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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, INVEGA SUSTENNA, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis (see Warnings and Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned).
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.
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.
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 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.
The effects of oral paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study 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 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 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 more than 2-fold the exposure observed with the maximum recommended 150 mg dose of INVEGA SUSTENNA administered in the deltoid muscle (predicted median Cmax ss = 50 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 three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).
In the four fixed-dose efficacy studies of INVEGA SUSTENNA in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study in subjects with schizophrenia, 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.
Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements 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.
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 SUSTENNA should be prescribed in a manner that is most likely to minimize 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 SUSTENNA, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA SUSTENNA. 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. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
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 hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 8. (See Table 8.)
Click on icon to see table/diagram/imageIn a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (150 mg) was evaluated, INVEGA SUSTENNA was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).
During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 9. (See Table 9.)
Click on icon to see table/diagram/imageIn a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (150 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 10. (See Table 10.)
Click on icon to see table/diagram/imageThe mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study in subjects with schizoaffective disorder are presented in Table 11. (See Table 11.)
Click on icon to see table/diagram/imageWeight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 12. (See Table 12.)
Click on icon to see table/diagram/imageIn a long-term open-label pharmacokinetic and safety study in which the highest dose available (150 mg) was evaluated, INVEGA SUSTENNA was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).
During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).
Orthostatic Hypotension and Syncope: Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with INVEGA SUSTENNA in the recommended dose range of 25 mg to 150 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of INVEGA SUSTENNA-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.
INVEGA SUSTENNA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of 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). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA SUSTENNA, an oral form of paliperidone. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA SUSTENNA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA SUSTENNA in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.
Hyperprolactinemia: Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. 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.
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin 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 hyperprolactinemia 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: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
Prolactin data from two long-term, double-blind, placebo-controlled studies with INVEGA SUSTENNA are presented as follows; one study was in a population of patients with schizophrenia; the second study was in patients with schizoaffective disorder.
Schizophrenia: In a long-term maintenance trial of INVEGA SUSTENNA in schizophrenia patients (Study PSY-3001), see Pharmacology: Pharmacodynamics: Clinical Studies: Schizophrenia under Actions, elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of the patients in the INVEGA SUSTENNA group than those in the placebo group in males (51.9% vs. 29.0%) and in females (50.5% vs. 42.9%). During the double-blind phase, 4 females (4.2%) in the INVEGA SUSTENNA group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the INVEGA SUSTENNA group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.
Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.
Schizoaffective Disorder: In a long-term maintenance trial of INVEGA SUSTENNA in patients with schizoaffective disorder (Study SCA-3004), see Pharmacology: Pharmacodynamics: Clinical Studies: Schizoaffective Disorder under Actions, elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15 month double-blind phase were noted in a higher percentage of patients in the INVEGA SUSTENNA group than those in the placebo group in males (55.6% vs. 23.2%) and in females (44.3% vs. 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the INVEGA SUSTENNA group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the INVEGA SUSTENNA group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.
Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% vs. 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.
Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA (see Clinical Trials Experience under Adverse Reactions). Antipsychotics, including INVEGA SUSTENNA, 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.
Seizures: In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with INVEGA SUSTENNA in the recommended dose range of 25 mg to 150 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.
Like other antipsychotic drugs, INVEGA SUSTENNA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA SUSTENNA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA SUSTENNA, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.
Disruption of 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 SUSTENNA 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.
Drug Abuse and Dependence: Controlled Substance: INVEGA SUSTENNA (paliperidone) is not a controlled substance.
Abuse: Paliperidone has not been systematically studied in animals or humans for its potential for abuse.
Dependence: Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Use in Specific Populations: Renal Impairment: Use of INVEGA SUSTENNA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) (see Dosage Adjustments under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: INVEGA SUSTENNA 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 Pharmacology: Pharmacokinetics under Actions.)
Patients with Parkinson's Disease or Lewy Body Dementia: Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA SUSTENNA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.
Use in Children: Safety and effectiveness of INVEGA SUSTENNA in patients < 18 years of age have not been established.
In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents.
Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The previously mentioned effects showed little or no reversibility in females after a 12-week drug-free recovery period.
The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.
Use in Elderly: Clinical studies of INVEGA SUSTENNA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions), who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function (see Dosage Adjustments under Dosage & Administration).
