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Medications: Invega® – paliperidone

MEDICATIONS

Invega® – paliperidone (View the FDA label)

INVEGA® is an atypical antipsychotic agent indicated for Treatment of schizophrenia (1.1)

  • Adults: Efficacy was established in three 6-week trials and one maintenance trial. (14.1)
  • Adolescents (ages 12-17): Efficacy was established in one 6-week trial. (14.1)
    Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants. (1.2)
  • Efficacy was established in two 6-week trials in adult patients. (14.2)

DOSAGE AND ADMINISTRATION

Initial Dose Recommended Dose Maximum Dose
Schizophrenia – adults (2.1) 6 mg/day 3 – 12 mg/day 12 mg/day
Schizophrenia-
adolescents (2.1)
Weight < 51kg 3 mg/day 3 – 6 mg/day 6 mg/day
Weight >= 51kg 3 mg/day 3 – 12 mg/day 12 mg/day
Schizoaffective disorder – adults (2.2) 6 mg/day 3 – 12 mg/day 12 mg/day

Tablet should be swallowed whole and should not be chewed, divided, or crushed. (2.3)

Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were (6)

  • Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia.
  • Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia.
  • Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.

Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with dementiarelated psychoses treated with atypical antipsychotics. (5.2)

Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3)

QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. (5.4)

Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5)

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.6)

  • Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.6)
  • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.6)
  • Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6)

Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7)

Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease. (5.8)

Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. (5.9)

Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including INVEGA®. Patients with a history of a clinically significant low white blood cell count (WBC) or a druginduced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.10)

Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.11)

Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.12)

Suicide: Closely supervise high-risk patients. (5.14)

  • Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. (7.1)
  • Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with INVEGA®. (7.1)
  • Co-administration with carbamazepine decreased mean steady-state Cmax and AUC of paliperidone by approximately 37%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2)
  • Co-administration of divalproex sodium increased Cmax and AUC of paliperidone by approximately 50%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2)

Human Experience
While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of INVEGA® 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 somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.

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 Overdosage
There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Uses

INVEGA® is an atypical antipsychotic agent indicated for Treatment of schizophrenia (1.1)

  • Adults: Efficacy was established in three 6-week trials and one maintenance trial. (14.1)
  • Adolescents (ages 12-17): Efficacy was established in one 6-week trial. (14.1)
    Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants. (1.2)
  • Efficacy was established in two 6-week trials in adult patients. (14.2)

DOSAGE AND ADMINISTRATION

Initial Dose Recommended Dose Maximum Dose
Schizophrenia – adults (2.1) 6 mg/day 3 – 12 mg/day 12 mg/day
Schizophrenia-
adolescents (2.1)
Weight < 51kg 3 mg/day 3 – 6 mg/day 6 mg/day
Weight >= 51kg 3 mg/day 3 – 12 mg/day 12 mg/day
Schizoaffective disorder – adults (2.2) 6 mg/day 3 – 12 mg/day 12 mg/day

Tablet should be swallowed whole and should not be chewed, divided, or crushed. (2.3)

Side Effects

Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were (6)

  • Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia.
  • Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia.
  • Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.
Precautions

Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with dementiarelated psychoses treated with atypical antipsychotics. (5.2)

Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3)

QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. (5.4)

Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5)

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.6)

  • Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.6)
  • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.6)
  • Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6)

Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7)

Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease. (5.8)

Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. (5.9)

Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including INVEGA®. Patients with a history of a clinically significant low white blood cell count (WBC) or a druginduced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.10)

Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.11)

Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.12)

Suicide: Closely supervise high-risk patients. (5.14)

Interactions
  • Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. (7.1)
  • Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with INVEGA®. (7.1)
  • Co-administration with carbamazepine decreased mean steady-state Cmax and AUC of paliperidone by approximately 37%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2)
  • Co-administration of divalproex sodium increased Cmax and AUC of paliperidone by approximately 50%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2)
Overdose

Human Experience
While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of INVEGA® 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 somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.

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 Overdosage
There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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