SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 18 DOSAGE AND ADMINISTRATION 20 OVERDOSAGE 21 ACTION AND CLINICAL PHARMACOLOGY 21 STORAGE AND STABILITY 25 DOSAGE FORMS, COMPOSITION AND PACKAGING 25
PHARMACEUTICAL INFORMATION 27 CLINICAL TRIALS 27 DETAILED PHARMACOLOGY 29 TOXICOLOGY 30 REFERENCES 31
PrINVEGA * paliperidone Extended-release Tablets 3 mg, 6 mg, 9 mg and 12 mg Antipsychotic Agent
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Extended-release Tablets/3 mg, 6 mg, 9 mg and 12 mg | Lactose For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. |
INVEGA (paliperidone) is indicated for the treatment of schizophrenia. In controlled clinical trials, INVEGA was found to improve the symptoms of schizophrenia, including positive and negative symptoms.
Geriatrics (> 65 years of age):
See WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box and Special Populations.
Pediatrics (< 18 years of age):
The safety and efficacy of INVEGA in children under the age of 18 have not been established.
INVEGA is contraindicated in patients who are hypersensitive to paliperidone, risperidone, or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
General
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 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. Serial ECG assessments were scheduled at multiple days and multiple timepoints during the day. Least square mean changes from baseline in QTcLD were calculated at each scheduled ECG assessment timepoint and day. In study R076477-SCH-1009 (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=44) showed a maximal (least square) mean change from baseline in QTcLD of 10.9 msec (90% CI:8.24; 13.62) and was noted 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 was more than twice the exposure observed with the maximum recommended 12 mg dose of INVEGA (Cmax ss = 113 and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone (Cmax ss = 35 ng/mL) showed a maximal (least square) mean change from baseline in QTcLD of 9.3 msec (90% CI: 6.56; 11.98) and was noted on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study. Also, in this study, a 400 mg dose of moxifloxacin (n=58) showed a maximal least square mean change from baseline in QTcLD of 6.1 msec (90% CI: 3.64; 8.53) and was noted on day 8 at 3 hours post-dose. Placebo (n=58) showed a maximal least square mean change from baseline in QTcLD of 3.5 msec (90% CI: 1.05; 5.95) and was noted on day 2 at 30 minutes post-dose.
Since paliperidone (9-hydroxy-risperidone) is the major active metabolite of risperidone, concomitant use of INVEGA with oral risperidone is not recommended since the combination of the two will lead to additive paliperidone exposure.
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA 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.
Carcinogenesis and Mutagenesis
For animal data, see Product Monograph Part II: TOXICOLOGY.
Cardiovascular
Orthostatic Hypotension
Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity. Based on pooled data from the three placebo-controlled, 6-week, fixed-dose trials with INVEGA (3, 6, 9 and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA compared with 0.8% of subjects treated with placebo. INVEGA 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 such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure.
Endocrine and Metabolism
Hyperglycemia
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has 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, and not in clinical trials. In clinical trials, there have been few reports of glucose-related adverse events (e.g., hyperglycemia) in subjects treated with INVEGA. 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, which did not include INVEGA, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because INVEGA was not marketed at the time these studies were performed, it is not known if INVEGA is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. 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 antidiabetic treatment despite discontinuation of the suspect drug. 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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
As with other atypical antipsychotics 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. 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. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin- elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. As is common with dopamine D2 antagonists, prolonged administration of risperidone in rodent carcinogenicity studies resulted in an increase in the incidence of pituitary gland, mammary gland, and endocrine pancreas hyperplasia and/or tumours (see WARNINGS AND PRECAUTIONS: Carcinogenesis and Mutagenesis). However, 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; the available evidence is considered too limited to be conclusive at this time. The carcinogenic potential of paliperidone, an active metabolite of risperidone, was assessed based on studies with risperidone conducted in mice and rats. In the three placebo-controlled, 6-week, fixed-dose trials with INVEGA (3, 6, 9, and 12 mg), the proportion of subjects who experienced potentially prolactin-related adverse events was similar for the placebo (1%) and INVEGA (1-2%) groups.
Gastrointestinal
Because the INVEGA tablet is nondeformable and does not appreciably change in shape in the GI tract, INVEGA should not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Due to the controlled-release design of the tablet, INVEGA should only be used in patients who are able to swallow the tablet whole (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
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 tumour.
Genitourinary
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, paliperidone shares this pharmacologic activity and, therefore, may be associated with this risk.
Hepatic/Biliary/Pancreatic
Paliperidone is not extensively metabolized in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of unbound paliperidone were similar to those of healthy subjects. No dose adjustment is required in patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment is unknown.
Neurologic
Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular blood pressure, tachycardia, cardiac arrhythmias, and diaphoresis). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 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. 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 including INVEGA, 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 requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrence of NMS has been reported.
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although TD appears to be most prevalent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD. It has been suggested that the occurrence of parkinsonian side effects is a predictor for the development of TD. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. However, antipsychotic treatment itself may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown. In view of these considerations, INVEGA should be prescribed in a manner that is most likely to minimize the risk of TD. As with any antipsychotic, INVEGA should generally be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of TD develop during treatment with INVEGA, withdrawal of the drug should be considered. However, some patients may require treatment with INVEGA despite the presence of the syndrome.
Somnolence, sedation and blurred vision were reported in subjects treated with INVEGA (see ADVERSE REACTIONS). Antipsychotics, including INVEGA, 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.
Antipsychotic drugs are known to lower the seizure threshold. During premarketing clinical trials (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), the number of reports of seizures was similar between subjects treated with INVEGA (3, 6, 9, 12 mg, 0.22%) and subjects treated with placebo (0.25%). As with other antipsychotic drugs, INVEGA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Physicians should weigh the risks versus the benefits when prescribing antipsychotic drugs, including INVEGA, 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.
Psychiatric
Suicide
The possibility of suicide or attempted suicide is inherent in psychosis, and thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
Renal
The dose should be reduced in patients with moderate to severe renal impairment (see DOSAGE AND ADMINISTRATION). The disposition of paliperidone was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (CrCl = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min), and 71% in severe (CrCl = 10 to < 30 mL/min) renal impairment. The mean terminal elimination half-life of paliperidone was 24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl >= 80 mL/min). INVEGA has not been studied in subjects with creatinine clearance < 10mL/min.
Special Populations
The safety of INVEGA during pregnancy has not been established. No teratogenic effect was noted in any animal study. Laboratory animals treated with a high dose of paliperidone showed a slight increase in fetal deaths. This high dose was toxic to the mothers. The offspring were not affected at exposures 20- to 34-fold the maximum human exposure. INVEGA should only be used if the benefits outweigh the risks. The effect of INVEGA on labour and delivery in humans is unknown.
Use of antipsychotic drugs during the last trimester of pregnancy has been associated with reversible extrapyramidal symptoms in the neonate.
In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Patients should be advised not to breast-feed an infant if they are taking INVEGA.
The safety and efficacy of INVEGA in children under the age of 18 years have not been established.
The number of patients 65 years of age or older exposed to INVEGA during a placebo-controlled clinical trial in elderly subjects receiving flexible doses (3 - 12 mg/day) was limited (n=76). In general, the types and frequencies of adverse events reported in these subjects in this study were similar to those reported in the younger population of adult subjects studied in three placebo-controlled, 6-week, fixed-dose trials. Based on the limited data and consistent with general clinical practice, a greater sensitivity of older individuals to adverse events, including cardiac events, cannot be ruled out.
Because elderly subjects may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal above and DOSAGE AND ADMINISTRATION).
Overall Mortality
In a meta-analysis of 13 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotic drugs had an increased risk of mortality compared to placebo. INVEGA is not indicated for the treatment of elderly patients with dementia.
Cerebrovascular Adverse Events (CVAEs) in Elderly Patients With Dementia
In placebo-controlled trials in elderly patients with dementia treated with some atypical antipsychotic drugs, including risperidone and olanzapine, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo. INVEGA is not indicated for the treatment of elderly patients with dementia.
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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Short-Term, Placebo-Controlled, Fixed-Dose Studies
The information presented in this section was derived from pooled data from three placebo- controlled, 6-week, fixed-dose studies conducted in non-elderly (mean age 38 years) patients with schizophrenia. The doses studied among these three trials included 3, 6, 9, 12, and 15 mg/day (see Product Monograph Part II: CLINICAL TRIALS). Body systems and adverse event/adverse drug reaction (ADR) terms are based on the MedDRA dictionary.
Adverse Events Associated with Discontinuation of Treatment
Overall, there was no difference in the incidence of discontinuation due to adverse events between patients who received INVEGA (5%) and placebo-treated patients (5%). The types of adverse events that led to discontinuation were similar between patients treated with INVEGA and placebo-treated patients, except for Nervous System Disorders (2% and 0%, respectively) and Gastrointestinal Disorders (1% and 0%, respectively) which were of greater incidence among patients treated with INVEGA than placebo-treated patients, and Psychiatric Disorders which were of greater incidence among placebo-treated patients than patients treated with INVEGA (3% and 1%, respectively).
Commonly Observed Adverse Drug Reactions
Table 1.1 enumerates all treatment-emergent adverse events, regardless of causality, reported at an incidence of $1% of patients treated with INVEGA in these studies, and for which the incidence in patients treated with INVEGA was greater than the incidence in patients treated with placebo. The most frequently reported ADRs, reported by >= 2% of patients treated with INVEGA, included: headache (13.2%; placebo 11.8%), tachycardia (6.6%; placebo 2.8%), akathisia (6.5%; placebo 3.9%), sinus tachycardia (5.5%; placebo 4.2%), extrapyramidal disorder (5.4%; placebo 2.3%), somnolence (4.9%; placebo 3.4%), dizziness (4.8%; placebo 3.9%), sedation (4.2%; placebo 3.7%), tremor (3.4%; placebo 3.4%), hypertonia (2.8%; placebo 1.1%), dystonia (2.6%; placebo 0.6%), orthostatic hypotension (2.5%; placebo 0.8%), and dry mouth (2.4%; placebo 0.6%).
Table 1.1: Treatment-Emergent Adverse Events, Regardless of Causality, Reported by >=1% of Patients with Schizophrenia in Any INVEGA Group and Which Occurred at Greater Incidence Than in the Placebo Group in the Three Placebo-Controlled, 6-Week, Double-Blind, Fixed-Dose Clinical Trials.
(Safety Analysis Set)
| Body System or Organ Class Dictionary-derived Term | Placebo (N=355) % | 3 mg (N=127) % | 6 mg (N=235) % | 9 mg (N=246) % | 12 mg (N=242) % |
| Cardiac disorders | |||||
| Atrioventricular block first degree | 1 | 2 | 0 | 2 | 1 |
| Bradycardia | 1 | 0 | 1 | 1 | 2 |
| Bundle branch block | 2 | 3 | 1 | 3 | <1 |
| Palpitations | 0 | 2 | 1 | 0 | 1 |
| Sinus arrhythmia | 0 | 2 | 1 | 1 | <1 |
| Sinus tachycardia | 4 | 9 | 4 | 4 | 7 |
| Tachycardia | 3 | 2 | 7 | 7 | 7 |
| Eye disorders | |||||
| Dry eye | 0 | 2 | 0 | <1 | <1 |
| Oculogyration | 0 | 0 | 0 | 2 | 0 |
| Vision blurred | 1 | 1 | <1 | 0 | 2 |
| Gastrointestinal disorders | |||||
| Abdominal pain | 1 | 0 | 2 | 1 | 1 |
| Abdominal pain upper | 1 | 1 | 3 | 2 | 2 |
| Diarrhea | 2 | 1 | 1 | 1 | 2 |
| Dry mouth | 1 | 2 | 3 | 1 | 3 |
| Dyspepsia | 4 | 2 | 3 | 2 | 5 |
| Nausea | 5 | 6 | 4 | 4 | 4 |
| Salivary hypersecretion | <1 | 0 | <1 | 1 | 4 |
| Stomach discomfort | <1 | 2 | 1 | <1 | 1 |
| Toothache | 1 | 2 | 2 | 2 | 2 |
| Vomiting | 5 | 2 | 3 | 4 | 5 |
| General disorders and administration site conditions | |||||
| Asthenia | 1 | 2 | <1 | 2 | 2 |
| Fatigue | 1 | 2 | 1 | 2 | 2 |
Table 1.1: Treatment-Emergent Adverse Events, Regardless of Causality, Reported by >=1% of Patients with Schizophrenia in Any INVEGA Group and Which Occurred at Greater Incidence Than in the Placebo Group in the Three Placebo-Controlled, 6-Week, Double-Blind, Fixed-Dose Clinical Trials(continued)
(Safety Analysis Set)
| Body System or Organ Class Dictionary-derived Term | Placebo (N=355) % | 3 mg (N=127) % | 6 mg (N=235) % | 9 mg (N=246) % | 12 mg (N=242) % |
| General disorders and administration site conditions (continued) | |||||
| Pyrexia | 1 | 1 | <1 | 2 | 2 |
| Infections and infestations | |||||
| Bronchitis | <1 | 0 | 1 | <1 | 1 |
| Nasopharyngitis | 3 | 3 | 2 | 2 | 2 |
| Rhinitis | <1 | 0 | 1 | 0 | <1 |
| Upper respiratory tract infection | 1 | 1 | 1 | 1 | 1 |
| Viral infection | <1 | 0 | <1 | 1 | 1 |
| Injury, poisoning and procedural complications | |||||
| Fall | <1 | 0 | 1 | 0 | 0 |
| Investigations | |||||
| Alanine aminotransferase increased | 1 | 1 | 2 | 1 | 1 |
| Blood creatine phosphokinase increased | 1 | 1 | 2 | 0 | <1 |
| Blood insulin increased | 1 | 2 | 1 | 1 | <1 |
| Blood pressure increased | 1 | 2 | <1 | <1 | 1 |
| Blood triglycerides increased | <1 | 2 | <1 | 0 | 0 |
| Electrocardiogram QT corrected interval prolonged | 3 | 3 | 4 | 3 | 5 |
| Electrocardiogram T wave abnormal | 1 | 2 | 1 | 2 | 1 |
| Electrocardiogram T wave inversion | 1 | 0 | <1 | 1 | 1 |
| Electrocardiogram abnormal | 0 | 0 | 0 | 2 | 1 |
| Heart rate increased | 1 | 3 | 1 | <1 | 1 |
| Insulin C-peptide increased | 1 | 2 | 1 | 1 | 0 |
| Weight decreased | 1 | 2 | 0 | 0 | 0 |
| Weight increased | 1 | 1 | 0 | 2 | 2 |
Table 1.1: Treatment-Emergent Adverse Events, Regardless of Causality, Reported by >=1% of Patients with Schizophrenia in Any INVEGA Group and Which Occurred at Greater Incidence Than in the Placebo Group in the Three Placebo-Controlled, 6-Week, Double-Blind, Fixed-Dose Clinical Trials(continued)
(Safety Analysis Set)
| Body System or Organ Class Dictionary-derived Term | Placebo (N=355) % | 3 mg (N=127) % | 6 mg (N=235) % | 9 mg (N=246) % | 12 mg (N=242) % |
| Metabolism and nutrition disorders Decreased appetite | 0 | 2 | <1 | <1 | 1 |
| Increased appetite | <1 | 2 | 0 | 1 | 1 |
| Musculoskeletal and connective tissue disorders Arthralgia | 1 | 0 | 2 | 1 | 0 |
| Back pain | 1 | 1 | 1 | 1 | 2 |
| Muscle rigidity | 0 | 1 | 0 | 1 | <1 |
| Neck pain | <1 | 0 | 0 | 0 | 1 |
| Pain in extremity | 1 | 0 | 1 | 0 | 2 |
| Shoulder pain | 0 | 1 | 1 | 1 | 1 |
| Nervous system disorders Akathisia | 4 | 4 | 3 | 8 | 10 |
| Dizziness | 4 | 6 | 5 | 4 | 5 |
| Dyskinesia | 1 | 0 | <1 | <1 | 2 |
| Dystonia | 1 | 1 | 1 | 4 | 4 |
| Extrapyramidal disorder | 2 | 5 | 2 | 7 | 7 |
| Headache | 12 | 11 | 12 | 14 | 14 |
| Hypertonia | 1 | 2 | 1 | 4 | 3 |
| Parkinsonism | 0 | 0 | <1 | 2 | 1 |
| Sedation | 4 | 1 | 5 | 3 | 6 |
| Somnolence | 3 | 5 | 3 | 7 | 5 |
| Syncope | <1 | 1 | 1 | 1 | <1 |
| Tremor | 3 | 3 | 3 | 4 | 3 |
| Psychiatric disorders Aggression | 1 | 2 | <1 | 1 | 1 |
| Anxiety | 8 | 9 | 7 | 6 | 5 |
Table 1.1: Treatment-Emergent Adverse Events, Regardless of Causality, Reported by >=1% of Patients with Schizophrenia in Any INVEGA Group and Which Occurred at Greater Incidence Than in the Placebo Group in the Three Placebo-Controlled, 6-Week, Double-Blind, Fixed-Dose Clinical Trials(continued)
(Safety Analysis Set)
| Body System or Organ Class Dictionary-derived Term | Placebo (N=355) % | 3 mg (N=127) % | 6 mg (N=235) % | 9 mg (N=246) % | 12 mg (N=242) % |
| Psychiatric disorders (continued) Depression | <1 | 0 | 1 | <1 | <1 |
| Nightmare | 0 | 0 | <1 | 1 | <1 |
| Suicidal ideation | 1 | 2 | 1 | <1 | <1 |
| Respiratory, thoracic and mediastinal disorders | |||||
| Cough | 1 | 3 | 2 | 3 | 2 |
| Nasal congestion | 1 | 1 | 1 | 1 | 1 |
| Skin and subcutaneous tissue disorders | |||||
| Pruritus | 1 | 0 | 1 | 1 | 0 |
| Vascular disorders | |||||
| Hypotension | <1 | 2 | <1 | 1 | 1 |
| Orthostatic hypotension | 1 | 2 | 1 | 2 | 4 |
Dose-Related Adverse Reactions
Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with INVEGA, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, Parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.
Elderly
The number of patients 65 years of age or older exposed to INVEGA during a placebo-controlled clinical trial in elderly subjects receiving flexible doses (3 - 12 mg/day) was limited (n=76). In general, the types and frequencies of adverse events reported in these subjects in this study were similar to those reported in the younger population of adult subjects studied in three placebo- controlled, 6-week, fixed-dose trials. Based on the limited data and consistent with general clinical practice, a greater sensitivity of older individuals to adverse events, including cardiac events, cannot be ruled out.
Extrapyramidal Symptoms (EPS)
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson- Angus global score, (2) the Barnes Akathisia Rating Scale global clinical rating score, (3) use of anticholinergic medications to treat emergent EPS, and (4) incidence of spontaneous reports of EPS. For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and INVEGA 3 mg and 6 mg doses for any of these EPS measures.
Percentage of Patients
INVEGA
Placebo 3 mg 6 mg 9 mg 12 mg once daily once daily once daily once daily
EPS Group
(N=355) (N=127) (N=235) (N=246) (N=242)
| Parkinsonism a | 9 | 11 | 3 | 15 | 14 |
| Akathisia b | 6 | 6 | 4 | 7 | 9 |
| Use of | |||||
| anticholinergic medications c | 10 | 10 | 9 | 22 | 22 |
a: For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global
score defined as total sum of items score divided by the number of items)
b: For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score >= 2 c: Percent of patients who received anticholinergic medications to treat emergent EPS
Percentage of Patients
INVEGA
Placebo 3 mg 6 mg 9 mg 12 mg once daily once daily once daily once daily
EPS Group
(N=355) (N=127) (N=235) (N=246) (N=242)
| Overall percentage of patients with EPS- | 11.0 | 12.6 | 10.2 | 25.2 | 26.0 |
| related AE | |||||
| Dyskinesia | 3.4 | 4.7 | 2.6 | 7.7 | 8.7 |
| Dystonia | 1.1 | 0.8 | 1.3 | 5.3 | 4.5 |
| Hyperkinesia | 3.9 | 3.9 | 3.0 | 8.1 | 9.9 |
| Parkinsonism | 2.3 | 3.1 | 2.6 | 7.3 | 6.2 |
| Tremor | 3.4 | 3.1 | 2.6 | 4.5 | 3.3 |
Dyskinesia group includes: Dyskinesia, Extrapyramidal disorder, Muscle twitching,
Tardive dyskinesia
Dystonia group includes: Dystonia, Muscle spasms, Oculogyration, Trismus Hyperkinesia group includes: Akathisia, Hyperkinesia
Parkinsonism group includes: Bradykinesia, Cogwheel rigidity, Drooling, Hypertonia, Hypokinesia, Muscle rigidity, Musculoskeletal stiffness,
Parkinsonism
Tremor group includes: Tremor
Weight Gain
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of patients meeting a weight gain criterion of >= 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA 9 mg and 12 mg (9% and 9%, respectively).
ECG Changes
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, between-group comparisons revealed no clinically important differences between INVEGA and placebo in the incidence of ECG parameters outside clinically important limits, with the exception of heart rate. Compared with placebo (23%), a higher percentage of subjects treated with INVEGA (36%, 3, 6, 9, 12 mg) had heart rate values >= 100 bpm.
Abnormal Hematologic and Clinical Chemistry Findings
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, a between-group comparison revealed no medically important differences between INVEGA and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA was associated with increases in serum prolactin (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of treatment (first post-baseline measurement), and remained above baseline levels at study endpoint. The incidence of potentially prolactin-related adverse events was small and similar to that for placebo.
Clinical Trial Adverse Drug Reactions in Short-Term, Placebo-Controlled, Fixed-Dose Studies The following ADRs, where a causal relationship is suspected between the drug and the reported event, were reported in patients treated with INVEGA (n=850) in the three placebo-controlled, 6- week, double-blind, fixed-dose clinical trials in patients with schizophrenia. The following terms and frequencies were applied: very common (>= 10%), common (frequent) (>= 1% to < 10%),
uncommon (infrequent) (>= 0.1% to < 1%), rare (>= 0.01% to < 0.1%), and very rare (< 0.01%). The majority of ADRs were mild to moderate in severity.
Cardiac disorders: common:atrioventricular block first degree, bradycardia, sinus tachycardia, tachycardia, bundle branch block; uncommon:palpitations, sinus arrhythmia
Eye disorders: uncommon:
oculogyration
Gastrointestinal disorders: common:
abdominal pain upper, dry mouth, salivary hypersecretion, vomiting
General disorders: common:asthenia, fatigue; uncommon:edema
Immune system disorders: uncommon:
anaphylactic reaction
Investigations: common:weight increased; uncommon:electrocardiogram abnormal Metabolism and nutrition disorders: uncommon:increased appetite Musculoskeletal and connective tissue disorders: uncommon:muscle rigidity
Nervous system disorders: very common:headache; common:akathisia, dizziness, dystonia, extrapyramidal disorder, hypertonia, Parkinsonism, sedation, somnolence, tremor; uncommon:dizziness postural, dyskinesia, grand mal convulsion, syncope
Psychiatric disorders: uncommon:
nightmare
Reproductive system and breast disorders: uncommon:
amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstruation irregular
Vascular disorders: common:orthostatic hypotension; uncommon:hypotension, ischemia
Adverse Drug Reactions in a Long-Term, Placebo-Controlled Study
The safety of INVEGA was also evaluated in a longer-term trial in adults with schizophrenia (see Product Monograph Part II: CLINICAL TRIALS). In general, the types, frequencies, and severities of ADRs reported during the initial 14-week open-label phase of this study were comparable to those reported in the 6-week, placebo-controlled, fixed-dose studies. The ADRs reported during the longer-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase, but occurred at generally lower frequencies.
Safety Information Reported with Risperidone
Paliperidone is the major active metabolite of risperidone. The release profile and pharmacokinetic characteristics of INVEGA are considerably different than those observed with oral immediate-release risperidone formulations (see ACTION AND CLINICAL PHARMACOLOGY); however, the receptor binding profile of paliperidone is very similar to that of the parent compound. Safety information reported with risperidone in clinical trials and postmarketing experience that may be relevant to INVEGA can be found in local labelling for risperidone.
Drug-Drug Interactions
Caution is advised when prescribing INVEGA with drugs known to prolong the QT interval.
Potential for INVEGA to Affect Other Drugs
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P-450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme-inducing properties. A population pharmacokinetic analysis to evaluate the influence of predicted CYP2D6 phenotype on exposure indicated that no adjustment in the paliperidone dose on the basis of predicted phenotype is warranted. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance of this with respect to P-gp mediated transport of other drugs is unknown. Given the primary CNS effects of paliperidone (see ADVERSE REACTIONS), INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension (see WARNINGS AND PRECAUTIONS, Cardiovascular), an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential.
Potential for Other Drugs to Affect INVEGA
Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5. This suggests that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). In an interaction study in healthy subjects in which INVEGA was administered concomitantly with paroxetine, a potent CYP2D6 inhibitor, no clinically relevant effects on the pharmacokinetics of paliperidone were observed. Carbamazepine and other potent CYP3A4 inducers: Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. As is typical of CYP3A4 inducers, carbamazepine is also a P-glycoprotein (P-gp) inducer. Although in- vitro studies have shown that paliperidone is a substrate of both P-gp and CYP3A4, the relative contributions of P-gp and CYP3A4 to changes in the pharmacokinetic parameters are unclear. On initiation of carbmazepine, the dose of INVEGA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA should be re- evaluated and decreased if necessary. Until more data are available, these recommendation should be extended to other potent CYP3A4 inducers and/or P-glycoprotein upregulators. Paliperidone, a cation under physiological pH, is primarily excreted unchanged by the kidneys, approximately half via filtration and half via active secretion. Concomitant administration of trimethoprim, a drug known to inhibit active renal cation drug transport, did not influence the pharmacokinetics of paliperidone.
Concomitant Use of INVEGA with Risperidone
Since paliperidone (9-hydroxy-risperidone) is the major active metabolite of risperidone, concomitant use of INVEGA with oral risperidone is not recommended since the combination of the two will lead to additive paliperidone exposure.
Drug-Food Interactions
Following administration of a single 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal, the mean Cmax and AUC values of paliperidone increased by 60% and 54%, respectively, compared with administration under fasting conditions. Although the presence or absence of food at the time of administration of INVEGA may increase or decrease exposure to paliperidone, these changes are not considered clinically relevant. Clinical trials establishing the safety and efficacy of INVEGA were carried out in subjects without regard to the timing of meals.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions
Smoking
No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any differences between smokers and non- smokers.
Dosing Considerations
Since paliperidone (9-hydroxy-risperidone) is the major active metabolite of risperidone,
concomitant use of INVEGA with oral risperidone is not recommended since the combination of the two will lead to additive paliperidone exposure. INVEGA should be administered orally once daily, preferably in the morning, without regard to meals. Clinical trials establishing the safety and efficacy of INVEGA were carried out in patients without regard to food intake. INVEGA must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool.
Recommended Dose and Dosage Adjustment
Adult
The recommended starting and target dose of INVEGA is 6 mg once daily. No initial dose titration is required. However, in some cases a lower dose of 3 mg/day may be sufficient. In clinical trials a dose range of 3 to 12 mg/day was studied and while efficacy was observed across all doses, there was a dose-related increase in adverse effects (see ADVERSE REACTIONS and Product Monograph Part II: CLINICAL TRIALS). Dose adjustments should be made after clinical reassessment and generally should occur at intervals of more than 5 days. When dose adjustments are indicated, small increments/decrements of 3 mg/day are recommended, up to a maximum of 12 mg/day.
Patients with Hepatic Impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. INVEGA has not been studied in patients with severe hepatic impairment.
Patients with Renal Impairment
For patients with mild renal impairment (creatinine clearance = 50 to < 80 mL/min), the maximum recommended dose is 6 mg once daily. For patients with moderate to severe renal impairment (creatinine clearance 10 to < 50 mL/min), the maximum recommended dose of INVEGA is 3 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment.
Elderly
Dosing recommendations for elderly patients with normal renal function (>= 80 mL/min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Patients with Renal Impairment above).
Pediatrics
Safety and effectiveness of INVEGA in patients < 18 years of age have not been studied.
Other Special Populations
No dose adjustment for INVEGA is recommended based on gender, race, or smoking status.
Symptoms
In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. In the case of acute overdosage, the possibility of multiple drug involvement should be considered.
Treatment
Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.
Mechanism of Action
Paliperidone is a centrally active dopamine D2 antagonist with predominant serotonergic 5-HT2A antagonistic activity. Paliperidone is also active as an antagonist at a1 and a2 adrenergic receptors and H1 histaminergic receptors. Paliperidone has no affinity for cholinergic muscarinic or b1- and b2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. Antagonism at receptors other than D2 and 5HT2A may explain some of the other effects of paliperidone.
Pharmacodynamics
Formulation Characteristics
The controlled rate of release of paliperidone from the extended-release technology results in a pharmacokinetic profile with a slower rate of absorption than an immediate-release formulation, leading to an ascending plasma concentration profile over 24 hours on Day 1 of dosing. In studies with paliperidone and risperidone, an ascending profile paliperidone formulation concept demonstrated a differential effect on orthostatic hypotension compared to a flat or immediate- release profile. In one study (n=27), paliperidone administered to achieve an ascending profile with a total dose of 4 mg compared to a lower dose (2 mg) of immediate release risperidone resulted in lower incidences of orthostatic hypotension (32% vs. 46%). The extended-release profile showed a lower incidence of orthostatic hypotension and allows for initiation of treatment at an effective dose without titration, as is the typical practice with antipsychotic drugs to address initial orthostatic intolerance.
Pharmacokinetics
Following a single dose, the plasma concentrations of paliperidone steadily rise to reach peak plasma concentration (Cmax) in approximately 24 hours after dosing. The pharmacokinetics of paliperidone following INVEGA administration are dose-proportional within the recommended clinical dose range (3 to 12 mg). The terminal elimination half-life of paliperidone, regardless of formulation, is approximately 23 hours. Steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects. The release characteristics of INVEGA result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone. In a study comparing the steady-state pharmacokinetics following once-daily administration of 12 mg paliperidone (administered as extended-release tablets) with 4 mg immediate-release risperidone in schizophrenic subjects, the fluctuation indexes were 38% for paliperidone extended-release compared to 125% for risperidone immediate-release (Figure 1.1).
Paliperidone ER (n=37)
Risperidone immediate release (n=37)
1 2 3 4 5 6 7
Time (Days)
Figure 1.1
Steady-state concentration profile following administration of 12 mg paliperidone administered as six 2 mg extended-release tablets once daily for 6 days (paliperidone concentrations are represented) compared with risperidone immediate-release administered as 2 mg once daily on Day 1 and 4 mg once daily on Days 2 to 6 (paliperidone+risperidone concentrations are represented).
Following administration of INVEGA, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.
The absolute oral bioavailability of paliperidone from INVEGA (i.e., the extended release formulation) is 28%. It is thought that this is due to a higher fraction of paliperidone being released in the colon, where absorption is lower.
Following administration of a single 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal, the mean Cmax and AUC values of paliperidone increased by 60% and 54%, respectively, compared with administration under fasting conditions. Although the presence or absence of food at the time of INVEGA administration may increase or decrease exposure to paliperidone, these changes are not considered clinically relevant. Clinical trials establishing the safety and efficacy of INVEGA were carried out in subjects without regard to the timing of meals (see DOSAGE AND ADMINISTRATION). Distribution: Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. The plasma protein binding of paliperidone is 74%. It binds primarily to a1-acid glycoprotein and albumin. In vitro, high therapeutic concentrations of diazepam (3 mcg/mL), sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused a slight increase in the free fraction of paliperidone at 50 ng/mL. These changes are not expected to be of clinical significance. Metabolism and Excretion: The following data are based on a human mass balance study using oral solution of 14C-paliperidone, a dosage form which has approximately 100% bioavailability. One week following administration of a single 1 mg dose of oral solution 14C-paliperidone, 59% of the administered dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, of which each accounted for no more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. In vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone; however, in vivo results indicate that these isozymes play a very limited role in the metabolism of paliperidone. Despite the large variation in the general population with regard to the ability to metabolize CYP2D6 substrates, population pharmacokinetic analyses indicated no discernable difference on the exposure and apparent clearance of paliperidone after administration of INVEGA between extensive metabolizers and poor metabolizers of CYP2D6 substrates. In vitro studies using microsomal preparations of heterologous systems indicate that CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5 are not involved in the metabolism of paliperidone. Paliperidone is not expected to have enzyme-inducing properties.
Special Populations and Conditions
No data available.
Geriatrics: No dosage adjustment is recommended based on age alone. However, because elderly subjects may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal Insufficiency below). Data from a pharmacokinetic study in elderly subjects (>= 65 years of age, n = 26) indicated that the apparent steady-state clearance of paliperidone following INVEGA administration was 20% lower compared to that of adult subjects (18-45 years of age, n = 28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction for age-related decreases in CrCl.
No dosage adjustment is recommended based on gender. The apparent clearance of paliperidone following INVEGA administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and creatinine clearance between men and women, as a population pharmacokinetics evaluation revealed no evidence of clinically significant gender-related differences in the pharmacokinetics of paliperidone following INVEGA administration after correction for lean body mass and creatinine clearance.
No dosage adjustment is recommended based on race. Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following INVEGA administration.
Paliperidone is not extensively metabolized in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of unbound paliperidone were similar to those of healthy subjects. No dose adjustment is required in patients with mild to moderate hepatic impairment. INVEGA has not been studied in patients with severe hepatic impairment.
The dose should be reduced in patients with moderate or severe renal impairment (see
). The disposition of paliperidone was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased
with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (CrCl = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min), and 71% in severe (CrCl = 10 to < 30 mL/min) renal impairment. The mean terminal elimination half-life of paliperidone was 24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl $ 80 mL/min). INVEGA has not been studied in subjects with creatinine clearance < 10 mL/min.
No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any differences between smokers and non-smokers.
INVEGA should be stored at 15 - 30oC. Protect from moisture. Keep out of the reach of children.
Dosage Forms and Packaging
INVEGA Extended-release Tablets contain paliperidone as the medicinal ingredient and are available in 3 mg, 6 mg, 9 mg, and 12 mg dosage strengths as follows: 3 mg: A white capsule-shaped tablet printed with "PAL 3". Orifices may or may not be visible. Bottles of 30 and 350 tablets, blisters of 30 tablets. 6 mg: A beige capsule-shaped tablet printed with "PAL 6". Orifices may or may not be visible. Bottles of 30 and 350 tablets, blisters of 30 tablets. 9 mg: A pink capsule-shaped tablet printed with "PAL 9". Orifices may or may not be visible. Bottles of 30 and 350 tablets, blisters of 30 tablets. 12 mg: A dark-yellow capsule-shaped tablet printed with "PAL 12". Orifices may or may not be visible. Bottles of 30 and 350 tablets, blisters of 30 tablets.
Composition
The following inactive ingredients are common to all tablet strengths: butylated hydroxytoluene, carnauba wax, cellulose acetate, ferric oxide red, ferric oxide yellow, hydroxyethyl cellulose, hypromellose, iron oxide black, polyethylene oxides, polyethylene glycol, propylene glycol, povidone, sodium chloride, stearic acid, and titanium dioxide. The 3 mg tablets also contain lactose monohydrate and triacetin.
System Components and Performance
INVEGA tablets utilize osmotic pressure to deliver paliperidone from the dosage form at a controlled rate. The system, which resembles a capsule-shaped tablet in appearance, comprises an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each strength is identified by a unique colour overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible colour overcoat erodes quickly. Water is then imbibed through the semi-permeable, rate- controlling membrane. The membrane controls the rate at which water enters the tablet core, which, in turn, controls drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The drug release rate from the system is designed to increase with time over a period of approximately 16 to 22 hours due to the drug-concentration gradient incorporated into the two drug layers of INVEGA. The ascending release rate of INVEGA allows patients to receive a therapeutically effective dose of paliperidone without the need for dose titration. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool, along with insoluble core components.