Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Use in patients who are in an acutely agitated or severely psychotic state 
Xeplion should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

QT interval

Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, paliperidone should be discontinued.

Tardive dyskinesia/extrapyramidal symptoms

Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including paliperidone, should be considered.

Caution is warranted in patients receiving both, psychostimulants (e.g., methylphenidate) and paliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with Xeplion.
Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of 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.

Hypersensitivity reactions

Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidone have been rarely reported during post-marketing experience (see sections 4.1 and 4.8).

If hypersensitivity reactions occur, discontinue use of Xeplion; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve (see sections 4.3 and 4.8).
Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes including diabetic coma and ketoacidosis, have been reported during treatment with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with Xeplion should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Weight gain

Significant weight gain has been reported with Xeplion use. Weight should be monitored regularly.
Use in patients with prolactin-dependent tumours

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Paliperidone should be used with caution in patients with a pre-existing tumour that may be prolactin-dependent.

Orthostatic hypotension

Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.
Based on pooled data from the three placebo-controlled, 6-week, fixed-dose trials with oral paliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo.
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 and hypovolaemia).

Seizures

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

Renal impairment

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

Hepatic impairment

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.

Elderly patients with dementia

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

The experience from risperidone cited below is considered valid also for paliperidone.

Overall mortality
In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.

Cerebrovascular adverse reactions
An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing Xeplion to patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics.
Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including risperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. During post-marketing surveillance, priapism has also been reported with oral paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 4 hours.

Body temperature regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing 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 medicinal products with anticholinergic activity or being subject to dehydration.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products.
Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Xeplion and preventative measures undertaken.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicinal products or of conditions such as intestinal obstruction, Reye’s syndrome and brain tumour.

Administration

Care must be taken to avoid inadvertent injection of Xeplion into a blood vessel.
Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as Xeplion (see section 4.8).
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicinal products with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

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

Effects on Driving

4.7    Effects on ability to drive and use machines

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to Xeplion is known.