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 antipsychotic drugs, including paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotic drugs, including INVEGA TRINZA, should be discontinued. 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: Drugs with dopamine receptor antagonistic properties 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 all antipsychotic drugs, including INVEGA TRINZA, should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA.
QT Interval: 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 Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. As with other antipsychotics, caution should be exercised when INVEGA TRINZA is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, and in concomitant use with drugs known to prolong the QT interval. (see Pharmacology: Pharmacodynamics: Effect on QT/QTc interval and cardiac electrophysiology under Actions).
If clinically significant QT prolongation has occurred with any paliperidone product, INVEGA TRINZA should not be used.
Hypersensitivity reactions: Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidone have been very rarely reported during post marketing experience with the 1-month paliperidone palmitate injectable product (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.)
Hyperglycemia and diabetes mellitus: Hyperglycemia, diabetes mellitus, and exacerbation of pre existing diabetes have been reported during treatment with antipsychotic drugs. 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 hyperglycemia-related adverse events is not completely understood. Any patient treated with atypical antipsychotics, including INVEGA TRINZA should be monitored for symptoms of hyperglycemia and diabetes mellitus. (See Adverse Reactions).
Weight gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Orthostatic Hypotension: Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity. INVEGA TRINZA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications).
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.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
INVEGA TRINZA is not approved for the treatment of patients with dementia-related psychosis (see Warnings).
Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, or INVEGA TRINZA in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis (see Wamings).
Overall Mortality: In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotic drugs, 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 Events: 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.
Leukopenia, neutropenia, and agranulocytosis: Events of leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents, including paliperidone. Agranulocytosis has been reported very rarely (<1/10000 patients) 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 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 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 INVEGA TRINZA and have their WBC followed until recovery.
Consideration should be given to the long-acting nature of INVEGA TRINZA.
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: Physicians should weigh the risks versus the benefits when prescribing antipsychotic drugs, including INVEGA TRINZA, 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 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 postmarketing surveillance (see Adverse Reactions).
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 overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.
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 alpha 1a-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 alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
Effects on Ability to Drive and Use Machines: INVEGA TRINZA may interfere with activities requiring mental alertness and may have visual effects (see Adverse Reactions). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.