Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Consideration should be given to the long-acting nature of INVEGA TRINZA.
If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.
If NMS has occurred with any paliperidone product, INVEGA TRINZA should not be used.
Tardive dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic, rhythmical movements, including those of the tongue and/or face, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, INVEGA TRINZA should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA TRINZA, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA. However, some patients may require treatment with INVEGA TRINZA despite the presence of the syndrome.
Extrapyramidal symptoms: As with other antipsychotics, EPS including akathisia have been reported (see Adverse Reactions). The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.
Extrapyramidal symptoms and psychostimulants: 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 one or both treatments should be considered (see Interactions).
QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalaemia or hypomagnesaemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicentre QT study with oral paliperidone in adults with schizophrenia and schizoaffective disorder and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
In the Thorough QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (Cmax ss = 113 ng/mL) was approximately 2-fold the PopPK predicted concentration with the maximum recommended 525 mg dose of INVEGA TRINZA administered in the deltoid muscle (predicted median Cmax ss = 56 ng/mL). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.
In the four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the long-term recurrence prevention study, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.
In the long-term relapse prevention trial of INVEGA TRINZA in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.
In the long-term non-inferiority study 1 subject each in the INVEGA TRINZA and 1-month paliperidone palmitate groups had a change in the QTcLD value of >60 msec during the DB Phase relative to the average predose value. In the INVEGA TRINZA subject, the absolute QTcLD value at the time of the increase was < 480 msec, and all QTc interval values were normal at the next study visit.
If clinically significant QT prolongation has occurred with any paliperidone product, INVEGA TRINZA should not be used.
Hypersensitivity reactions: Although tolerability with oral paliperidone or risperidone should be established prior to initiating treatment with INVEGA TRINZA, very rare cases of anaphylactic reactions have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone (see Dosage & Administration and Adverse Reactions).
If hypersensitivity reactions occur, discontinue use of INVEGA TRINZA; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve. (See Contraindications and Adverse Reactions).
Orthostatic hypotension and Syncope: Paliperidone may induce orthostatic hypotension in some patients based on its alpha-adrenergic blocking activity.
In the non-inferiority study, 2 subjects (0.4%) in the INVEGA TRINZA group and 7 subjects (1.4%) in the 1-month paliperidone palmitate group reported adverse events related to orthostatic hypotension (dizziness postural, orthostatic hypotension). In the long-term relapse study, 1 subject (0.3%) on INVEGA TRINZA during the Maintenance phase experienced a treatment-emergent adverse event related to orthostatic hypotension and during the Double-blind Phase, 1 subject in the placebo group (0.7%) experienced a treatment-emergent adverse event related to orthostatic hypotension (dizziness postural). No adverse events of syncope were observed following treatment with INVEGA TRINZA in either study.
INVEGA TRINZA 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).
Use in Patients with Concomitant Illness: Clinical experience with INVEGA TRINZA in patients with certain concomitant illnesses is limited.
Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
INVEGA TRINZA has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with INVEGA TRINZA, caution should be observed in patients with known cardiovascular disease (see Precautions).
Seizures: As with other antipsychotic drugs, INVEGA TRINZA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. INVEGA TRINZA and other antipsychotic drugs should be used cautiously in patients at risk of aspiration pneumonia.
Suicide: The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy.
Thrombotic Thrombocytopenic Purpura (TTP): No cases of TTP were observed during clinical studies with oral paliperidone, the 1-month paliperidone palmitate injectable product, or INVEGA TRINZA. Although cases of TTP have been reported in association with risperidone administration, the relationship to risperidone therapy is unknown.
Hyperprolactinaemia: Like other drugs that antagonise dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration (see Adverse Reactions). Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.
Hyperprolactinaemia, regardless of aetiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinaemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Leukopoenia, neutropoenia, and agranulocytosis: Events of leukopoenia, neutropoenia, and agranulocytosis have been reported with antipsychotic agents, including paliperidone. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance.
Possible risk factors for leukopoenia/neutropoenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopoenia/neutropoenia. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopoenia/neutropoenia should be monitored during the first few months of therapy and discontinuation of INVEGA TRINZA 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 neutropoenia 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 neutropoenia (absolute neutrophil count < 1000/mm3) should discontinue INVEGA TRINZA and have their WBC followed until recovery. Consideration should be given to the long-acting nature of INVEGA TRINZA. If clinically significant drug‐induced leukopoenia/neutropoenia has occurred with any paliperidone product, INVEGA TRINZA should not be used.
Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA (see Adverse Reactions). Antipsychotics, including INVEGA TRINZA, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.
Venous thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with INVEGA TRINZA and preventive measures undertaken.
Parkinson's disease and Dementia with Lewy Bodies: Patients with Parkinson's disease or Dementia with Lewy Bodies (DLB) may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with paliperidone during post-marketing surveillance (see Adverse Reactions). Severe priapism may require surgical intervention.
Body temperature regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA TRINZA 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.
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 overdose with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.
Administration: Care must be taken to avoid inadvertent injection of INVEGA TRINZA 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 INVEGA TRINZA (see Adverse Reactions).
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
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 all atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics 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 atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Weight Gain: Weight gain has been observed with INVEGA TRINZA and other atypical antipsychotics. Clinical monitoring of weight is recommended.
In the double-blind placebo-controlled phase of the long-term relapse prevention trial, abnormal increases of ≥ 7% in body weight from double-blind baseline to double-blind end point were reported for 15 subjects (10%) in the INVEGA TRINZA group and 1 subject (1%) in the placebo group. Conversely, abnormal decreases in body weight (≥ 7%) from double-blind baseline to double-blind end point were reported for 2 subjects (1%) in the INVEGA TRINZA group and 12 subjects (8%) in the placebo group. The mean changes in body weight from double-blind baseline to double-blind end point were +0.94 kg and -1.28 kg for the INVEGA TRINZA and placebo groups, respectively. In the non-inferiority study, 15% of subjects in the INVEGA TRINZA group and 16% of subjects in the 1-month paliperidone palmitate treatment group had an increase in body weight of ≥ 7% from double-blind baseline to double-blind end point.
Alcohol: Given the primary CNS effects of paliperidone, patients should be advised to avoid alcohol while taking this medicine.
Use in hepatic impairment: INVEGA TRINZA 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.
Use in renal impairment: INVEGA TRINZA has not been systematically studied in patients with renal impairment (see Pharmacology under Actions). A reduced dose is recommended in patients with mild renal impairment; INVEGA TRINZA is not recommended in patients with moderate or severe renal impairment (see Dosage & Administration).
Effects of laboratory tests: No data available.
Use in elderly: This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment (see Pharmacology under Actions), who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Dosage & Administration).
Use in elderly patients with dementia: Overall mortality: Elderly patients with dementia, treated with atypical antipsychotic drugs, had an increased risk of mortality compared to placebo. INVEGA TRINZA (paliperidone palmitate) is not approved for the treatment of dementia-related psychosis.
Cerebrovascular Adverse Events including Stroke, in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials in elderly patients with dementia treated with some atypical antipsychotic drugs, including risperidone, aripiprazole, and olanzapine, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities, compared to placebo. Oral paliperidone and INVEGA TRINZA were not marketed at the time these studies were performed and are not approved for the treatment of patients with dementia-related psychosis.
Use in Children: In a 7-week oral toxicity study in juvenile rats with paliperidone at doses of 0.16, 0.63, and 2.5 mg/kg/day, no effects on growth, sexual maturation or reproductive performance were observed. Doses up to 2.5 mg/kg/day did not affect neurobehavioural development, except for an impairment of learning and memory in females treated at 2.5 mg/kg/day, which was not observed after discontinuation of treatment. Respective exposures (plasma AUC) at these doses were 0.1, 0.4, and 1.3 times exposure in adolescents at the maximal recommended dose (12 mg/day).
A 39-day oral toxicity study with risperidone (which is extensively converted to paliperidone) in juvenile rats noted increased pup mortality, a delay in physical development and, in a small proportion of animals, impairment of auditory startle, at exposures (plasma AUC) less than that of the maximum recommended paediatric risperidone dose (6 mg/day).
The clinical relevance of these findings for adolescents is uncertain, given the relative immaturity of the rat pups upon commencement of treatment.
A 40-week oral toxicity study with risperidone (which is extensively converted to paliperidone) in juvenile dogs noted delayed sexual maturation, probably secondary to hormonal changes. Long bone growth was slightly reduced at exposures (plasma AUC) of 3-fold and greater than those at the maximum dose in children and adolescents (6 mg/day); exposure at the no-effect dose was similar to human exposure.
Effects of Ability to Drive and Operate Machines: As INVEGA TRINZA has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA TRINZA therapy does not affect them adversely.