder who participated in
three placebo-controlled, double-blind trials, of whom 739 subjects received INVEGA.
21
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
Infections and
infestations
urinary tract
infection
Immune system
disorders
angioedema
anaphylactic
reaction,
hypersensitivity
Endocrine
disorders
hyperprolactinaemia
Metabolism and
nutrition
disorders
weight increased,
increased appetite
hyperglycaemia
Psychiatric
disorders
agitation
nightmare
Nervous system
disorders
headache
dystonia
extrapyramidal
disorder, akathisia,
tremor, hypertonia, ,
dizziness, drooling,
sedation,
somnolence
syncope, tardive
dyskinesia,
dysarthria,
parkinsonism,
dyskinesia,
dizziness postural.
lethargy
transient ischaemic
attack, grand mal
convulsion,
convulsion,
parkinsonian gait,
cogwheel rigidity
cerebrovascular
accident,
neuroleptic
malignant
syndrome
Eye disorders
vision blurred
oculogyric crisis
Cardiac disorders
sinus tachycardia,
tachycardia, bundle
branch block
atrioventricular
block first degree,
bradycardia, bundle
branch block left,
palpitations,
electrocardiogram
abnormal, sinus
arrhythmia
electrocardiogram
QT prolonged
Vascular
disorders
orthostatic
hypotension
hypotension
ischaemia
Respiratory,
thoracic and
mediastinal
disorders
pharyngolaryngeal
pain, nasal
congestion
pneumonia
aspiration
Gastrointestinal
disorders
vomiting, abdominal
pain upper, stomach
discomfort, nausea,
dyspepsia, dry
mouth, constipation
salivary
hypersecretion,
flatulence
small intestinal
obstruction,
swollen tongue
Skin and
subcutaneous
tissue disorders
pruritus
rash
rash papular
Musculoskeletal,
connective tissue
and bone
disorders
arthralgia, back
pain, pain in
extremity
muscle rigidity,
muscle spasms,
muscle twitching,
musculoskeletal
pain, trismus
torticollis
Renal and urinary
disorders
urinary retention
urinary incontinence
Reproductive
system and breast
disorders
erectile dysfunction,
galactorrhoea,
amenorrhoea,
retrograde
ejaculation
gynaecomastia,
breast discharge,
menstruation
irregular, breast
tenderness
priapism
22
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
General disorders
asthenia, fatigue
oedema, oedema
peripheral
Elderly
In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen
in non-elderly subjects. INVEGA 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).
Events of Particular interest to the class
Extrapyramidal Symptoms (EPS).
In clinical trials, there was no difference observed between placebo
and the 3 and 6 mg doses of INVEGA. Dose dependence for EPS was seen with the two higher doses
of INVEGA (9 and 12 mg). EPS included a pooled analysis of the following terms: dyskinesia,
dystonia, hyperkinesia, Parkinsonism, and tremor.
Weight Gain.
In 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 INVEGA 3 mg and
6 mg compared with placebo, and a higher incidence of weight gain for INVEGA 9 mg and 12 mg
compared with placebo.
Laboratory Tests: Serum Prolactin.
In clinical trials, median increases in serum prolactin were
observed with INVEGA in 67% of subjects. Adverse events that may suggest increase in prolactin
levels (e.g., amenorrhoea, galactorrhoea, gynaecomastia) were reported overall in 2% of subjects.
Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of
treatment, but remained above baseline levels at study endpoint.
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.
4.9
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 prolonged-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. Gastric lavage (after intubation if the patient is unconscious) and
23
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.
5.1
Pharmacodynamic properties
Pharmacologic group: other antipsychotics
ATC code: N05AX13
INVEGA 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.
Pharmacodynamic Effects
Clinical Efficacy
The efficacy of INVEGA was established in three multi-centre, placebo-controlled, double-blind, 6-
week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA doses, which varied
across the three studies, ranged from 3 to 15 mg 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. All tested doses of INVEGA 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, INVEGA was superior to placebo on
PSP and CGI-S.
24
Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From
Baseline to End Point- LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-
SCH-305: Intent-to-Treat Analysis Set
Placebo
3 mg
6 mg
9 mg
12 mg
R076477-SCH-303
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=126)
94.1 (10.74)
-4.1 (23.16)
(N=123)
94.3 (10.48)
-17.9 (22.23)
<0.001
-13.7 (2.63)
(N=122)
93.2 (11.90)
-17.2 (20.23)
<0.001
-13.5 (2.63)
(N=129)
94.6 (10.98)
-23.3 (20.12)
<0.001
-18.9 (2.60)
R076477-SCH-304
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=105)
93.6 (11.71)
-8.0 (21.48)
(N=111)
92.3 (11.96)
-15.7 (18.89)
0.006
-7.0 (2.36)
(N=111)
94.1 (11.42)
-17.5 (19.83)
<0.001
-8.5 (2.35)
R076477-SCH-305
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=120)
93.9 (12.66)
-2.8 (20.89)
(N=123)
91.6 (12.19)
-15.0 (19.61)
<0.001
-11.6 (2.35)
(N=123)
93.9 (13.20)
-16.3 (21.81)
<0.001
-12.9 (2.34)
Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine
at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the
PANSS was used.
A 15 mg dose was also included in Study R076477-SCH-305, but results are not
presented since this is above the maximum recommended daily dose of 12 mg.
In a long-term trial designed to assess the maintenance of effect, INVEGA 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 stabilized for an additional 8 weeks with
INVEGA (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind
manner to either continue on INVEGA 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 INVEGA compared to placebo (p=0.0053).
5.2
Pharmacokinetic properties
The pharmacokinetics of paliperidone following INVEGA administration are dose
proportional within the available dose range.
Absorption
Following a single dose, INVEGA exhibits a gradual ascending release rate, allowing the plasma
concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax)
approximately 24 hours after dosing. With once-daily dosing of INVEGA, 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 INVEGA 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 INVEGA administration is 28% (90% CI
of 23%-33%).
Administration of paliperidone prolonged-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.
25
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 1 mg immediate-release
14
C-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 discernable
difference on the apparent clearance of paliperidone after administration of INVEGA 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 metabolized 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 [Cr Cl] =
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 INVEGA 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.
Race
Population pharmacokinetics analysis revealed no evidence of race-related differences in the
pharmacokinetics of paliperidone following INVEGA administration.
Gender
The apparent clearance of paliperidone following INVEGA 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.
26
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.
6.
6.1
List of excipients
For the 3 mg tablet:
Coated tablet core:
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Ferric oxide (yellow) (E172)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Colour overcoat:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Triacetin
Carnauba wax
Printing ink:
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
27
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 prolonged-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 prolonged-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 prolonged-release tablets.
Or
• Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-through layer.
Pack sizes of 14, 28, 49, 56, and 98 prolonged-release tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
Janssen-Cilag International NV,
Turnhoutseweg 30,
B-2340 Beerse,
Belgium.
28
9.
EU/1/07/395/001 - 005
EU/1/07/395/021 - 025
EU/1/07/395/041 - 044
EU/1/07/395/057 - 058
EU/1/07/395/065 - 067
9.
Date of first authorisation: 25/06/2007
10.
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA):
http://www.emea.europa.eu/
29
1.
INVEGA 6 mg prolonged-release tablets
2.
Each prolonged-release tablet contains 6 mg of paliperidone.
For a full list of excipients, see section 6.1.
3.
Prolonged-release tablet
Trilayer capsule-shaped beige tablets
printed with “PAL 6”
4.
4.1
INVEGA is indicated for the treatment of schizophrenia
.
4.2
Adults
INVEGA is for oral administration. The recommended dose of INVEGA is 6 mg once daily,
administered in the morning. The administration of INVEGA should be standardised in relation to
food intake (see section 5.2). The patient should be instructed to always take INVEGA in the fasting
state or always take it together with breakfast and not to alternate between administration in the
fasting state or in the fed state. Initial dose titration is not required. Some patients may benefit from
lower or higher doses within the recommended range of 3 to 12 mg once daily. Dosage adjustment, if
indicated, should occur only after clinical reassessment. When dose increases are indicated,
increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
INVEGA 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.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA
has not been studied in patients with severe hepatic impairment, caution is recommended in such
patients.
Patients with renal impairment
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 INVEGA is 1.5 mg every day, which may be increased to 3 mg once
30
daily after clinical reassessment. As INVEGA has not been studied in patients with creatinine
clearance below 10 ml/min, use is not recommended in such patients.
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 Patients
with Renal Impairment above). INVEGA should be used with caution in elderly patients with
dementia with risk factors for stroke (see section 4.4).
Paediatric population
Safety and efficacy of INVEGA in patients < 18 years of age have not been studied. There is no
experience in children.
Other special populations
No dose adjustment for INVEGA is recommended based on gender, race, or smoking status. (For
pregnant women and breast-feeding mothers, see section 4.6)
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from INVEGA 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.
4.3
Hypersensitivity to the active substance, risperidone, or to any of the excipients.
4.4
QT interval
As with other antipsychotics, caution should be exercised when INVEGA 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 antipsychotics , including 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 INVEGA, should be discontinued.
Tardive dyskinesia
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 INVEGA, should be considered.
Hyperglycemia
Rare cases of glucose related adverse reactions, e.g., increase in blood glucose, have been reported in
clinical trials with INVEGA. As with other antipsychotics, appropriate clinical monitoring is
advisable in diabetic patients and in patients with risk factors for the development of diabetes
mellitus.
31
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 INVEGA (3,
6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA
compared with 0.8% of subjects treated with placebo. INVEGA should be used with caution in
patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia,
conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to
hypotension (e.g., dehydration and hypovolemia).
Seizures
INVEGA 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 INVEGA tablet is non-deformable and does not appreciably change shape in the
gastrointestinal tract, INVEGA 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, INVEGA
should only be used in patients who are able to swallow the tablet whole.
Conditions with decreased gastro-intestinal transit time
Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe
diarrhoea, may result in a reduced absorption of 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 section 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
INVEGA has not been studied in elderly patients with dementia. Hence, until data demonstrate
otherwise 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. INVEGA should be used with caution in elderly patients with
dementia who have risk factors for stroke.
32
Parkinson’s disease and dementia with Lewy bodies
Physicians should weigh the risks versus the benefits when prescribing antipsychotic medicinal
products, including INVEGA, 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 drugs (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
medicines. Appropriate care is advised when prescribing INVEGA to patients who will be
experiencing conditions which may contribute to an elevation in core body temperature, e.g.,
exercising strenuously, exposure to extreme heat, receiving concomitant medication with
anticholinergic activity, or being subject to dehydration.
Venous Thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since
patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk
factors for VTE should be identified before and during treatment with INVEGA and preventive
measures undertaken.
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.
4.5
Caution is advised when prescribing INVEGA 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 INVEGA to affect other medicines
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with
medicines that are metabolised by cytochrome P-450 isozymes.
Given the primary CNS effects of paliperidone (see section 4.8), INVEGA 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 INVEGA is administered with other therapeutic agents that have this potential, e.g.,
other antipsychotics, tricyclics.
33
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.).
Potential for other medicines to affect INVEGA
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 INVEGA 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 INVEGA 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 INVEGA should be re-evaluated and increased if necessary. Conversely,
on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if
necessary.
It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer
the effect wears off over a similar time period. Other medicinal products or herbals which are
inducers, e.g. rifampicin and St 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.
Concomitant use of INVEGA with risperidone
Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active
metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.
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).
The use of antipsychotics during the last trimester of pregnancy has resulted in long term but
reversible neurological disturbances of extrapyramidal nature in the infant. INVEGA 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. INVEGA should not be used
while breast feeding.
4.7
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 INVEGA is known.
34
The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were headache,
akathisia, somnolence, sedation, dizziness, extrapyramidal disorder, tachycardia, agitation,
constipation, nausea, tremor, dyspepsia, vomiting, dry mouth, hypertonia, sinus tachycardia, weight
increased, dystonia, and fatigue.
The ADRs that appeared to be dose-related in the schizophrenia clinical trials included weight
increased, headache, salivary hypersecretion, vomiting, dyskinesia, akathisia, dystonia,
extrapyramidal disorder, hypertonia, and parkinsonism.
The following are all ADRs that were reported in clinical trials and postmarketing. The following
terms and frequencies are applied:
very common
(≥ 1/10),
common
(≥ 1/100 to < 1/10),
uncommon
(≥
1/1000 to < 1/100),
rare
(≥ 1/10,000 to < 1/1000),
very rare
(< 1/10,000), and
not known
(cannot be
estimated from the available clinical trial data). Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
The frequency category is determined based on the pooled dataset of six placebo-controlled, double-
blind studies in schizophrenia and bipolar disorder. There were a total of 1205 adult subjects with
schizophrenia who participated in three placebo-controlled, 6-week, double-blind clinical trials, of
whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily. In
addition, the pooled dataset includes 1257 adult subjects with bipolar disorder who participated in
three placebo-controlled, double-blind trials, of whom 739 subjects received INVEGA.
35
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
Infections and
infestations
urinary tract
infection
Immune system
disorders
angioedema
anaphylactic
reaction,
hypersensitivity
Endocrine
disorders
hyperprolactinaemia
Metabolism and
nutrition
disorders
weight increased,
increased appetite
hyperglycaemia
Psychiatric
disorders
agitation
nightmare
Nervous system
disorders
headache
dystonia,
extrapyramidal
disorder, akathisia,
tremor, hypertonia,
dizziness, drooling,
sedation,
somnolence
syncope, tardive
dyskinesia,
dysarthria,
parkinsonism,
dyskinesia,
dizziness postural.
lethargy
transient ischaemic
attack, grand mal
convulsion,
convulsion,
parkinsonian gait,
cogwheel rigidity
cerebrovascular
accident,
neuroleptic
malignant
syndrome
Eye disorders
vision blurred
oculogyric crisis
Cardiac disorders
sinus tachycardia
tachycardia, , bundle
branch block
atrioventricular
block first degree,
bradycardia, bundle
branch block left,
palpitations,
electrocardiogram
abnormal, sinus
arrhythmia
electrocardiogram
QT prolonged
Vascular
disorders
orthostatic
hypotension
hypotension
ischaemia
Respiratory,
thoracic and
mediastinal
disorders
pharyngolaryngeal
pain, nasal
congestion
pneumonia
aspiration
Gastrointestinal
disorders
vomiting, abdominal
pain upper, stomach
discomfort, nausea,
dyspepsia, dry
mouth, constipation
salivary
hypersecretion,
flatulence
small intestinal
obstruction,
swollen tongue
Skin and
subcutaneous
tissue disorders
pruritus
rash
rash papular
Musculoskeletal,
connective tissue
and bone
disorders
arthralgia, back
pain, pain in
extremity
muscle rigidity,
muscle spasms,
muscle twitching,
musculoskeletal
pain, trismus
torticollis
Renal and urinary
disorders
urinary retention
urinary incontinence
Reproductive
system and breast
disorders
erectile dysfunction,
galactorrhoea,
amenorrhoea,
retrograde
ejaculation
gynaecomastia,
breast discharge,
menstruation
irregular, breast
tenderness
priapism
36
System Organ
Class
Adverse Drug Reaction
Frequency
Very
common
Common
Uncommon
Rare
Not Known
General disorders
asthenia, fatigue
oedema, oedema
peripheral
Elderly
In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen
in non-elderly subjects. INVEGA 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).
Events of Particular interest to the class
Extrapyramidal Symptoms (EPS).
In clinical trials, there was no difference observed between placebo
and the 3 and 6 mg doses of INVEGA. Dose dependence for EPS was seen with the two higher doses
of INVEGA (9 and 12 mg). EPS included a pooled analysis of the following terms: dyskinesia,
dystonia, hyperkinesia, Parkinsonism, and tremor.
Weight Gain.
In 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 INVEGA 3 mg and
6 mg compared with placebo, and a higher incidence of weight gain for INVEGA 9 mg and 12 mg
compared with placebo.
Laboratory Tests: Serum Prolactin.
In clinical trials, median increases in serum prolactin were
observed with INVEGA in 67% of subjects. Adverse events that may suggest increase in prolactin
levels (e.g., amenorrhoea, galactorrhoea, gynaecomastia) were reported overall in 2% of subjects.
Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of
treatment, but remained above baseline levels at study endpoint.
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.
4.9
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 prolonged-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. Gastric lavage (after intubation if the patient is unconscious) and
37
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.
5.1
Pharmacodynamic properties
Pharmacologic group: other antipsychotics
ATC code: N05AX13
INVEGA 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.
Pharmacodynamic Effects
Clinical Efficacy
The efficacy of INVEGA was established in three multi-centre, placebo-controlled, double-blind, 6-
week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA doses, which varied
across the three studies, ranged from 3 to 15 mg 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. All tested doses of INVEGA 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, INVEGA was superior to placebo on
PSP and CGI-S.
38
Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From
Baseline to End Point- LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-
SCH-305: Intent-to-Treat Analysis Set
Placebo
3 mg
6 mg
9 mg
12 mg
R076477-SCH-303
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=126)
94.1 (10.74)
-4.1 (23.16)
(N=123)
94.3 (10.48)
-17.9 (22.23)
<0.001
-13.7 (2.63)
(N=122)
93.2 (11.90)
-17.2 (20.23)
<0.001
-13.5 (2.63)
(N=129)
94.6 (10.98)
-23.3 (20.12)
<0.001
-18.9 (2.60)
R076477-SCH-304
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=105)
93.6 (11.71)
-8.0 (21.48)
(N=111)
92.3 (11.96)
-15.7 (18.89)
0.006
-7.0 (2.36)
(N=111)
94.1 (11.42)
-17.5 (19.83)
<0.001
-8.5 (2.35)
R076477-SCH-305
Mean baseline (SD)
Mean change (SD)
P-value (vs, Placebo)
Diff. of LS Means (SE)
(N=120)
93.9 (12.66)
-2.8 (20.89)
(N=123)
91.6 (12.19)
-15.0 (19.61)
<0.001
-11.6 (2.35)
(N=123)
93.9 (13.20)
-16.3 (21.81)
<0.001
-12.9 (2.34)
Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine
at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the
PANSS was used.
A 15 mg dose was also included in Study R076477-SCH-305, but results are not
presented since this is above the maximum recommended daily dose of 12 mg.
In a long-term trial designed to assess the maintenance of effect, INVEGA 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 stabilized for an additional 8 weeks with
INVEGA (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind
manner to either continue on INVEGA 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 INVEGA compared to placebo (p=0.0053).
5.2
Pharmacokinetic properties
The pharmacokinetics of paliperidone following INVEGA administration are dose
proportional within the available dose range.
Absorption
Following a single dose, INVEGA exhibits a gradual ascending release rate, allowing the plasma
concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax)
approximately 24 hours after dosing. With once-daily dosing of INVEGA, 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 INVEGA 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 INVEGA administration is 28% (90% CI
of 23%-33%).
Administration of paliperidone prolonged-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.
39
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 1 mg immediate-release
14
C-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 discernable
difference on the apparent clearance of paliperidone after administration of INVEGA 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 metabolized 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 [Cr Cl] =
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 INVEGA 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.
Race
Population pharmacokinetics analysis revealed no evidence of race-related differences in the
pharmacokinetics of paliperidone following INVEGA administration.
Gender
The apparent clearance of paliperidone following INVEGA 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.
40
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.
6.
6.1
List of excipients
For the 6 mg tablet:
Coated tablet core:
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Colour overcoat:
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400
Ferric oxide (yellow) (E172)
Ferric oxide (red) (E172)
Carnauba wax
Printing ink:
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
41
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 prolonged-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 prolonged-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 prolonged-release tablets.
Or
• Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-through layer.
Pack sizes of 14, 28, 49, 56, and 98 prolonged-release tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
Janssen-Cilag International NV,
Turnhoutseweg 30,
B-2340 Beerse,
Belgium.
42
10.
EU/1/07/395/6 - 10
EU/1/07/395/26 - 30
EU/1/07/395/45 - 48
EU/1/07/395/59 - 60
EU/1/07/395/68 - 70
9.
Date of first authorisation: 25/06/2007
10.
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA):
http://www.emea.europa.eu/
43
1.
6. FURTHER INFORMATION
What INVEGA contains
- The active substance is paliperidone
Each INVEGA 1.5 mg prolonged-release tablet contains 1.5 mg of paliperidone
Each INVEGA 3 mg prolonged-release tablet contains 3 mg of paliperidone.
Each INVEGA 6 mg prolonged-release tablet contains 6 mg of paliperidone.
Each INVEGA 9 mg prolonged-release tablet contains 9 mg of paliperidone.
Each INVEGA 12 mg prolonged-release tablet contains 12 mg of paliperidone.
The other ingredients are:
Coated tablet core:
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Ferric Oxide (Yellow) (E172) (3, 12 mg tablet only)
Polyethylene Oxide 7000K
Ferric Oxide (Red) (E172)
Hydroxyethyl Cellulose
Polyethylene glycol 3350
Cellulose acetate
Iron oxide (Black) (E172)
(1.5, 9 mg tablet only)
Colour overcoat:
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400 (1.5, 6, 9 and 12 mg tablet only)
Ferric Oxide (Yellow) (E172) (1.5, 6, 12 mg tablet only)
Ferric Oxide (Red) (E172) (1.5, 6, 9 mg tablet only)
Lactose monohydrate (3 mg tablet only)
131
Triacetin (3 mg tablet only)
Carnauba wax
Printing ink:
Iron oxide (Black) (E172)
Propylene glycol
Hypromellose
What INVEGA looks like and contents of the pack
INVEGA Prolonged-Release Tablets are capsule shaped. The 1.5 mg tablets are orange-brown and
printed with “PAL 1
.
5”, the 3 mg tablets are white and printed with “PAL 3”, the 6 mg tablets are
beige and printed with “PAL 6”, the 9 mg tablets are pink and printed with “PAL 9”, and the 12 mg
tablets are dark yellow and printed with “PAL 12”. All tablets are available in the following pack
sizes:
- Bottles: 30 tablet and 350 tablet high-density polyethylene bottles with child-resistant closures. Each
bottle contains two silica gel pouches which are provided to absorb moisture and keep the tablets dry.
- Blisters: 14, 28, 30, 49, 56, and 98 tablets in polyvinyl chloride laminated with
polychlorotrifluoroethylene/ aluminium push-through layer (white or clear) or 14, 28, 49, 56, and 98
tablets in oriented polyamidealuminium- polyvinyl chloride/aluminium push-through layer.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Janssen-Cilag International NV,
Turnhoutseweg 30,
B-2340 Beerse,
Belgium
Manufacturer
Janssen-Cilag SpA
Via C. Janssen
04010 Borgo San Michele,
Latina
Italy
132
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation.
België/Belgique/Belgien
JANSSEN-CILAG N.V./S.A.
Tél/Tel: + 32 3 280 54 11
Luxembourg/Luxemburg
JANSSEN-CILAG N.V./S.A.
Tél: +32 3 280 54 11
България
Представителство на Johnson & Johnson,
Тел.:+359 2 489 9400(05)
Magyarország
JANSSEN-CILAG Kft.
Tel:+36 23 513-800
Česká republika
JANSSEN-CILAG s.r.o.
Tel:+420 227 012 222
Malta
AM MANGION LTD
Tel: +356 2397 6000
Danmark
JANSSEN-CILAG A/S
Tlf: +45 45 94 82 82
Nederland
JANSSEN-CILAG B.V.
Tel: +31 13 583 73 73
Deutschland
JANSSEN-CILAG GmbH
Tel: +49 2137-955-955
Norge
JANSSEN-CILAG AS
Tlf: + 47 24 12 65 00
Eesti
JANSSEN-CILAG Polska Sp. z o.o. Eesti filiaal
Tel.: + 372 6789 3561
Österreich
JANSSEN-CILAG PHARMA GmbH
Tel: +43 1 610 300
Ελλάδα
JANSSEN-CILAG Φαρμακευτική Α.Ε.Β.Ε
Tηλ: +30 210 61 40 061
Polska
JANSSEN–CILAG Polska Sp. z o.o.,
Tel.: + 48 22 237 6000
España
JANSSEN-CILAG, S.A.
Tel: +34 91 722 81 00
Portugal
JANSSEN-CILAG FARMACEUTICA,
LDA
Tel: +351 21-4368835
France
JANSSEN-CILAG
Tel: 0800 25 50 75 / + 33 1 55 00 44 44
România
JOHNSON AND JOHNSON d.o.o
Tel: +40 21 207 1800
Ireland
JANSSEN-CILAG Ltd.
Tel: +44 1 494 567 567
Slovenija
Johnson & Johnson d.o.o.
Tel: + 386 1401 18 30
Ísland
JANSSEN-CILAG
c/o Vistor hf.
Sími: +354 535 7000
Slovenská republika
JOHNSON & JOHNSON s.r.o,
Tel: +421 233 552 600
133
Italia
JANSSEN-CILAG SpA
Tel: +39 02/2510.1
Suomi/Finland
JANSSEN-CILAG OY
Puh/Tel: +358 9 4155 5300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Tηλ: +357 22 755 214
Sverige
JANSSEN-CILAG AB
Tel: +46 8 626 50 00
Latvija
JANSSEN-CILAG Polska Sp. z o.o. filiāle Latvijā
Tel. +371 6789 3561
United Kingdom
JANSSEN-CILAG Ltd.
Tel: +44 1494 567 567
Lietuva
UAB Johnson & Johnson
Tel.: +370 5 278 68 88
This leaflet was last approved in MM/YYYY
Detailed information on this product is available on the website of the European Medicines
Evaluation Agency (EMEA): http://www.emea.europa.eu/.
134
Source: European Medicines Agency
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