Xeplion

/ Janssen

For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with it. Recommended initiation  is with a dose of 150 mg on treatment day 1 and 100 mg one week later, both administered in the deltoid muscle. The recommended monthly maintenance dose is 75 mg; however, based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the additional available strengths ( 50mg, 100mg, and 150 mg). Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics should be considered, as the full effect of the dose adjustment may not be evident for several months.
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For the acute and maintenance treatment of schizophrenia in adults.

Known hypersensitivity to either paliperidone or risperidone or to any of the excipients.
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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 palecbo-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 infections (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. XEPLION (paliperidone palmitate) is not approved for the treatment of patients with dementia-related psychosis.
Cerebrovascular Adverse Events, 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. Oral paliperidone and XEPLION were not marketed at the time these studies were performed and are not approved for the treatment of patients with dementia-related psychosis.
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 Torsade 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 XEPLION® 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 postdose. In the three fixed-dose efficacy studies of oral paliperidone extended release, 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 XEPLION®, 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, 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.
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The adverse reactions most frequently reported in clinical trials were insomnia, headache, anxiety, upper respiratory tract infection, injection site reaction, parkinsonism, weight increased, akathisia, agitation, sedation/somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhoea, fatigue, and dystonia. Of these, akathisia and sedation/somnolence appeared to be dose-related.
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Because paliperidone palmitate is hydrolyzed to paliperidone results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. Caution is advised when prescribing XEPLION with medicinal products known to prolong the QT interval, e.g. class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g. mefloquine). This list is indicative and not exhaustive.
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Pregnancy Category C.
Risk summary: Adequate and well controlled studies with XEPLION® have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. XEPLION should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical considerations Fetal/Neonatal Adverse Reactions: Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization Data.
Human Data: There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Animal Data: There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 250 mg/kg, which is 10 times the maximum recommended human150 mg dose of XEPLION on a mg/m2 body surface area basis. In studies in pregnant rats and rabbits in which paliperidone was given orally during the period of organogenesis, there were no increases in fetal abnormalities up to the highest doses tested (10 mg/kg/day in rats and 5 mg/kg/day in rabbits, which are each 8 times the maximum recommended human dose of 12 mg/day of orally administered paliperidone [INVEGA®] on a mg/m2 body surface area basis). In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, increases in pup deaths were seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 body surface area basis.
Labor and Delivery: The effect of XEPLION on labor and delivery in humans is unknown.
Nursing Mothers: In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric Use: Safety and effectiveness of XEPLION 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 above 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.

Human Experience: No cases of overdose were reported in premarketing studies with this drug. Because it is to be administered by health care professionals, the potential for overdose by patients is low. While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert
Management of Overdose: Contact a Certified Poison Control Center for the most up to date information on the management overdose. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdose with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone Consider the prolonged-release characteristics  and the long apparent half-life of paliperidone when assessing treatment needs and recovery.