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 
TREVICTA 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. Consideration should be given to the long-acting nature of TREVICTA.

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. Consideration should be given to the long-acting nature of TREVICTA.

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

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with paliperidone. 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 TREVICTA 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 TREVICTA and have their WBC followed until recovery.
Consideration should be given to the long-acting nature of TREVICTA.

Hypersensitivity reactions
Hypersensitivity reactions can occur even in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.8).

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes, including diabetic coma and ketoacidosis, have been reported with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with TREVICTA 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 TREVICTA 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-adrenergic blocking activity. In the clinical trials of TREVICTA, 0.3% of subjects reported orthostatic hypotension related adverse reaction. TREVICTA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia).

Seizures

TREVICTA 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. For patients with mild renal impairment (creatinine clearance ≥ 50 ml/min to < 80 ml/min), dose should be adjusted and the patient stabilised using 1-monthly paliperidone palmitate injectable, then transitioned to TREVICTA. TREVICTA 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
TREVICTA has not been studied in elderly patients with dementia. TREVICTA is not recommended to treat elderly patients with dementia due to increased risk of overall mortality and cerebrovascular adverse reactions.

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

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 TREVICTA 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 paliperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 4 hours.

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 TREVICTA 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 TREVICTA 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 TREVICTA 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 TREVICTA (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 TREVICTA is known.