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XEPLION
®
XEPLION
®
cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10,
CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, XEPLION is not
expected to inhibit clearance of medicines that are metabolised by these
metabolic pathways in a clinically relevant manner. XEPLION is also not
expected to have enzyme inducing properties.
XEPLION is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations.
No in vivo data are available and the clinical relevance is unknown.
Given the primary CNS effects of paliperidone (see Side Effects) XEPLION
should be used with caution in combination with other centrally acting
medicines and alcohol. XEPLION may antagonize the effect of levodopa
and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension (see Special
Precautions: Orthostatic Hypotension), an additive effect may be observed
when XEPLION is administered with other therapeutic agents that have
this potential.
Pharmacokinetic interaction between XEPLION and lithium is unlikely.
Potential for Other Medicines to Affect XEPLION
Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19,
and CYP3A5. This suggests that an interaction with inhibitors or inducers
of these isozymes is unlikely. While in vitro studies indicate that CYP2D6
and CYP3A4 may be minimally involved in paliperidone metabolism, there
are no indications in vitro or in vivo that these isozymes play a significant
role in the metabolism of paliperidone. In vitro studies have shown that
paliperidone is a P-gp substrate.
Paliperidone is metabolized to a limited extent by CYP2D6 (see Pharmacokinetics: Metabolism and Elimination). In an interaction study in healthy
subjects in which oral paliperidone was administered concomitantly with
paroxetine, a potent CYP2D6 inhibitor, no clinically relevant effects on the
pharmacokinetics of paliperidone were observed.
Co-administration of oral paliperidone extended release once daily with
carbamazepine 200 mg twice daily caused a decrease of approximately
37 % in the mean steady-state Cmax and AUC of paliperidone. This decrease
is caused, to a substantial degree, by a 35 % increase in renal clearance
of paliperidone likely as a result of induction of renal P-gp by carbamazepine.
A minor decrease in the amount of medicine excreted unchanged in the urine
suggests that there was little effect on the CYP metabolism or bioavailability
of paliperidone during carbamazepine co-administration. On initiation of
carbamazepine, the dose of XEPLION should be re-evaluated and increased
if necessary. Conversely, on discontinuation of carbamazepine, the dose
of XEPLION should be re-evaluated and decreased if necessary.
Paliperidone, a cation under physiological pH, is primarily excreted unchanged
by the kidneys, approximately half via filtration and half via active secretion.
Concomitant administration of trimethoprim, a medicine known to inhibit
active renal cation medicine transport, did not influence the pharmacokinetics
of paliperidone.
Concomitant Use of XEPLION with Risperidone
Concomitant use of XEPLION with risperidone has not been studied.
Since paliperidone is an active metabolite of risperidone, co-administration
of risperidone with XEPLION is not recommended.
SEE INSTRUCTIONS FOR USE AND HANDLING
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side Effects:
The most frequently reported side effects reported in clinical trials were
insomnia, headache, anxiety, upper respiratory tract infection, injection site
reactions, Parkinsonism, weight increased, akathisia, agitation, somnolence,
nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor,
abdominal discomfort, vomiting, diarrhoea, fatigue and dystonia. Of these
akathisia and somnolence appeared to be dose-related.
The following are all ADRs that were reported with XEPLION by frequency
category estimated from XEPLION clinical trials.
The following terms and frequencies are applied: very common (≥ 1/10),
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare
(≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot
be estimated from the available data).
Adverse Drug reaction
System
organ class
Infections and
Infestations
XEPLION
®
Prolonged release suspension for
intramuscular injection
SCHEDULING STATUS
Schedule 5.
PROPRIETARY NAME (and dosage form)
XEPLION 50 mg
XEPLION 75 mg
XEPLION 100 mg
XEPLION 150 mg
(Prolonged release suspension for intramuscular injection).
64 % in moderate (CrCl = 30 to < 50 mL/min), and 71 % in severe (CrCl = 10 to
< 30 mL/min) renal impairment, corresponding to an average increase
in exposure (AUCinf) of 1,5; 2,6 and 4,8 fold, respectively, compared
to healthy subjects.
Elderly: No dosage adjustment is recommended based on age alone.
However, dose adjustment may be required because of age-related
decreases in creatinine clearance (see Renal Impairment above and
DOSAGE AND DIRECTIONS FOR USE).
Gender: No clinically significant differences were observed between men
and women.
Smoking Status: Based on in vitro studies utilising human liver enzymes,
paliperidone is not a substrate for CYP1A2; smoking should, therefore,
not have an effect on the pharmacokinetics of paliperidone. Consistent
with these in vitro results, population pharmacokinetic evaluation has not
revealed any differences between smokers and non-smokers.
COMPOSITION
Each pre-filled syringe contains sterile paliperidone palmitate equivalent
to 50 mg paliperidone.
Each pre-filled syringe contains sterile paliperidone palmitate equivalent
to 75 mg paliperidone.
Each pre-filled syringe contains sterile paliperidone palmitate equivalent
to 100 mg paliperidone.
Each pre-filled syringe contains sterile paliperidone palmitate equivalent
to 150 mg paliperidone.
Inactive ingredients in XEPLION are polysorbate 20, polyethylene glycol 4000,
citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium
dihydrogen phosphate monohydrate, sodium hydroxide, water for injection.
INDICATIONS
XEPLION is indicated for the treatment of schizophrenia and for the prevention of recurrence of symptoms of schizophrenia.
PHARMACOLOGICAL CLASSIFICATION
A.2.6.5 Central nervous system depressants. Miscellaneous structures.
WARNINGS
Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome (NMS), characterized by hyperthermia,
muscle rigidity, autonomic instability, altered consciousness, and elevated
serum creatine phosphokinase levels has been reported to occur with
XEPLION. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms
indicative of NMS, XEPLION, should be discontinued.
PHARMACOLOGICAL ACTION
Pharmacodynamic properties
Paliperidone palmitate, the active ingredient, is a psychotropic agent belonging
to the chemical class of benzisoxazole derivatives, and is a metabolite of
risperidone
Mechanism of Action
Paliperidone palmitate is hydrolysed to paliperidone.
Paliperidone is a centrally active dopamine D2 antagonist with predominant
serotonergic 5-HT2A antagonistic activity. Paliperidone is also active as an
antagonist at 1 and 2 adrenergic receptors and H1 histaminergic receptors.
Paliperidone has no affinity for cholinergic muscarinic or 1- and 2-adrenergic
receptors. The pharmacological activity of the (+)– and (-)- paliperidone
enantiomers is qualitatively and quantitatively similar.
The mechanism of action of paliperidone, is unknown. However, it has been
proposed that the medicine’s therapeutic activity in schizophrenia is mediated
through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2A)
receptor antagonism. Antagonism at receptors other than D2 and 5HT2A
may explain some of the other effects of paliperidone.
Electrophysiology
The effects of oral paliperidone on the QT interval were evaluated in two
randomized, double-blind, multicenter, phase 1 studies in adults with
schizophrenia and schizoaffective disorder, and in three placebo- and
active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
Clinical Efficacy
The efficacy of paliperidone palmitate in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week)
double-blind, randomized, placebo-controlled, fixed-dose studies of acutely
relapsed adult inpatients who met DSM-IV criteria for schizophrenia and
who did tolerate risperidone or oral paliperidone. The fixed doses of paliperidone palmitate in these studies were given on days 1, 8, and 36 in the
9-week study, and additionally on day 64 of the 13-week studies, i.e., at
a weekly interval for the initial two doses and then every 4 weeks for
maintenance.
Pharmacokinetic properties
Absorption and Distribution
Due to the extremely low water solubility, paliperidone palmitate dissolves
slowly after intramuscular injection before being hydrolysed to paliperidone
and absorbed into the systemic circulation. Following a single intramuscular
dose, the plasma concentrations of paliperidone gradually rise to reach
maximum plasma concentrations at a median tmax of 13 days. The release
of the medicine starts as early as day 1 and lasts for as long as 126 days.
Following intramuscular injection of single doses (25-150 mg) in the deltoid
muscle, on average, a 28 % higher Cmax was observed compared with
injection in the gluteal muscle. The two initial deltoid intramuscular injections
of 150 mg on day 1 and 100 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen results in sustained
therapeutic concentrations. The total exposure (AUC) of paliperidone
following administration was dose proportional over a 25-150 mg dose
range but was less than dose proportional for Cmax for doses exceeding
50 mg. The mean steady state peak: trough ratio for a dose of 100 mg was
1,8 following gluteal administration and 2,2 following deltoid administration.
The median apparent half-life of paliperidone following administration over
the dose range of 25-150 mg ranged from 25-49 days.
Metabolism and Elimination
One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59 % of the dose was excreted unchanged
into urine, indicating that paliperidone is not extensively metabolised in 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 oral paliperidone between
extensive metabolisers and poor metabolisers of CYP2D6 substrates.
In vitro studies in human liver microsomes showed that paliperidone does
not substantially inhibit the metabolism of medicines metabolised by
cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10,
CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
Paliperidone palmitate is designed to deliver paliperidone over a monthly
period. In general, overall initiation plasma levels with paliperidone palmitate
were within the exposure range observed with 6-12 mg extended-release
oral paliperidone. The use of the paliperidone palmitate initiation regimen
allowed patients to stay in this exposure window of 6-12 mg extendedrelease oral paliperidone even on trough pre-dose days (Day 8 and Day 36).
The intersubject variability for paliperidone pharmacokinetics following
delivery from paliperidone palmitate was lower relative to the variability
determined from extended-release oral paliperidone tablets. Because of
the difference in median pharmacokinetic profiles between the two products,
caution should be exercised when making a direct comparison of their
pharmacokinetic properties.
Special Populations
Hepatic Impairment:
Paliperidone is not extensively metabolised in the liver. Although paliperidone
palmitate was not studied on patients with hepatic impairment, no dose
adjustment is required in patients with mild or moderate hepatic impairment.
In a study with oral paliperidone in subjects with moderate hepatic impairment
(Child-Pugh class B), the plasma concentrations of free paliperidone were
similar to those of healthy subjects. Paliperidone has not been studied in
patients with severe hepatic impairment.
Renal Impairment:
The dose of paliperidone palmitate should be reduced in patients with
mild renal impairment; paliperidone palmitate is not recommended for use
in patients with moderate or severe renal impairment (see CONTRAINDICATIONS and DOSAGE AND DIRECTIONS FOR USE).
Elimination of paliperidone decreased with decreasing estimated creatinine
clearance. Total clearance of paliperidone was reduced in subjects with
impaired renal function by 32 % on average in mild (CrCl = 50 to < 80 mL/min),
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CONTRA-INDICATIONS
XEPLION is contraindicated in patients with a known hypersensitivity to
paliperidone or to any of the components in the formulation.
XEPLION is contraindicated in patients with a known hypersensitivity
or intolerance to risperidone as paliperidone is an active metabolite of
risperidone
Moderate to severe renal impairment
Parkinson’s disease and Dementia with Lewy Bodies
Tardive Dyskinesia
Medicines with dopamine receptor antagonistic properties such as XEPLION
have been associated with the induction of tardive dyskinesia characterized
by rhythmical, involuntary movements, predominantly of the tongue and/or
face. If signs and symptoms of tardive dyskinesia appear, the discontinuation
of XEPLION, should be considered.
Leukopenia, neutropenia, and agranulocytosis
Events of leucopenia, neutropenia, and agranulocytosis have been reported
with XEPLION. Agranulocytosis has been reported during postmarketing
surveillance.
Patients with a history of a clinically significant low white blood cell count
(WBC) or a drug-induced leukopenia/neutropenia should be monitored
during the first few months of therapy and discontinuation of XEPLION
should be considered at the first sign of a clinically significant decline in WBC
in the absence of other causative factors. Patients with clinically significant
neutropenia should be carefully monitored for fever or other symptoms or
signs of infection and treated promptly if such symptoms or signs occur.
Patients with severe neutropenia (absolute neutrophil count < 1 X 109/L)
should discontinue XEPLION and have their WBC followed until recovery.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with XEPLION.
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 XEPLION and preventative measures undertaken.
Elderly Patients with Dementia
XEPLION has not been studied in elderly patients with dementia. Since
paliperidone is an active metabolite of risperidone, elderly patients with
dementia should not be treated with XEPLION as there is an overall
increase in mortality, cardiovascular and cerebrovascular adverse events.
(see Contra-indications).
Hyperglycaemia and Diabetes Mellitus
Hyperglycaemia, in some cases extreme and associated with ketoacidosis
or hyperosmolar coma or death, has been reported in patients treated
with XEPLION
Patients with an established diagnosis of diabetes mellitus, who are started
on XEPLION should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g. obesity, family history
of diabetes) who are starting treatment with XEPLION should be monitored
for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia
and weakness.
Patients who develop symptoms of hyperglycaemia during treatment with
XEPLION should undergo fasting blood glucose testing. In some cases,
hyperglycaemia has resolved when XEPLION was discontinued; however,
other patients required continuation of anti-diabetic treatment despite discontinuation of XEPLION.
Weight gain
Weight gain has been observed. Clinical monitoring of weight is recommended.
Parkinson’s Disease and Dementia with Lewy Bodies
XEPLION, is contra-indicated in patients with Parkinson’s Disease or patients
with Dementia with Lewy Bodies (DLB) (See Contra-indications) since
both groups may be at increased risk of Neuroleptic Malignant Syndrome
as well as having an increased sensitivity to antipsychotic medications
such as XEPLION.
Manifestation of this increased sensitivity can include confusion, obtundation,
postural instability with frequent falls, in addition to extrapyramidal symptoms.
In addition, in clinical trials, elderly risperidone treated patients had a higher
mortality than placebo treated elderly patients.
Priapism
Medicines with alpha-adrenergic blocking effects have been reported
to induce priapism. Priapism has been reported with paliperidone during
postmarketing surveillance.
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.
Administration
Care must be taken to avoid inadvertent injection of XEPLION into a blood
vessel.
Intraoperative Floppy Iris Syndrome
Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic
antagonist effect, such as XEPLION.
IFIS may increase the risk of eye complications during and after the
operation. Current or past use of XEPLION should be made known
to the ophthalmic surgeon in advance of surgery. The potential benefit
of stopping XEPLION therapy prior to cataract surgery has not been
established and must be weighed against the risk of stopping the
XEPLION therapy.
INTERACTIONS:
Caution is advised when prescribing XEPLION with medicines known to
prolong the QT interval.
Since XEPLION is hydrolysed to paliperidone (see Pharmacokinetic Properties), results from studies with oral paliperidone should be taken into
consideration when assessing interaction potential.
Potential for XEPLION to Affect Other Medicines
XEPLION is not expected to cause clinically important pharmacokinetic
interactions with medicines that are metabolised by cytochrome P-450
isozymes. In vitro studies in human liver microsomes showed that paliperidone
does not substantially inhibit the metabolism of medicines metabolised by
Very
Common
Common
Upper
respiratory
tract infection,
urinary tract
infection,
influenza
Blood and
lymphatic
system
disorders
Endocrine
Disorder
Metabolism
and
nutrition
disorders
Inappropriate
antidiuretic
hormone
secretion
Hyperglycaemia,
weight
increased,
weight
decreased,
blood triglycerides increased
Sleep disorder, Anorgasmia
mania,
confusional
state, libido
decreased,
nervousness
night-mare
Nervous
system
disorders
Headache Dystoniac
parkinsonismc
akathisiac,
dyskinesiac,
tremor,
dizziness,
sedation/
somnolence,
Tardive
dyskinesia,
convulsionsc,
syncope,
psychomotor
hyperactivity,
dizziness
postural,
disturbance
in attention,
dysarthria,
dysgeusia,
hypoaesthesia,
paraesthesia
Neuroleptic
malignant
syndrome,
cerebral
ischaemia,
unresponsive to
stimuli, loss of
consciousness,
depressed
level of
consciousness,
balance
disorder
Blurred vision,
conjunctivitis,
dry eye
Eye movement
disorder,
eye rolling,
photophobia,
lacrimation
increased,
ocular
hyperaemia
Vertigo, tinnitus,
ear, pain
Cardiac
disorders
Bradycardia,
tachycardia
Atrial
Sinus
fibrillation,
arrhythmias
atrioventricular
block,
electrocardiogram QT
prolonged,
postural
orthostatic
tachycardia
syndrome,
palpitations,
abnormal
electrocardiogram
Vascular
disorders
Hypertension
Hypotension,
orthostatic
hypotension
Respiratory
thoracic and
mediastinal
disorders
Cough, nasal
congestion
Dyspnoea,
Respiratory
pulmonary
tract
congestion,
congestion
wheezing,
pharyngolaryngeal pain,
epistaxis
Vomiting,
abdominal
pain
diarrhoea,
nausea,
constipation,
toothache,
dyspepsia
Abdominal
discomfort
gastroenteritis,
dry mouth,
flatulence
Deep vein
thrombosis,
flushing
Pancreatitis,
swollen
tongue, faecal
incontinence,
faecaloma,
dysphagia
Transaminases Gamincreased
maglutamyltransferase
increased,
hepatic
enzyme
increased
Skin and
Subcutaneous tissue
disorders
Rash
Musculoskeletal and
connective
tissue
disorders
Musculoskeletal Muscle
pain,
spasms, joint
back pain,
stiffness, neck
pain, arthralgia
Urticaria,
Drug eruption,
pruritus,
hyperkeratosis,
alopecia,
dandruff
eczema, dry
skin, erythema,
acne
Blood creatine
phosphokinase
increased,
joint
swelling,
muscular
weakness
Urinary
incontinence,
pollakiuria,
dysuria
Urinary
retention
Reproductive
system
and breast
disorders
Gynaecomastia,
erectile
dysfunction,
ejaculation
disorder, sexual
dysfunction,
galactorrhoea,
amenorrhoea,
menstruation
delayed,
menstrual
disorderc,
vaginal
discharge
Breast pain,
breast
engorgement,
breast
enlargement,
breast
discharge,
breast
discomfort
Face oedema,
oedemac, gait
abnormal,
chest
discomfort,
chest pain.
malaise,
induration
Hypothermia,
chills, body
temperature
increased,
thirst,
injection site
abscess,
injection site
cellulitis,
injection
site haematoma
Injury,
poisoning
and
procedural
complications
Pyrexia,
asthenia,
fatigue,
injection site
reaction
Fall
Hyperprolactinaemia can in some cases lead to gynaecomastia, menstual disturbances,
amenorrhoea, and galactorrhoea.
In placebo-controlled trials, diabetes mellitus was reported in 0.32% in XEPLION-treated
subjects compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.47% in all XEPLION-treated subjects
Insomnia includes: initial insomnia, middle insomnia; EPS included a pooled analysis of the
following terms: Parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness,
Parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle
tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex
abnormal, parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia,
and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis,
athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, muscle
contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis,
facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus,
tongue spasm, and trismus), and tremor. It should be noted that a broader spectrum of
symptoms are included that do not necessarily have an extrapyramidal origin. Convulsion
includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral,
pitting oedema. Menstrual disorder includes: menstruation irregular, oligomenorrhoea
Instructions for Use and Handling and Disposal
The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch
22 gauge needle and a 1-inch 23 gauge needle) for intramuscular injection.
Adverse reactions identified during post-marketing experience with
XEPLION
Blood and lymphatic system
disorders
Agranulocytosis
Metabolism and nutrition disorders Water intoxication, diabetic
ketoacidosis
Immune system disorder
Anaphylactic reaction
Psychiatric disorders
Blunted affect
Nervous system disorders
Diabetic coma, coordination
abnormal, head titubation
Eye Disorder
Glaucoma, floppy iris syndrome
(intraoperative)
Vascular disorders
Pulmonary embolism, ischaemia
Respiratory thoracic and
mediastinal disorders
Sleep apnoea syndrome,
hyperventilation,
Pneumonia aspiration, dysphonia
Gastrointestinal disorders
Intestinal obstruction, cheilitis.
paralytic ileus
Hepatobiliary disorders
Jaundice
Skin and Subcutaneous tissue
disorders
Seborrhoeic dermatitis,
angioedema, skin
discolouration
Musculoskeletal and connective
tissue disorders
Rhabdomyolysis, posture abnormal
Pregnancy, puerperium and
perinatal conditions
Drug withdrawal syndrome neonatal
Reproductive system and breast
disorders
Priapism
General disorders and
Administration site conditions
Body temperature decreased, drug
withdrawal syndrome, injection
site cyst
Cases of anaphylactic reaction after injection with XEPLION have been
reported during postmarketing experience in patients who have previously
tolerated oral risperidone or oral paliperidone.
Weight Gain. Dose-related weight gain of ≥ 7 % occurs in between 6 %
and 13 % of patients.
Laboratory Tests: Serum Prolactin. Based on pooled data from the two
13-week, fixed-dose double-blind, placebo-controlled trials, median
increases in serum prolactin were observed in subjects of both genders
who received XEPLION IM. The results from the 13-week study involving
150 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebocontrolled trial, and the double-blind phase of the recurrence prevention
trial exhibited comparable findings.
A-22Gx1½″ Gray hub; B-23Gx1″ Blue hub; C-Prefilled Syringe; D-Hub;
E-Tip cap
XEPLION IM is for single use only.
1. Shake the syringe vigorously for a minimum of 10 seconds to ensure
a homogeneous suspension.
2. Select the appropriate needle.
For DELTOID injection, if the patient weighs < 200 lb (< 90 kg), use the
1-inch 23 gauge needle (needle with blue colored hub); if the patient
weighs ≥ 200 lb (≥ 90 kg), use the 1 ½-inch 22 gauge needle (needle
with grey coloured hub).
For GLUTEAL injection, use the 1 ½-inch 22 gauge needle (needle with
grey coloured hub).
3. While holding the syringe upright, remove the rubber tip cap with an
easy clockwise twisting motion.
4. Peel the safety needle pouch half way open. Grasp the needle sheath
using the plastic peel pouch. Attach the safety needle to the luer
connection of the syringe with an easy clockwise twisting motion.
Special Precautions:
QT Interval
Caution should be exercised when XEPLION is prescribed in patients
with a history of cardiac dysrhythmias, in patients with congenital long QT
syndrome, and in concomitant use with medicines known to prolong the
QT interval.
Orthostatic Hypotension
Paliperidone may induce orthostatic hypotension in patients based on its
alpha-blocking activity. XEPLION 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
hypovolaemia, and treatment with antihypertensive medications).
5. Pull the needle sheath away from the needle with a straight pull. Do not
twist the sheath as the needle may be loosened from the syringe.
Seizures
XEPLION should be used cautiously in patients with a history of seizures
or other conditions that potentially lower the seizure threshold.
Body Temperature Regulation
Disruption of the body’s ability to reduce core body temperature may occur.
Appropriate care is advised when prescribing XEPLION 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.
Effects on ability to drive and use machines:
XEPLION can have an influence on the ability to drive and use machines
due to potential nervous system effects (see SIDE EFFECTS). Therefore,
patients should be advised not to drive or operate machines until their
individual susceptibility to XEPLION is known.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS
TREATMENT
Symptoms
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 the setting of overdose with oral paliperidone.
In the case of acute overdosage, the possibility of multiple drug involvement
should be considered.
Treatment
Consideration should be given to the extended-release nature of XEPLION
and the long apparent half-life of paliperidone 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. In case of
severe extrapyramidal symptoms, anticholinergic agents should be
administered. Close supervision and monitoring should continue until the
patient recovers.
IDENTIFICATION
Prolonged-release suspension in prefilled syringes. The suspension is white
to off-white, free from visible foreign material. The suspension is homogenous
after shaking.
PRESENTATION
Kit containing a syringe (cyclic-olefin-copolymer) prefilled with either 50 mg
(0,5 ml), 75 mg (0,75 ml), 100 mg (1,0 ml), or 150 mg (1,5 ml) paliperidone
(as 39 mg, 78 mg, 117 mg, 156 mg, or 234 mg paliperidone palmitate)
suspension with a plunger stopper and tip cap (bromobutyl rubber),
a 1 ½-inch 22 gauge safety needle, and a 1-inch 23 gauge safety needle.
STORAGE INSTRUCTIONS
Store at or below 25° C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.
XEPLION injection is for single use only. Any unused portion should be
discarded.
Renal and
urinary
disorders
General
disorders and
Administration
site
conditions
Glucose
urine
present
Hypoglycaemia
Diabetes
polydipsia
mellitusb
hyperinsulinaemia, increased
appetite,
anorexia,
decreased
appetite,
increased blood
cholesterol
Insomniac Agitation,
depression,
anxiety
Hepatobiliary
disorders
c
Neutropenia,
thrombocytopenia
Psychiatric
disorders
Gastrointestinal
disorders
Not
Known
Pneumonia,
Onychomycosis
bronchitis,
respiratory tract
infection,
sinusitis,
cystitis, ear
infection,
eye infection,
tonsillitis,
cellulitis,
acarodermatitis,
subcutaneous
abscess
Hyperprolactinaemiaa
Ear and
labyrinth
disorders
b
Rare
Hypersensitivity
Eye Disorder
a
Uncommon
White blood
cell count
decreased,
anaemia,
haematocrit
decreased,
eosinophil
count
increased
Immune
System
Disorder
PREGNANCY AND LACTATION
Pregnancy
The safety of intramuscularly-injected XEPLION or orally-dosed paliperidone
for use during human pregnancy has not been established. Neonates
exposed to XEPLION during the third trimester of pregnancy are at risk
for extrapyramidal and/or withdrawal symptoms that may be severe. These
symptoms in the neonates may include agitation, hypertonia, hypotonia,
tremor, somnolence, respiratory distress, or feeding disorder.
Lactation
In animal studies with paliperidone and in human studies with risperidone,
paliperidone was excreted in the milk. Therefore, women receiving XEPLION
should not breast-feed infants.
DOSAGE AND DIRECTIONS FOR USE
For patients who have never taken oral paliperidone, or oral or
injectable risperidone, it is recommended to establish tolerability
with oral paliperidone or oral risperidone prior to initiating treatment
with XEPLION.
The recommended initiation of XEPLION is with a dose of 150 mg on
treatment Day 1 and 100 mg one week later, both administered in the
deltoid muscle. The recommended monthly maintenance dose is 75 mg;
some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability
and/or efficacy. Following the second dose, monthly maintenance doses
can be administered in either the deltoid or gluteal muscle.
Adjustment of the maintenance dose may be made monthly. When making
dose adjustments, the prolonged-release characteristics of XEPLION should
be considered (see Pharmacokinetic Properties), as the full effect of the
dose adjustment may not be evident for several months.
Missed Doses
Avoiding missed doses:
It is recommended that the second initiation dose of XEPLION be given one
week after the first dose. To avoid a missed dose, patients may be given
the second dose 2 days before or after the one-week (day 8) time point.
Similarly, the third and subsequent injections after the initiation regimen
are recommended to be given monthly. To avoid a missed monthly dose,
patients may be given the injection up to 7 days before or after the monthly
time point.
If the target date for the second XEPLION injection (day 8 ± 2 days) is
missed, the recommended reinitiation depends on the length of time which
has elapsed since the patient's first injection.
Missed second initiation dose (< 4 weeks from first injection):
If less than 4 weeks have elapsed since the first injection, then the patient
should be administered the second injection of 100 mg in the deltoid
muscle as soon as possible. A third XEPLION injection of 75 mg in either
the deltoid or gluteal muscles should be administered 5 weeks after the
first injection (regardless of the timing of the second injection). The normal
monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg
to 150 mg based on individual patient tolerability and/or efficacy should
be followed thereafter.
Missed second initiation dose (4 - 7 weeks from first injection)
If 4 to 7 weeks have elapsed since the first injection of XEPLION, resume
dosing with two injections of 100 mg in the following manner:
1. a deltoid injection as soon as possible,
2. another deltoid injection one week later,
3. resumption of the normal monthly cycle of injections in either the deltoid
or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy.
Missed second initiation dose (> 7 weeks from first injection)
If more than 7 weeks have elapsed since the first injection of XEPLION,
initiate dosing as described for the initial recommended initiation of XEPLION
above.
Missed monthly maintenance dose (1 month to 6 weeks):
After initiation, the recommended injection cycle of XEPLION is monthly.
If less than 6 weeks have elapsed since the last injection, then the previously
stabilised dose should be administered as soon as possible, followed by
injections at monthly intervals.
Missed monthly maintenance dose (> 6 weeks to 6 months):
If more than 6 weeks have elapsed since the last injection of XEPLION,
the recommendation is as follows:
For patients stabilised with doses of 25 to 100 mg:
1. a deltoid injection as soon as possible at the same dose the patient
was previously stabilised on
2. another deltoid injection (same dose) one week later (day 8)
3. resumption of the normal monthly cycle of injections in either the deltoid
or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy
For patients stabilised with 150 mg:
1. a deltoid injection as soon as possible at the 100 mg dose
2. another deltoid injection one week later (day 8) at the 100 mg dose
3. resumption of the normal monthly cycle of injections in either the deltoid
or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy
Missed monthly maintenance dose (> 6 months):
If more than 6 months have elapsed since the last injection of XEPLION,
initiate dosing as described for the initial recommended initiation of XEPLION
above.
Administration Information
XEPLION is intended for deep intramuscular use only. Inject slowly, deep
into the muscle. Care should be taken to avoid inadvertent injection into
a blood vessel.
Each injection should be administered by a health care professional.
Administration should be in a single injection. Do not administer the dose
in divided injections. Do not administer intravascularly or subcutaneously.
The recommended needle size for administration of XEPLION into the
deltoid muscle is determined by the patient’s weight. For those ≥ 90 kg
(≥ 200 lb), the 1½ inch, 22-gauge needle is recommended. For those
< 90 kg (< 200 lb), the 1-inch, 23 gauge needle is recommended. Deltoid
injections should be alternated between the two deltoid muscles.
The recommended needle size for administration of XEPLION into the
gluteal muscle is the 1½-inch, 22 gauge needle. Administration should be
made into the upper-outer quadrant of the gluteal area. Gluteal injections
should be alternated between the two gluteal muscles.
Concomitant use of XEPLION with oral paliperidone or oral or injectable
risperidone has not been studied and it is not recommended.
Patients with Hepatic Impairment
XEPLION has not been studied in patients with hepatic impairment.
Based on a study with oral paliperidone, no dose adjustment is required
in patients with mild or moderate hepatic impairment. Paliperidone has not
been studied in patients with severe hepatic impairment. (See Pharmacokinetic Properties)
Patients with Renal Impairment
XEPLION has not been systematically studied in patients with renal
impairment (see Pharmacokinetic Properties). For patients with mild renal
impairment (creatinine clearance ≥ 50 to < 80 mL/min), recommended
initiation of XEPLION is with a dose of 100 mg on treatment day 1, and
75 mg one week later, both administered in the deltoid muscle. Thereafter,
follow with monthly injections of 50 mg in either the deltoid or gluteal muscle,
adjusted within the range of 25 to 100 mg based on patient tolerability
and/or efficacy.
XEPLION is not recommended in patients with moderate or severe renal
impairment (creatinine clearance < 50 ml/min). (See Contra-indications)
Elderly
In general, recommended dosing of XEPLION for elderly patients with
normal renal function is the same as for younger adult patients with normal
renal function. As elderly patients may have reduced renal function,
see Patients with Renal Impairment above for dosing recommendations in
patients with renal impairment.
Adolescents and Children
Safety and effectiveness of XEPLION in patients < 18 years of age have
not been studied.
Other Special Populations
No dose adjustment for XEPLION is recommended based on gender,
race, or smoking status. (For pregnant women and nursing mothers, see
Pregnancy and Lactation).
Switching From Other Antipsychotic Agents
There are no systematically collected data to specifically address switching
schizophrenic patients from other antipsychotics to XEPLION, or concerning
concomitant administration with other antipsychotics. Previous oral antipsychotics can be discontinued at the time of initiation of treatment with
XEPLION.
When switching patients currently at steady-state on a long acting injectable
antipsychotic, initiate XEPLION therapy in place of the next scheduled
injection. XEPLION should then be continued at monthly intervals.
The one-week initiation dosing regimen as described under “Dosage and
Directions for Use” above is not required.
Frequency
Adverse reactions experienced with risperidone formulations:
Paliperidone is the active metabolite of risperidone, therefore, the adverse
reaction profiles of these compounds (including both the oral and injectable
formulations) are relevant to one another.
In addition to the above adverse reactions, the following adverse reactions
have been noted with the use of risperidone products and can be expected
to occur with XEPLION.
Nervous system disorders: cerebrovascular disorder.
Respiratory, thoracic and mediastinal disorders: rales.
General disorders and administration site conditions (observed with
injectable formulation of risperidone): injection site necrosis, injection site
ulcer.
REGISTRATION NUMBER(s)
XEPLION® 50 mg – 44/2.6.5/0866
XEPLION® 75 mg – 44/2.6.5/0867
XEPLION® 100 mg – 44/2.6.5/0868
XEPLION® 150 mg – 44/2.6.5/0870
NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/011122/07)
Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191
Tel: 27 (11) 518 7000
www.janssen.co.za
DATE OF PUBLICATION OF THE PACKAGE INSERT
June 2013
6. Bring the syringe with the attached needle in upright position to de-aerate.
De-aerate the syringe by moving the plunger rod carefully forward.
7. Inject the entire contents intramuscularly into the selected deltoid
or gluteal muscle of the patient. Do not administer intravascularly
or subcutaneously.
8. After the injection is complete, use either thumb or finger of one hand
(8a, 8b) or a flat surface (8c) to activate the needle protection system.
The needle protection system is fully activated when a ‘click’ is heard.
Discard the syringe with needle appropriately.
8a
8b
8c
XEPLION
®
Langwerkend-vrystelling suspensie
vir intramuskulêre inspuiting
SKEDULERINGSTATUS
Skedule 5
EIENDOMSNAAM (en doseervorm)
XEPLION 50 mg
XEPLION 75 mg
XEPLION 100 mg
XEPLION 150 mg
(Langwerkend-vrystelling suspensie vir intramuskulêre inspuiting).
SAMESTELLING
Elke vooraf-gevulde spuit bevat 50, 75, 100 of 150 mg steriele paliperidoon
Onaktiewe bestanddele in XEPLION is polisorbaat 20, poliëtileenglikool
4 000, sitroensuur monohidraat, dinatriumwaterstoffosfaat anhidries, natriumdiwaterstoffosfaat monohidraat, natriumhidroksied, water vir inspuiting.
FARMAKOLOGIESE KLASSIFIKASIE
A. 2.6.5 Stimulante vir sentrale senuweestelsel. Diverse strukture.
FARMAKOLOGIESE WERKING
Farmakodinamiese eienskappe
Paliperidoonpalmitaat, die aktiewe bestanddeel, is ’n psigotropiese middel
wat chemies deel vorm van die bensisokasool devirate en ’n metaboliet
is van risperidoon.
Meganisme van werking
Paliperidoonpalmitaat word tot paliperidoon gehidroliseer.
Paliperidoon is ’n sentraal werkende dopamien D2-antagonis met oorwegend
serotonergiese 5-HT2A antagonistiese werking. Paliperidoon is ook aktief
as ’n antagonis by 1 en 2 adrenergiese reseptore en H1 histaminergiese
reseptore. Paliperidoon het geen affiniteit vir cholinergiese muskariene of
1- en 2-adrenergiese reseptore nie. Die farmakologiese werking van die
(+)– en (-)- paliperidoon enantiomere kom kwalitatief en kwantitatief ooreen.
Die werkingsmeganisme van paliperidoon is onbekend. Daar is egter voorgestel dat die medisyne se terapeutiese werksaamheid by skisofrenie bemiddel
word deur ’n kombinasie van dopamien Tipe 2 (D2) en serotonien Tipe 2
(5HT2A) reseptor antagonisme. Antagonisme by ander reseptors as D2 en
5HT2A kan sommige van die ander effekte van paliperidoon verduidelik.
Elektrofisiologie
Die werking van orale paliperidoon op die QT-interval is ondersoek by twee
ewekansige, dubbelblinde, multisentrum, fase-1 navorsingstudies by volwassenes met skisofrenie en skiso-affektiewe steuring en by drie plaseboen aktief-gekontroleerde 6-week, vaste-dosis doeltreffendheidsproewe by
volwassenes met skisofrenie.
Kliniese doeltreffendheid
Die doeltreffendheid van paliperidoonpalmitaat by die akute behandeling van
skisofrenie is ondersoek met vier korttermyn (een 9-week en drie 13-week)
dubbelblinde, ewekansige, plasebo-beheerde, vaste dosis navorsingstudies
oor akute-terugval volwasse binnepasiënte wat voldoen aan die DSM-IV
kriteria vir skisofrenie en wat risperidoon of orale paliperidoon verdra het.
Die vaste doserings van paliperidoonpalmitaat in hierdie navorsingstudies
is gegee op dae 1, 8 en 36 in die 9-weke navorsingstudie en ook op dag
64 van die 13-week navorsingstudies, d.i., met ’n weeklikse interval vir die
aanvanklike twee dosisse en dan elke 4 weke vir instandhouding.
Farmakokinetiese eienskappe
Absorpsie en verspreiding
Te wyte aan die buitengewone lae oplosbaarheid in water, los paliperidoonpalmitaat stadig op na intramuskulêre inspuiting voordat dit gehidroliseer word
na paliperidoon en geabsorbeer word in die sistemiese sirkulasie. Na ’n enkele
intramuskulêre dosis, styg die plasmakonsentrasie van paliperidoon geleidelik om maksimum plasmakonsentrasies by ’n mediane tmaks van 13 dae.
Die vrystelling van die medisyne begin reeds op dag 1 en dit duur tot 126 dae.
Na intramuskulêre inspuiting van enkel dosisse (25-150 mg) in die deltaspier,
is daar gemiddeld 28 % hoër Kmaks waargeneem, vergeleke met inspuiting
in die gluteale spier. Die aanvanklike twee deltaspier inspuitings van 150 mg
op dag 1 en 100 mg op dag 8 help om terapeutiese konsentrasies vinnig
te bereik. Die vrystellingsprofiel en doseringsregimen resulteer in verlengde
terapeutiese konsentrasies. Die totale blootstelling (AOK) van paliperidoon na toediening was eweredig met die dosis oor ’n 25-150 mg dosisreikwydte maar dit was minder as dosis-eweredig vir Kmaks vir dosisse bo
50 mg. Die gemiddelde vaste toestand piek:trog-verhouding vir ’n dosis van
100 mg was 1,8 na gluteale toediening en 2,2 na deltaspier-toediening.
Die mediane skynbare half-leeftyd van paliperidoon na toediening oor die
dosis-reikwydte 25-150 mg het gestrek van 25-49 dae.
Metabolisme and uitskeiding
Een week na toediening van ’n enkele orale dosis van 1 mg onmiddellikevrystelling 14C-paliperidoon, word 59 % van die dosis onveranderd in die
urine uitgeskei, wat daarop dui dat paliperidoon nie uitgebreid in die lewer
gemetaboliseer word nie. Ongeveer 80 % van die toegediende radioaktiwiteit
is in urine herwin en 11 % in die feses. Vier metaboliese weë, waarvan nie
een vir die afbraak van meer as 6,5 % van die dosis verantwoordelik is nie,
is in vivo geïdentifiseer: dealkilering, hidroksilasie, dehidrogenasie en
bensisoksasool splitsing.
Alhoewel in vitro navorsingstudies daarop gedui het dat CYP2D6 en CYP3A4
’n rol speel in die metabolisme van paliperidoon, is daar geen in vivo bewys
dat hierdie isoënsieme ’n belangrike rol by die metabolisme van paliperidoon
speel nie. Populasie-farmakokinetiese analises na toediening van paliperidoon
het nie op enige duidelike verskille tussen vinnige en stadige metaboliseerders
van CYP2D6-substrate in die opklaring van paliperidoon gedui nie. In vitro
navorsingstudies met mens lewermikrosome dui daarop dat paliperidoon nie
die afbraak van geneesmiddels, wat deur die sitochroom P450 isoënsieme,
insluitende CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4
en CYP3A5, gemetaboliseer word, tot ’n beduidende mate inhibeer nie.
Paliperidoonpalmitaat is ontwerp om paliperidoon oor ’n tydperk van een
maand vry te stel. Oor die algemeen was die algehele aanvangsplasmavlakke met paliperidoonpalmitaat binne die reikwydte van blootstelling,
waargeneem met 6-12 mg verlengde-vrystelling orale paliperidoon.
Die gebruik van die paliperidoonpalmitaat aanvangsregimen het toegelaat
dat pasiënte bly binne hierdie blootstellingsvenster van 6-12 mg verlengdevrystelling orale paliperidoon selfs op trog voor-dosering dae (Dag 8 en
Dag 36). Die inter-proefpersoon veranderlikheid vir paliperidoon farmakokinetika na lewering van paliperidoonpalmitaat was laer relatief tot die
variabiliteit bepaal uit verlengde-vrystelling orale paliperidoon tablette.
As gevolg van die verskil in mediane farmakokinetiese profiele tussen die
twee produkte, moet versigtigheid uitgeoefen word wanneer daar ’n direkte
vergelyking gemaak word van hulle farmakokinetiese eienskappe.
Spesiale populasies
Lewerinkorting:
Paliperidoon word nie uitgebreid in die lewer gemetaboliseer nie. Alhoewel
paliperidoonpalmitaat nie nagevors is by pasiënte met lewerinkorting nie,
is geen dosis aanpassing nodig by pasiënte met ligte tot matige lewerinkorting nie. In ’n navorsingstudie met orale paliperidoon by proefpersone
met matige lewerinkorting (Child-Pugh klas B), was die plasmakonsentrasies van vrye paliperidoon soortgelyk aan die van gesonde proefpersone.
Paliperidoon is nie bestudeer by pasiënte met erge lewerinkorting nie.
Nierinkorting:
Die dosis van paliperidoonpalmitaat moet verminder word by pasiënte met
ligte nierinkorting; paliperidoonpalmitaat word nie aanbeveel vir gebruik by
pasiënte met matige of ernstige nierinkorting nie (kyk KONTRAÏNDIKASIES
en DOSIS EN GEBRUIKSAANWYSINGS).
Uitskeiding van paliperidoon het verminder met afnemende geskatte kreatinien
opklaring. Totale opklaring van paliperidoon was verlaag by proefpersone
met ingekorte nierfunksie, met gemiddeld 32 % by ligte nierinkorting
(CrCl = 50 tot < 80 mL/min), 64 % by matige (CrCl = 30 tot < 50 mL/min)
en 71 % by ernstige nierinkorting (CrCl = 10 tot < 30 mL/min), wat ooreengekom het met ’n gemiddelde toename in blootstelling (AOKinf) van
onderskeidelik 1,5; 2,6; en 4,8- voudig, vergeleke met gesonde proefpersone.
Bejaardes. Geen dosisaanpassing slegs gegrond op ouderdom word
aanbeveel nie. Dosis aanpassing kan egter benodig word as gevolg van
ouderdomsverwante afnames in kreatinien opklaring (kyk Nierinkorting bo
en DOSIS EN GEBRUIKSAANWYSINGS).
Geslag. Geen klinies beduidende verskille tussen mans en vroue is waargeneem nie.
Rook status. Gebaseer op in vitro navorsingstudies met behulp van menslike lewerensieme, is paliperidoon nie ’n substraat vir CYP1A2 nie; rook
behoort dus nie ’n effek op die farmakokinetika van paliperidoon te hê nie.
In ooreenstemming met hierdie in vitro resultate, het populasie farmakokinetiese evaluering nie enige verskille tussen rokers en nie-rokers opgelewer nie.
INDIKASIES
XEPLION word aangedui vir die behandeling van skisofrenie en om te
voorkom dat die simptome van skisofrenie weer terugkeer.
KONTRAÏNDIKASIES
XEPLION word teenaangedui by pasiënte met ’n bekende hipersensitiwiteit
vir paliperidoon of vir enige van die komponente in die formulering.
XEPLION word teenaangedui by pasiënte met ’n bekende hipersensitiwiteit
of intoleransie vir risperidoon, aangesien paliperidoon ’n aktiewe metaboliet
is van risperidoon.
Matige tot ernstige nierinkorting.
Parkinson-siekte en demensie met Lewy-liggame.
WAARSKUWINGS
Neuroleptiese maligne sindroom
Neuroleptiese maligne sindroom (NMS), gekenmerk deur hipertermie,
spierstyfheid, outonome onstabiliteit, gewysigde bewussyn en verhoogde
serum-kreatienfosfokinase vlakke, het na berig word met XEPLION voorgekom. Bykomende kliniese tekens kan insluit mioglobienurie (rabdomiolise)
en akute nierversaking. Indien ’n pasiënt tekens of simptome ontwikkel
wat dui op NMS, moet XEPLION gestaak word.
Tardiewe diskinese
Medisyne met dopamien-reseptor antagonistiese eienskappe, soos XEPLION,
is geassosieer met die induksie van tardiewe diskinese, gekenmerk deur
ritmiese, onwillekeurige bewegings, hoofsaaklik van die tong en/of gesig.
Indien tekens en simptome van tardiewe diskinese voorkom, moet daar
oorweeg word om XEPLION te staak.
Leukopenie, neutropenie en agranulositose
Voorvalle van leukopenie, neutropenie en agranulositose is aangemeld met
XEPLION. Agranulositose is aangemeld tydens na-bemarking bewaking.
Pasiënte met ’n geskiedenis van ’n klinies beduidende lae witbloedseltelling (WBC) of ’n geneesmiddel-geïnduseerde leukopenie/neutropenie
moet gemoniteer word tydens die eerste paar maande van behandeling
en staking van XEPLION moet oorweeg word by die eerste tekens van
’n klinies beduidende afname in WBC (witbloedseltelling) sonder ander
oorsaaklike faktore. Pasiënte met klinies beduidende neutropenie moet
deeglik gemoniteer word vir koors of ander simptome of tekens van infeksie en vinnig behandel word indien sulke simptome of tekens voorkom.
Pasiënte met erge neutropenie (absolute neutrofieltelling < 1 X 109/L)
moet XEPLION staak en hulle WBC laat nagaan totdat hulle herstel het.
Veneuse tromboëmbolisme
Gevalle van veneuse tromboëmbolisme (VTE) is met XEPLION aangemeld.
Aangesien pasiënte wat met antipsigotiese middels behandel word dikwels
presenteer met verworwe risikofaktore vir VTE, moet alle moontlike risikofaktore vir VTE voor en tydens behandeling met XEPLION geïdentifiseer
word en voorkomende maatreëls getref word.
Bejaarde pasiënte met demensie
XEPLION is nie by bejaarde pasiënte met demensie bestudeer nie. Aangesien
paliperidoon ’n aktiewe metaboliet is van risperidoon, moet bejaarde
pasiënte met demensie nie met XEPLION behandel word nie aangesien
daar ’n algehele toename in mortaliteit, kardiovaskulêre en serebrovaskulêre
newe-effekte (kyk Kontraïndikasies) is.
Hiperglukemie en diabetes mellitus
Hiperglukemie, in sommige gevalle erg en geassosieer met ketoasidose
of hiperosmolêre koma of sterfte, is aangemeld by pasiënte wat met
XEPLION behandel is.
662692.pdf - Page 2 of 3 - May 26, 2015 - 12:58:08
Pasiënte met bevestigde diagnose van diabetes mellitus, wat begin word
op XEPLION, moet gereeld gemoniteer word vir agteruitgang in beheer
oor glukose. Pasiënte met risikofaktore vir diabetes mellitus (bv. vetsug,
familiegeskiedenis van diabetes) wat begin met XEPLION – behandeling
moet gemoniteer word vir simptome van hiperglukemie insluitende
polidipsie, poliurie, polifagie en swakheid. Pasiënte wat simptome van
hiperglukemie ontwikkel tydens behandeling met XEPLION moet getoets
word vir vastende bloed-glukose. In sommige gevalle het hiperglukemie
opgeklaar toe XEPLION gestaak is; ander pasiënte het egter voortsetting van
anti-diabetiese behandeling benodig, ten spyte van staking van XEPLION.
Gewigstoename
Gewigstoename is waargeneem. Kliniese monitering van gewig word aanbeveel.
Parkinson-siekte en demensie met Lewy-liggame
XEPLION is teenaangewys by pasiënte met Parkinson-siekte of pasiënte
met demensie met Lewy-liggame (DLB) (kyk Kontraïndikasies) aangesien
albei groepe ’n verhoogde risiko loop vir Neuroleptiese Maligne Sindroom
en ook vir verhoogde gevoeligheid vir antipsigotiese medikasies soos
XEPLION. Hierdie verhoogde gevoeligheid kan manifesteer as verwarring,
afstomping, posturale onstabiliteit met herhaaldelike valle, bykomend tot
ekstrapiramidale simptome. In kliniese proewe het bejaarde pasiënte wat met
risperidoon behandel is, ook ’n hoër mortaliteit as plasebo-behandelde
bejaarde pasiënte gehad.
Priapisme
Daar word vermeld dat medisyne met alfa-adrenergiese blokkeringseffek
priapisme induseer. Priapisme is aangemeld met paliperidoon tydens
na-bemarking toesighouding.
Anti-emetiese effek
’n Anti-emetiese effek is waargeneem met pre-kliniese navorsingstudies
met paliperidoon. Hierdie effek, indien dit by mense voorkom, kan die tekens
en simptome van oordosering met sekere medisyne of van toestande
soos inwendige obstruksie, Reye-sindroom en breingewas, maskeer.
Toediening
Wees versigtig om nie per abuis XEPLION in ’n bloedvat te spuit nie.
Intra-operatiewe slap-iris-sindroom
Intra-operatiewe slap-iris-sindroom (ISIS) is tydens katarakoperasies waargeneem by pasiënte wat met medisyne met alfa-1a-adrenergiese antagonistiese uitwerking, insluitende XEPLION, behandel is (kyk Newe-effekte).
ISIS kan die risiko van oogkomplikasies tydens en na die operasie verhoog.
Huidige of vorige gebruik van XEPLION moet voor die operasie aan die
oogchirurg bekend gemaak word. Die moontlike voordele om XEPLION
behandeling voor die katarakoperasie te staak, is nie vasgestel nie en moet
opgeweeg word teen die risiko om die XEPLION behandeling te staak.
INTERAKSIES:
Versigtigheid word aangeraai wanneer XEPLION saam met medisyne
voorgeskryf word om die QT-interval te verleng.
Aangesien XEPLION gehidroliseer word tot paliperidoon (kyk Farmakokinetiese eienskappe), moet resultate uit navorsingstudies met orale paliperidoon
in ag geneem word wanneer interaksies bepaal word.
Moontlikheid dat XEPLION ander medisyne sal affekteer
Daar word nie verwag dat XEPLION klinies belangrike farmakokinetiese
interaksies met medisyne wat deur sitochroom P-450 isosieme gemetaboliseer word, sal veroorsaak nie. In vitro navorsingstudies by mens lewermikrosome het getoon dat paliperidoon nie die metabolisme van medisyne wat
deur sitochroom P450 isosiem, insluitende CYP1A2, CYP2A6, CYP2C8/9/10,
CYP2D6, CYP2E1, CYP3A4, en CYP3A5, gemetaboliseer word, aansienlik
inhibeer nie. Gevolglik word daar nie verwag dat XEPLION die opklaring
van medisyne wat deur hierdie metaboliese bane gemetaboliseer word
op ’n klinies beduidende wyse inhibeer nie. Daar word ook nie vermoed
dat XEPLION ensiem-induserende eienskappe het nie.
XEPLION is ’n swak inhibeerder van P-glikoproteïen (P-gp) by hoë konsentrasies. Geen in vivo data is beskikbaar nie en die kliniese relevansie
is onbekend.
In die lig van die primêre SSS-effek van paliperidoon (kyk Newe-effekte)
moet XEPLION met versigtigheid gebruik word in kombinasie met ander
sentraal-werkende medisyne en alkohol. XEPLION kan die effek van
levodopa en ander dopamien-agoniste antagoniseer.
As gevolg van die potensiaal om ortostatiese hipotensie te induseer
(kyk Spesiale voorsorgmaatreëls: Ortostatiese hipotensie), kan ’n additiewe
effek waargeneem word wanneer XEPLION saam met ander terapeutiese
middels wat hierdie potensiaal het, toegedien word.
Farmakokinetiese interaksie tussen XEPLION en litium is onwaarskynlik.
Potensiaal vir ander medisyne om XEPLION te affekteer
Paliperidoon is nie ’n substraat vir CYP1A2, CYP2A6, CYP2C9, CYP2C19,
en CYP3A5 nie. Dit dui daarop dat ’n interaksie met inhibeerders of induseerders van hierdie isoënsieme onwaarskynlik is. Terwyl in vitro navorsingstudies daarop dui dat CYP2D6 en CYP3A4 minimaal betrokke kan wees
by paliperidoon metabolisme, is daar geen indikasie in vitro of in vivo dat
hierdie isosieme ’n beduidende rol speel by die metabolisme van paliperidoon
nie. In vitro navorsingstudies het daarop gedui dat paliperidoon ’n P-gp
substraat is.
Paliperidoon word tot ’n beperkte mate gemetaboliseer deur CYP2D6
(kyk Farmakokinetika: Metabolisme en Uitskeiding). In ’n interaksie navorsingstudie by gesonde proefpersone by wie orale paliperidoon gesamentlik
met paroksetien – ’n kragtige CYP2D6 inhibeerder - toegedien is, is geen
klinies beduidende effekte op die farmakokinetika van paliperidoon waargeneem nie.
Ko-administrasie van orale paliperidoon verlengde-vrystelling een keer
daagliks met karbamasepien 200 mg twee keer per dag het ’n afname
van ongeveer 37 % in die mediane bestendige toestand Kmaks en AOK
van paliperidoon veroorsaak. Hierdie afname word tot ’n aansienlike mate
veroorsaak deur ’n 35 % toename in renale opklaring van paliperidoon,
waarskynlik as gevolg van induksie van renale P-gp deur karbamasepien.
’n Geringe vermindering in die hoeveelheid medisyne wat onveranderd in
die urien uitgeskei word, dui daarop dat daar min uitwerking op die CYP
metabolisme of biobeskikbaarheid van paliperidoon tydens karbamasepien
ko-administrasie is. Met aanvang van karbamasepien moet die dosis van
XEPLION herevalueer word en verhoog word indien nodig. Omgekeerd,
wanneer karbamasepien gestaak word, moet die dosis van XEPLION
herevalueer en verminder word, indien nodig.
Paliperidoon, ’n katioon by fisiologiese pH, word hoofsaaklik onveranderd
uitgeskei deur die niere, ongeveer die helfte deur filtrasie en die helfte deur
aktiewe uitskeiding. Gesamentlike toediening van trimetoprim, ’n medisyne
met bekende inhibering van aktiewe renale katioon transportasie van
medisyne, het nie die farmakokinetika van paliperidoon beïnvloed nie.
Gesamentlike gebruik van XEPLION met risperidoon
Die gesamentlike gebruik van XEPLION met risperidoon is nie bestudeer nie.
Aangesien paliperidoon ’n aktiewe metaboliet is van risperidoon, word
ko-administrasie van risperidoon met XEPLION nie aanbeveel nie.
SWANGERSKAP EN LAKTASIE
Swangerskap
Die veiligheid van intramuskulêr – toegediende XEPLION, of oraal-gedoseerde paliperidoon vir gebruik tydens mens swangerskap is nie bepaal
nie. Pasgeborenes wat aan XEPLION tydens die derde trimester van
swangerskap blootgestel word, loop ’n risiko vir ekstrapiramidale en/of
onttrekkingsimptome na die bevalling, wat ernstig kan wees. Hierdie
simptome by die pasgeborenes kan insluit agitasie, hipertonie, hipotonie,
tremor, slaapsug, respiratoriese nood, of voedingsversteuring.
Laktasie
By dierestudies met paliperidoon en by mens navorsingstudies met risperidoon, is paliperidoon in die melk uitgeskei. Gevolglik moet vroue wat
XEPLION ontvang nie babas borsvoed nie.
DOSIS EN GEBRUIKSAANWYSINGS
Vir pasiënte wat nog nooit orale paliperidoon, of orale of parenterale
risperidoon, geneem het nie, word daar aanbeveel dat duldbaarheid
met orale paliperidoon of orale risperidoon bepaal word voordat
behandeling met XEPLION begin word.
Die aanbevole aanvangsdosis van XEPLION is 150 mg op Dag 1 van
behandeling en 100 mg een week later, albei toegedien in die deltaspier.
Die aanbevole maandelikse onderhoudsdosis is 75 mg; sommige pasiënte
kan baat by laer of hoër dosisse binne die aanbevole reikwydte van 25 tot
150 mg gebaseer op duldbaarheid en/of doeltreffendheid by die individuele
pasiënt. Na die tweede dosis kan maandelikse onderhoudsdosisse in óf
die deltaspier of gluteale spier toegedien word.
Aanpassing van die onderhoudsdosis kan maandeliks gemaak word.
Wanneer dosis aanpassings gemaak word, moet die verlengde-vrystelling
eienskappe van XEPLION in ag geneem word (kyk Farmakokinetiese
eienskappe), aangesien die volledige effek van die dosisaanpassing vir
etlike maande nie duidelik sal wees nie.
Oorgeslaande dosisse
Vermyding van oorgeslaande dosisse:
Daar word aanbeveel dat die tweede aanvangsdosis van XEPLION een
week na die eerste een gegee word. Om ’n oorgeslaande dosis te vermy,
kan die tweede dosis 2 dae vóór of ná die een-week (dag 8) tydstip aan
pasiënte toegedien word. Dit word aangeraai dat die derde en daaropvolgende
inspuitings na aanvang van behandeling insgelyks maandeliks toegedien
word. Om die oorslaan van ’n maandelikse dosis te vermy, kan die inspuiting
tot 7 dae voor of na die maandelikse tydstip aan pasiënte toegedien word.
Indien die teikendatum vir die tweede XEPLION inspuiting (dag 8 ± 2 dae)
oorgeslaan is, hang die aanbevole behandeling met herinstelling af van
die tydsverloop ná die pasiënt se eerste inspuiting.
Oorgeslaande tweede aanvangsdosis (< 4 weke na die eerste inspuiting)
Indien minder as 4 weke verloop het sedert die eerste inspuiting, moet
die pasiënt die tweede inspuiting van 100 mg in die deltaspier sodra
moontlik ontvang. ’n Derde XEPLION inspuiting van 75 mg in óf die deltaóf gluteale spiere moet 5 weke na die eerste inspuiting toegedien word
(ongeag die tydstip van die tweede inspuiting). Die normale maandelikse
siklus van inspuitings in óf die deltaspier óf die gluteale spier van 25 mg tot
150 mg, gegrond op individuele pasiënt duldbaarheid en/of doeltreffendheid,
moet daarna gevolg word.
Oorgeslaande tweede aanvangsdosis (4-7 weke na eerste inspuiting)
Indien 4 tot 7 weke verloop het na die eerste XEPLION-inspuiting, hervat
dosering met twee inspuitings van 100 mg, op die volgende wyse:
1. ’n deltaspier-inspuiting, sodra moontlik,
2. ’n volgende deltaspier-inspuiting een week later,
3. hervatting van die normale maandelikse siklus van inspuitings, óf in die
deltaspier óf in die gluteale spier van 25 mg tot 150 mg, gebaseer op
die duldbaarheid van die individuele pasiënt en/of doeltreffendheid.
Oorgeslaande aanvangsdosis (> 7 weke vanaf die eerste inspuiting)
Indien meer as 7 weke verloop het sedert die eerste XEPLION - inspuiting,
begin dosering soos hierbo beskryf vir die aanbevole aanvangsdosis van
XEPLION.
Oorgeslaande maandelikse dosis (1 maand tot 6 weke)
Na aanvangsbehandeling is die aanbevole inspuitingsiklus van XEPLION
maandeliks. Indien minder as 6 weke verloop het sedert die vorige inspuiting,
moet die vorige stabiliseringsdosis toegedien word sodra moontlik en
opgevolg word met maandelikse inspuitings.
Oorgeslaande maandelikse onderhoudsdosis (> 6 weke tot 6 maande)
Indien meer as 6 weke verloop het sedert die vorige XEPLION-inspuiting,
is die aanbeveling soos volg:
Vir pasiënte wat gestabiliseer is by dosisse van 25 tot 100 mg:
1. ’n deltaspier-inspuiting sodra moontlik by dieselfde dosis as waarop die
pasiënt voorheen gestabiliseer is
2. ’n ander deltaspier inspuiting (selfde dosis) een week later (dag 8)
3. hervatting van die normale maandelikse siklus van inspuitings in die
deltaspier of gluteale spier van 25 mg tot 150 mg gebaseer op individuele
pasiënt duldbaarheid en/of doeltreffendheid.
Vir pasiënte gestabiliseer op 150 mg:
1. ’n deltaspier-inspuiting, sodra moontlik, met die 100 mg dosis
2. nog ’n deltaspier-inspuiting, een week later (dag 8), met ’n 100 mg dosis
3. hervatting van die normale maandelikse siklus van inspuitings in óf die
deltaspier of gluteale spier van 25 mg tot 150 mg, gebaseer op duldbaarheid by die individuele pasiënt en/of doeltreffendheid.
Oorgeslaande maandelikse onderhoudsdosis (> 6 maande). Indien meer
as 6 maande verloop het sedert die laaste XEPLION inspuiting, begin die
dosis soos hierbo beskryf vir aanvanklike behandeling met XEPLION.
Inligting oor die toediening
XEPLION is slegs bedoel vir diep intramuskulêre gebruik. Spuit stadig in,
diep in die spier. Daar moet versigtig te werk gegaan word om nie per ongeluk
in ’n bloedvat te spuit nie.
Elke inspuiting moet deur ’n gesondheidsorgkundige toegedien word.
Toediening moet as ’n enkel inspuiting geskied. Moenie die dosis in verdeelde inspuitings toedien nie. Moenie intravaskuler of subkutaan toedien nie.
Die aanbevole naaldgrootte vir toediening van XEPLION in die deltaspier
word deur die pasiënt se gewig bepaal. Vir diegene ≥ 90 kg (≥200 lb) word
die 1½ duim, 22-dikte, naald aanbeveel. Vir dié < 90 kg (< 200 lb), word
die 1-duim, 23-dikte, naald aanbeveel. Deltaspier-inspuitings moet tussen
die twee deltaspiere afgewissel word.
Die aanbevole naaldgrootte vir toediening van XEPLION in die gluteale spier
is die 1½-duim, 22-dikte naald. Toediening moet in die boonste kwadrant
van die gluteale spier gedoen word. Gluteale inspuitings moet afgewissel
word tussen die twee gluteale spiere.
Gesamentlike gebruik van XEPLION met orale paliperidoon of orale of
parenterale risperidoon is nie ondersoek nie en word nie aanbeveel nie.
Pasiënte met lewerinkorting
XEPLION is nie ondersoek by pasiënte met lewerinkorting nie. Gegrond
op ’n navorsingstudie met orale paliperidoon, is daar nie ’n dosisaanpassing
nodig by pasiënte met ligte tot matige lewerinkorting nie. Paliperidoon is nie
ondersoek by pasiënte met erge lewerinkorting nie (kyk Farmakokinetiese
eienskappe).
Pasiënte met nierinkorting
XEPLION is nie sistematies ondersoek by pasiënte met nierinkorting nie
(kyk Farmakokinetiese eienskappe). Vir pasiënte met ligte nierinkorting
(kreatinienopklaring ≥ 50 tot < 80 mL/min), is die aanbevole aanvangsdosis 100 mg XEPLION op dag 1 van behandeling en 75 mg een week later,
beide in die deltaspier toegedien. Volg dit daarna op met maandelikse
inspuitings van 50 mg in óf die deltaspier óf die gluteale spier, aangepas
binne die bestek van 25 tot 100 mg, gebaseer op duldbaarheid by die
pasiënt en/of doeltreffendheid.
XEPLION word nie aanbeveel by pasiënte met matige of ernstige nierinkorting (kreatinienopklaring < 50 ml/min) nie (kyk Kontraïndikasies).
Bejaardes
Oor die algemeen is die aanbevole dosering van XEPLION vir bejaarde
pasiënte met normale nierfunksie dieselfde as by jonger volwasse pasiënte
met normale nierfunksie. Aangesien bejaarde pasiënte ’n verminderde
nierfunksie kan hê, kyk bo by Pasiënte met nierinkorting vir dosis aanbevelings by pasiënte met ingekorte nierfunksie.
Adolessente en kinders
Veiligheid en doeltreffendheid van XEPLION by pasiënte < 18 jaar oud is
nie bestudeer nie.
Ander spesiale populasies
Daar word nie enige dosisaanpassing vir XEPLION aanbeveel op grond
van geslag, ras, of rookgewoonte nie. (Vir swanger vroue en vroue wat
borsvoed, kyk Swangerskap en Laktasie).
Oorskakeling van ander antipsigotiese middels
Daar is geen sistematies-versamelde gegewens om spesifiek die oorskakeling van skisofreniese pasiënte van ander antipsigotiese middels
na XEPLION, of die gelyke toediening met ander antipsigotiese middels,
aan te spreek nie. Vorige orale antipsigotiese middels kan gestaak word
wanneer behandeling met XEPLION begin word.
Wanneer pasiënte wat tans by bestendige toestand op ’n langwerkende
parenterale antipsigotiese middel is, oorgeskakel word, word XEPLION terapie begin in die plek van die volgende geskeduleerde inspuiting. Daar
moet dan met XEPLION volgehou word, met maandelikse intervalle.
Die een-week aanvangsdosis regimen, soos hierbo beskryf onder “Dosis en
gebruiksaanwysings” is dan nie nodig nie.
KYK AANWYSINGS VIR GEBRUIK EN HANTERING.
NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS
Newe-effekte:
Met kliniese proewe was die mees algemene newe-effekte wat aangemeld
is slaaploosheid, hoofpyn, angs, boonste lugweginfeksie, reaksies by die plek
van inspuiting, parkinsonisme, toename in gewig, akatisie, prikkelbaarheid,
slaapsug, naarheid, hardlywigheid, duiseligheid, skeletspier-pyn, tagikardie,
tremor, buik-ongemak, braking, diarree, moegheid en distonie. Onder hierdie
newe-effekte is akatisie en lomerigheid skynbaar dosis-afhanklik.
Die volgende is almal OGRs wat met paliperidoon aangemeld is, volgens
die frekwensie kategorie geskat vir XEPLION tydens kliniese proewe.
Die volgende terminologie en frekwensies is toegepas: baie algemeen
(≥ 1/10), algemeen (≥ 1/100 tot < 1/10), ongewoon (≥ 1/1 000 tot < 1/100),
seldsaam (≥ 1/10 000 tot < 1/1 000), baie seldsaam (< 1/10 000) en
onbekend (kan nie geskat word uit die beskikbare data nie).
Ongunstige geneesmiddelreaksies
Sisteem
orgaanklas
Frekwensie
Baie
algemeen
Infeksies en
besmettings
Algemeen
Boonste
lugweginfeksie,
urienweginfeksie,
influensa
Ongewoon
Seldsaam
Pneumonie,
Onigomikose
brongitis,
respiratoriese
weg infeksie,
sinusitis, sistitis,
oorinfeksie,
ooginfeksie,
tonsillitis,
sellulitis,
akarodermatitis,
subkutane
abses
Bloed- en
limfatiese
stelsel
siektes
WitbloedselNeutropenie,
telling laer,
trombositopenie
anemie,
hematokrit
laer, eosinofieltelling hoër
Immuunstelsel siekte
Hipersensitiwiteit
Endokriene
siekte
Hiperprolaktinemiea
Metabolisme
en voeding
siektes
Hiperglukemie,
gewigstoename,
gewigsafname,
bloedtrigliseriede
hoër
Psigiatriese
siektes
Slaaploos- Agitasie,
depressie,
heidc
angs
Distoniec,
parkinsonismec
akatisiec,
diskinesiec,
tremor,
duiseligheid,
kalmering/
slaperigheid.
Ontoepaslike
antidiuretiese
hormoon
afskeiding
Diabetes
mellitusb
hiperinsulienemie, toename
in eetlus,
anoreksie,
afname
in eetlus,
verhoogde
bloedcholesterol
Hipoglukemie,
polidipsie
Slaapsiekte,
Anorgasme
mania,
verwarde
toestand, libido
verminder,
senuagtigheid,
nagmerries
Tardiewe
diskinesie,
konvulsiesc,
sinkopee,
psigomotoriese
hiperaktiwiteit,
posturale
duiseligheid,
aandagversteuring,
disartrie,
disgeusie,
hipoëstesie,
parestesie
Neuroleptiese
maligne
sindroom,
serebrovaskulêre voorval,
reageer nie
op stimuli nie,
verlies aan
bewussyn,
onderdrukte
vlak van
bewussyn,
balansversteuring
Oogsiekte
Dowwe visie,
konjunktivitis,
droë oog
Oogbeweging
siekte, oogtolling, fotofobie,
verhoogde
traanvorming,
okulêre
hiperemie
Oor- en
doolhof
siektes
Vertigo,
tinnitus, oorpyn
Senuweestelsel
siektes
Hoofpyn
Hartsiektes
Bradikardie,
tagikardie
Atriale fibrillasie, Sinus-arritmie
atrioventrikulêre
blok, elektrokardiogram
QT verleng,
posturale
ortostatiese
tagikardie
sindroom,
palpitasies,
abnormale elektrokardiogram
Vaatsiektes
Hipertensie
Hipotensie,
ortostatiese
hipotensie
Respiratoriese, bors en
mediastinale
siektes
Hoes, neus
kongestie
Dispnee,
Respiratoriese
pulmonêre
weg kongestie
kongestie,
fluitende bors,
faringolaringeale
pyn, epistakse
Gastroïntestinale siektes
Braking, buikpyn, diarree,
naarheid,
hardlywigheid,
tandpyn,
dispepsie
Buik-ongemak,
gastroënteritis,
droë mond,
winderigheid
Hepatobiliêre
siektes
Transaminase
verhoog
Gammaglutamieltransferase
hoër, lewerensieme hoër
Vel- en
onderhuidse
weefselsiektes
Uitslag
Urtikarie,
pruritus,
alopesie,
ekseem, droë
vel, eriteem,
aknee
Skeletspier
en bindweefsel siektes
Skeletspierpyn, Spierspasmas,
rugpyn
gewrigstyfheid,
nekpyn,
artralgie
Nier- en
urienweg
siektes
Onbekend
Urinêre
inkontinensie,
pollakurie,
disurie
Diep-veneuse
trombose,
gloede
Pankreatitis,
geswelde
tong, fekale
inkontinensie,
fekaloom,
disfagie
Geneesmiddel
uitbraak,
hiperkeratose,
skilfers.
Bloed-kreatien
fosfokinase
hoër,
gewrigspyn,
spierswakheid
Urien-retensie
Voortplantingstelsel en
bors siektes
Algemene
siektes en
toestande by
die plek van
toediening
Pireksie,
astenie,
moegheid,
reaksie by
die plek van
toediening
Besering,
vergiftiging en
komplikasie
vanweë die
prosedure
a
b
c
Ginekomastie,
erektiele
disfunksie,
ejakulasie
versteuring,
seksuele
disfunksie,
galaktorree,
amenorree,
menstruasie
vertraag,
menstruele
versteuringc,
vaginale
afskeiding
Bors-pyn,
bors-stuwing,
bors-vergroting,
bors-afskeiding,
bors-ongemak
Gesigsedeem,
edeemc, stap
abnormaal,
bors ongemak,
bors- pyn,
siektegevoel,
verharding
Hipotermie,
koue rillings,
verhoogde
liggaamstemperatuur, dors,
abses by plek
van inspuiting,
sellulitis by plek
van inspuiting,
hematoom
by plek van
inspuiting
Aanwysings vir gebruik, hantering en wegdoening
Die pakkie bevat ’n vooraf-gevulde spuit en 2 veiligheidsnaalde (’n 1½-duim,
22-dikte, naald en ’n 1-duim, 23-dikte, naald) vir intramuskulêre inspuiting.
A-22Gx1½″ Grys hub; B-23Gx1″ Blou naaf; C-Voorafgevulde spuit;
D-Naaf; E-Dop op punt
XEPLION IM is slegs vir enkele gebruik.
1. Skud die spuit kragtig vir ten minste 10 sekondes, om ’n homogene
suspensie te verseker.
Val
Hiperprolaktinemie kan by sommige gevalle lei tot ginekomastie, menstruele afwykings,
amenorree en galaktorree
By plasebo-gekontroleerde proewe is diabetes mellitus by 0,32 % XEPLION-behandelde
pasiënte aangemeld, vergeleke met ’n koers van 0,39 % by die plasebogroep. Die algehele
insidensie uit alle kliniese proewe was 0,47 % by alle XEPLION-behandelde proefpersone.
Slaaploosheid sluit in: aanvanklike slaaploosheid, middel-van-die-nag slaaploosheid; EPS
(ekstrapiramidale simptome) het ’n saamgevoegde analise van die volgende terme ingesluit:
Parkinsonisme (insluitend hipersekresie van speeksel, skeletspier-styfheid, parkinsonisme,
kwyling, tandratrigiditeit, bradikinesie, hipokinesie, maskergesig, spierstyfheid, akinesie,
nekholte-stramheid, stram spiere, parkinsonagtige loopgang en abnormale glabella-refleks,
Parkinson-agtige rus-tremor), akatisie (insluitend akatisie, rusteloosheid, hiperkinesie
en rustelose bene sindroom), diskinesie (diskinesie, spiertrekkings, choreoatetose, atetose
en mioklonus), distonie (insluitende distonie, hipertonie, stywe/skewe nek, onwillekeurige
spiersametrekkings, kontraktuur van die spiere, blefarospasma, oogtolling, verlamming van die
tong, gesigspasma, laringospasma, miotonie, opistotonus, orofaringeale spasma, pleurototonus,
tong-spasma en trismus) en bewing. Daar moet besef word dat ’n breër spektrum van simptome
ingesluit is, wat nie noodwendig ’n ekstrapiramidale oorsprong het nie. Konvulsie sluit in:
grand mal konvulsie; Edeem sluit in: veralgemeende edeem, perifere edeem, putvretende
edeem. Menstruele afwykings sluit in: ongereelde menstruasie, oligomenorree
Ongunstige reaksies ervaar met risperidoon-formulerings:
Paliperidoon is die aktiewe metaboliet van risperidoon, gevolglik het die
ongunstige reaksie profiele van hierdie verbindings (wat die orale sowel
as die inspuitbare formulerings insluit) betrekking op mekaar.
Bykomend tot die bogenoemde newe-effekte is die volgende ongunstige
reaksies waargeneem met die gebruik van risperidoon produkte en kan
daar ook verwag word dat dit met XEPLION kan voorkom:
Senuweestelsel siektes: serebrovaskulêre aandoening.
Respiratoriese, bors en mediastinale siektes: râle
Algemene siektes en toestande by die plek van toediening (waargeneem
met die inspuitbare formulering van risperidoon): nekrose by die plek van
inspuiting, sweer by plek van inspuiting.
2. Kies die geskikte naald.
Vir DELTASPIER – inspuiting, indien die pasiënt < 200 lb (< 90 kg) weeg,
gebruik die 1-duim, 23 dikte, naald (naald met bloukleurige doppie);
indien die pasiënt ≥ 200 lb (≥ 90 kg) weeg, gebruik die 1 ½-duim, 22-dikte,
naald (naald met gryskleurige doppie).
Vir GLUTEALE inspuiting, gebruik die 1½-duim, 22 – dikte, naald
(naald met gryskleurige doppie).
3. Terwyl die spuit regop gehou word, verwyder die rubberdoppie op die
punt, met ’n gemaklike kloksgewyse draaibeweging.
4. Trek die veiligheidsnaald sakkie halfpad oop. Hou vas aan die naaldskede
met behulp van die plastiek-aftrekbare sakkie. Bevestig die veiligheidsnaald
aan die luer-konneksie van die spuit met ’n gemaklike kloksgewysedraaibeweging.
Ongunstige reaksies waargeneem met ervaring na bemarking van
XEPLION
Bloed- en limfatiese stelsel siekte
Agranulositose.
Metabolisme en voeding siekte
Water intoksikasie, diabetiese
ketoasidose.
Immuunstelsel siekte
Anafilaktiese reaksie.
Psigiatriese siektes
Affektiewe afstomping.
Senuweestelsel siekte
Diabetiese koma, abnormale
koördinasie, kop-wankeling.
Oogsiekte
Gloukoom, , slap-iris-sindroom
(intra-operatief).
Vaatsiekte
Pulmonêre embolie, iskemie.
5. Trek die skede met ’n reguit beweging van die naald af. Moenie die skede
draai nie, want die naald kan dan loskom van die spuit.
Respiratoriese, bors en mediastinale Slaap-apnee sindroom,
siektes
hiperventilasie, pneumonie
aspirasie, disfonie.
Gastroïntestinale siektes
Intestinale obstruksie, lipontsteking, dermverlamming.
Hepato-biliêre siektes
Geelsug.
Vel- en onderhuidse weefsel-siektes Dermatitis-seborreïes, angioëdeem,
velverkleuring.
Skeletspier en bindweefsel siektes Rabdomiolise, postuur abnormal.
Swangerskap, puerperium
en perinatale toestande
Geneesmiddel onttrekking
sindroom neonatal.
Voortplantingstelsel en bors siektes Priapism.
Algemene siektes en toestande
by die plek van toediening
Glukose
in urien
Liggaamstemperatuur verlaag,
geneesmiddel- onttrekking sindroom,
sweer by die plek van inspuiting.
Gevalle van 'n anafilaktiese reaksie na inspuiting van XEPLION by pasiënte
wat voorheen mondelike risperidoon of mondelike paliperidoon verdra
het, tydens nabemarkingservaring aangemeld.
Gewigstoename.
Dosis-verwante gewigstoename van ≥ 7 % kom voor by 6 % tot 13 % van
die pasiënte.
Laboratoriumtoetse: Serum-prolaktien. Gebaseer op saamgevoegde data
uit die twee 13-week, vaste-dosis dubbelblinde, plasebo-beheerde proewe,
is mediane toenames in serum prolaktien waargeneem by pasiënte van albei
geslagte wat XEPLION I.M. ontvang het. Die resultate van die 13-week
navorsingstudie wat ’n 150 mg aanvangsdosis behels het, die 9-week,
vaste-dosis, dubbelblinde, plasebo-beheerde proef en die dubbelblinde fase
van die herhaling-voorkomende proef het vergelykbare bevindings opgelewer.
Spesiale voorsorgmaatreëls:
QT-interval
Versigtigheid moet uitgeoefen word wanneer XEPLION voorgeskryf word
by pasiënte met ’n geskiedenis van hart disritmie, by pasiënte met kongenitale lang- QT sindroom en by die gesamentlike gebruik met medisyne
bekend om die QT interval te verleng.
Ortostatiese hipotensie
Paliperidoon kan ortostatiese hipotensie by pasiënte veroorsaak op grond van
die alfa-blokkerende werking daarvan. XEPLION moet met versigtigheid
gebruik word by pasiënte met bekende kardiovaskulêre siekte (bv., hartversaking, miokardiale infarksie of iskemie, geleidingsabnormaliteite), serebrovaskulêre siekte, of toestande wat die pasiënt predisponeer tot hipotensie
(bv., dehidrasie-hipovolemie en behandeling met antihipertensiewe medikasies).
Stuipe
XEPLION moet versigtig gebruik word by pasiënt met ’n geskiedenis van
stuipe of ander toestande wat potensieel die stuipe drempel verlaag.
Liggaamstemperatuur beheer
Onderbreking van die liggaam se vermoë om die kern-liggaamstemperatuur
te verminder kan voorkom. Toepaslike sorg word aangeraai wanneer
XEPLION voorgeskryf word aan pasiënte wat toestande ervaar wat kan bydra
tot ’n verhoging in kern-liggaamstemperatuur, bv. ywerige oefening, blootstelling aan buitensporige hitte, die neem van gesamentlike medikasie met
anticholinergiese werking, of pasiënte wat onderworpe is aan dehidrasie.
Effekte op vermoë om te bestuur en masjinerie te hanteer:
XEPLION kan die vermoë om te bestuur en masjinerie te hanteer beïnvloed,
as gevolg van die potensiële senuweestelsel effekte (kyk NEWE-EFFEKTE).
Gevolglik moet pasiënte aangeraai word om nie te bestuur of masjinerie
te opereer totdat hulle individuele vatbaarheid vir XEPLION bekend is nie.
BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE
VAN DIE BEHANDELING DAARVAN
Simptome
Oor die algemeen word tekens en simptome verwag soos met oordrewe
bekende farmakologiese effekte van paliperidoon, d.i., lomerigheid en sedasie,
tagikardie en hipotensie, QT-verlenging en ekstrapiramidale simptome.
Torsade de pointes en ventrikulêre fibrillasie is aangemeld met die oordosering van orale paliperidoon. In die geval van akute oordosering, moet die
moontlikheid van veelvuldige geneesmiddel betrokkenheid oorweeg word.
Behandeling
Die eienskap van langdurige-vrystelling van XEPLION en die lang skynbare
halfleeftyd van paliperidoon moet in ag geneem word wanneer die behoefte
aan behandeling en herstel geassesseer word. Daar is geen spesifieke
teenmiddel teen paliperidoon nie. Algemene ondersteunende maatreëls
moet toegepas word. Bevestig en behou ’n oop lugweg en verseker
voldoende oksigenering en ventilasie. Kardiovaskulêre monitering moet
dadelik begin en moet insluit deurlopende elektrokardiografiese monitering vir moontlike arritmie. Hipotensie en sirkulatoriese ineenstorting moet
met geskikte maatreëls behandel word, soos intraveneuse vloeistof en/of
simpatomimetiese middels. In geval van ernstige ekstrapiramidale simptome,
moet anticholinergiese middels toegedien word. Noulettende toesig en
monitering moet volgehou word totdat die pasiënt herstel.
IDENTIFIKASIE
Langwerkende-vrystelling suspensie in vooraf-gevulde spuite. Die suspensie
is wit tot naaswit, vry van sigbare vreemde deeltjies. Die suspensie is
homogeen nadat dit geskud is.
AANBIEDING
’n Pakkie met ’n spuit (sikliese-olefien-kopolimeer), vooraf-gevul met óf 50 mg
(0,5 ml), 75 mg (0,75 ml), 100 mg (1,0 ml), of 150 mg (1,5 ml) paliperidoon
(as 39 mg, 78 mg, 117 mg, 156 mg, of 234 mg paliperidoonpalmitaat)
suspensie met ’n plunjerprop en ’n (bromobutielrubber) doppie oor die puntjie,
’n 1½-duim, 22-dikte, veiligheidsnaald en ’n 1-duim, 23-dikte, veiligheidsnaald.
BERGINGSAANWYSINGS
Bewaar by of onder 25 °C. Beskerm teen lig.
HOU BUITE BEREIK VAN KINDERS.
XEPLION inspuiting is slegs vir enkel gebruik. Enige ongebruikte gedeelte
moet weggegooi word.
REGISTRASIENOMMER (s)
XEPLION® 50 mg – 44/2.6.5/0866
XEPLION® 75 mg – 44/2.6.5/0867
XEPLION® 100 mg – 44/2.6.5/0868
XEPLION® 150 mg – 44/2.6.5/0870
NAAM EN BESIGHEIDSADRES VAN DIE APPLIKANT
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/011122/07)
Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191
Tel: 27 (11) 518 7000
www.janssen.co.za
DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET
Junie 2013
6. Bring die spuit met die aangehegte naald in ’n regop posisie om van die
lug ontslae te raak. Verwyder die lug uit die spuit deur die plunjerstang
versigtig na vore te beweeg.
7. Spuit die hele inhoud intramuskulêr in die verkose deltaspier of gluteale
spier van die pasiënt. Moenie binneaars of subkutaan toedien nie.
8. Na die inspuiting afgehandel is, gebruik óf die duim of vinger van die een
hand (8a, 8b) of ’n plat oppervlakte (8c) om die naald-beskermingstelsel
te aktiveer. Die naald-beskermingstelsel word ten volle geaktiveer wanneer
’n ‘kliek’ gehoor word. Doen op geskikte wyse weg met die naald.
8a
8b
8c
L
JANSSEN-CILAG
Graphic Services
Tel. Inge Vermeiren: +32 14606915 - E-mail: [email protected]
Tel. François Vermeylen: +32 14606865 - E-mail: [email protected]
INSERT XEPLION
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