INVEGA: Package Insert and Label Information (Page 4 of 6)

6.8 Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons 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 (5.7)

6.9 Other Adverse Reactions Observed During Premarketing Evaluation of INVEGA ®

The following additional adverse reactions occurred in < 2% of INVEGA -treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA -treated subjects who participated in other clinical studies. ® ®

bradycardia, palpitations Cardiac disorders:

eye movement disorder Eye disorders:

flatulence Gastrointestinal disorders:

edema General disorders:

anaphylactic reaction Immune system disorders:

urinary tract infection Infections and infestations:

alanine aminotransferase increased, aspartate aminotransferase increased Investigations:

arthralgia, pain in extremity Musculoskeletal and connective tissue disorders:

opisthotonus Nervous system disorders:

agitation, insomnia, nightmare Psychiatric disorders:

breast discomfort, menstruation irregular, retrograde ejaculation Reproductive system and breast disorders:

nasal congestion Respiratory, thoracic and mediastinal disorders:

pruritus, rash Skin and subcutaneous tissue disorders:

hypertension Vascular disorders:

The safety of INVEGA was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA in adults with schizophrenia . In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase. ® ® [see ] Clinical Studies (14)

6.10 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INVEGA ; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention. ®

6.11 Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

7 DRUG INTERACTIONS

7.1 Potential for INVEGA to Affect Other Drugs ®

Given the primary CNS effects of paliperidone , 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. [see , )] Adverse Reactions (6.16.2®

Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential . ® [see ] Warnings and Precautions (5.9)

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. 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. In vitro

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No data are available and the clinical relevance is unknown. in vivo

Pharmacokinetic interaction between lithium and INVEGA is unlikely. ®

In a drug interaction study, co-administration of INVEGA (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC and C ) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when INVEGA 3–15 mg/day was added to their existing valproate treatment. ® 24h max,ss ®

7.2 Potential for Other Drugs to Affect INVEGA ®

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. studies have shown that paliperidone is a P-gp substrate. in vitro in vivo In vitro

Co-administration of INVEGA 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, 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. ® max ® ®

Paliperidone is metabolized to a limited extent by CYP2D6 . In an interaction study in healthy subjects in which a single 3 mg dose of INVEGA was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. [see ] Clinical Pharmacology (12.3) ®

Co-administration of a single dose of INVEGA 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C and AUC of paliperidone. Dosage reduction for INVEGA should be considered when INVEGA is co-administered with valproate after clinical assessment. ® max ® ®

Pharmacokinetic interaction between lithium and INVEGA is unlikely. ®

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

. Pregnancy Category C

There are no adequate and well controlled studies of INVEGA in pregnant women. ®

Use of first generation antipsychotic drugs during the last trimester of pregnancy has been associated with extrapyramidal symptoms in the neonate. These symptoms are usually self-limited. It is not known whether paliperidone, when taken near the end of pregnancy, will lead to similar neonatal signs and symptoms.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended human dose of paliperidone (on a mg/m basis). 2

In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, there were increases in pup deaths seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m basis (see risperidone package insert). 2

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. 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.

INVEGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ®

8.3 Nursing Mothers

Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone.

8.4 Pediatric Use

Safety and effectiveness of INVEGA in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. ® ®

Safety and effectiveness of INVEGA for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of INVEGA for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied. ® ®

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 INVEGA on growth and sexual maturation have not been fully evaluated in children and adolescents. ®

8.5 Geriatric Use

The safety, tolerability, and efficacy of INVEGA were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of INVEGA (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of INVEGA (3 mg to 15 mg once daily) . There were no subjects ≥ 65 years of age in the schizoaffective disorder studies. ® ® ® [see ] Clinical Studies (14)

Overall, of the total number of subjects in schizophrenia clinical studies of INVEGA (n = 1796), including those who received INVEGA or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ® ®

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . [see ] Clinical Pharmacology (12.3) [see ] Dosage and Administration (2.5)

8.6 Renal Impairment

Dosing must be individualized according to the patient’s renal function status . [see ] Dosage and Administration (2.5)

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. INVEGA has not been studied in patients with severe hepatic impairment. ®

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

INVEGA (paliperidone) is not a controlled substance. ®

9.2 Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of INVEGA misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). ®

9.3 Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

10 OVERDOSAGE

10.1 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.

10.2 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.

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