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Dosing Information
Convenient, once-daily dosing
INVEGA® (paliperidone) Extended-Release Tablets are available in 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. INVEGA® utilizes OROS® osmotic drug-release technology (see full US Prescribing Information under Delivery System Components and Performance).
- Patients can start with the recommended 6-mg dose; no initial dose titration necessary
- Dosing flexibility for patients who may benefit from higher or lower doses: 3 mg to 12 mg
- Due to the extended-release formulation, morning administration is recommended
The recommended dose of INVEGA (paliperidone) Extended-Release Tablets is 6 mg once daily, administered in the morning. Initial dose titration is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse effects. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, small increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.
INVEGA can be taken with or without food. 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. Tablets should 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 in their stool something that looks like a tablet.
Concomitant use of INVEGA with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with INVEGA.
Dosing in Special Populations
Hepatic Impairment
For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended, (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Dosing in Special Populations: Hepatic Impairment).
Renal Impairment
Dosing must be individualized according to the patient’s renal function status. 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 recommended dose of INVEGA is 3 mg once daily.
Elderly
Because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status. In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. 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 (see Renal Impairment above).
Race
No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians.
Gender
No dosage adjustment is recommended based on gender. No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women.
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.
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INVEGA® (paliperidone) extended-release tablets are indicated for the acute and maintenance treatment of schizophrenia.
IMPORTANT SAFETY INFORMATION FOR INVEGA®
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical 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 the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA® (paliperidone) is not approved for the treatment of patients with dementia-related psychosis.
Elderly patients with dementia-related psychosis treated with atypical 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 the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA® (paliperidone) is not approved for the treatment of patients with dementia-related psychosis.
Cerebrovascular Adverse Events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking atypical antipsychotics in clinical trials. INVEGA® is not approved for treating these patients.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including INVEGA®. Clinical manifestations include muscle rigidity, fever, altered mental status and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.
QT Prolongation: INVEGA® causes a modest increase in the corrected QT (QTc) interval. INVEGA® should be avoided in combination with other drugs that are known to prolong the QTc interval, in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Certain circumstances may increase the risk of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.
Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose. Elderly patients appeared to be at increased risk for TD. Prescribing should be consistent with the need to minimize the risk of TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.
Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA® elevates prolactin levels and the elevation persists during chronic administration.
Potential for Gastrointestinal INVEGA® should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing. Rare instances of obstructive symptoms have been reported in patients with known strictures taking nondeformable formulations. INVEGA® should only be used in patients who are able to swallow the tablet whole.
Orthostatic Hypotension and Syncope: INVEGA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. Monitoring should be considered in patients for whom this may be of concern. INVEGA® should be used with caution in patients with known cardiovascular disease, and conditions that would predispose patients to hypotension.
Potential for Cognitive and Motor Impairment: INVEGA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA® does not affect them adversel
Seizures: INVEGA® should be used cautiously in patients with a history of seizures.
Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy.
Maintenance Treatment: Physicians who elect to use INVEGA® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Drug Interactions: Co-administration of INVEGA® 6 mg once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. On initiation of discontinuation of carbamazepine, the dose of INVEGA® should be re-evaluated and adjusted if necessary. Given the primary CNS effects of INVEGA®, INVEGA® should be used with caution in combination with other centrally acting drugs and the use of alcohol should be avoided.
Extrapyramidal Symptoms (EPS): Total EPS-related adverse events in the higher 9-mg and 12-mg treatment groups were 25% and 26%, respectively, versus 11% for the placebo group.
Weight Gain: The proportion of subjects having a weight gain of >7% body weight were comparable to placebo (5%) for 3 mg (7%) and 6 mg (6%). A higher incidence was seen for 9 mg (9%) and 12 mg (9%).
Renal Impairment: Dosing must be individualized according to the patient's renal function status. The maximum recommended dose of INVEGA® is 6 mg for patients with mild renal impairment and 3 mg for patients with moderate to severe renal impairment (see Dosing for Special Populations)..
Elderly: No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance (see Dosing for Special Populations).
Commonly observed adverse reactions: The most commonly observed adverse reactions, occurring at an incidence of >5% and at least 2 times placebo, were akathisia and extrapyramidal disorder.
Use with Risperidone: Concomitant use of paliperidone with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is co-administered.
01JN776R1
Please see the full US Prescribing Information.
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This page was last modified on: Oct 16 2008 at 16:04:56 EDT