INVEGA: Package Insert and Label Information (Page 2 of 6)

5.7 Hyperprolactinemia

Like other drugs that antagonize dopamine D receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs. 2

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats . 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, but the available evidence is too limited to be conclusive. in vitro [see ] Nonclinical Toxicology (13.1)

5.8 Potential for Gastrointestinal Obstruction

Because the INVEGA tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, INVEGA should ordinarily 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 pseudoobstruction, or Meckel’s diverticulum). 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. Because of the controlled-release design of the tablet, INVEGA should only be used in patients who are able to swallow the tablet whole . ® ® ® [see and ] Dosage and Administration (2.3)Patient Counseling Information (17.8)

A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract.

5.9 Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with INVEGA (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. INVEGA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension. ® ®

5.10 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including INVEGA . Agranulocytosis has also been reported. Class Effect: ®

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced 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. ®

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm ) should discontinue INVEGA and have their WBC followed until recovery. 3 ®

5.11 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with INVEGA . 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. ® [see , )] Adverse Reactions (6.16.2®

5.12 Seizures

During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with INVEGA (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, INVEGA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. ® ®

5.13 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. ®

5.14 Suicide

The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for INVEGA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. ®

5.15 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with INVEGA during postmarketing surveillance. Severe priapism may require surgical intervention. ®

5.16 Thrombotic Thrombocytopenic Purpura (TTP)

No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP have been reported in association with risperidone administration, the relationship to risperidone therapy is unknown.

5.17 Body Temperature Regulation

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. ®

5.18 Antiemetic Effect

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 tumor.

5.19 Use in Patients with Concomitant Illness

Clinical experience with INVEGA in patients with certain concomitant illnesses is limited . ® [see ] Clinical Pharmacology (12.3)

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

INVEGA has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with INVEGA , caution should be observed in patients with known cardiovascular disease . ® ® [see ] Warnings and Precautions (5.9)

5.20 Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

6 ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Increased mortality in elderly patients with dementia-related psychosis [see and ] Boxed WarningWarnings and Precautions (5.1)
  • Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see ] Warnings and Precautions (5.2)
  • Neuroleptic malignant syndrome [see ] Warnings and Precautions (5.3)
  • QT prolongation [see ] Warnings and Precautions (5.4)
  • Tardive dyskinesia [see ] Warnings and Precautions (5.5)
  • Metabolic changes [see ] Warnings and Precautions (5.6)
  • Hyperprolactinemia [see ] Warnings and Precautions (5.7)
  • Potential for gastrointestinal obstruction [see ] Warnings and Precautions (5.8)
  • Orthostatic hypotension and syncope [see ] Warnings and Precautions (5.9)
  • Leukopenia, neutropenia, and agranulocytosis [see ] Warnings and Precautions (5.10)
  • Potential for cognitive and motor impairment [see ] Warnings and Precautions (5.11)
  • Seizures [see ] Warnings and Precautions (5.12)
  • Dysphagia [see ] Warnings and Precautions (5.13)
  • Suicide [see ] Warnings and Precautions (5.14)
  • Priapism [see ] Warnings and Precautions (5.15)
  • Thrombotic thrombocytopenic purpura (TTP) [see ] Warnings and Precautions (5.16)
  • Disruption of body temperature regulation [see ] Warnings and Precautions (5.17)
  • Antiemetic effect [see ] Warnings and Precautions (5.18)
  • Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see ] Warnings and Precautions (5.19)
  • Diseases or conditions that could affect metabolism or hemodynamic responses [see ] Warnings and Precautions (5.19)

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. ® ®

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA -treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA -treated subjects. . ® ® [See ] Adverse Reactions (6.4)

The safety of INVEGA was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA at daily doses within the range of 3 mg to 15 mg (n=104), is also included. ® ® ®

The safety of INVEGA was 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. ® ®

The safety of INVEGA was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA : 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the other study, 214 subjects received flexible doses of INVEGA (3–12 mg once daily). Both studies included subjects who received INVEGA either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. ® ® ® ®

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ® ®

6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia in Adults and Adolescents

Adult Patients with Schizophrenia

enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with INVEGA in any of the dose groups, and for which the incidence in INVEGA -treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 4 ® ®

Table 4. Adverse Reactions Reported by ≥ 2% of INVEGA -Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials ® *
Percentage of Patients
INVEGA ®
Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily
Body System or Organ Class (N=355) (N=127) (N=235) (N=246) (N=242)
Dictionary-Derived Term
*
Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily INVEGA doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg . Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the INVEGA incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting. ® ® [see ] Clinical Studies (14) ®
Total percentage of subjects with adverse reactions 37 48 47 53 59
Cardiac disorders
Atrioventricular block first degree 1 2 0 2 1
Bundle branch block 2 3 1 3 <1
Sinus arrhythmia 0 2 1 1 <1
Tachycardia 7 14 12 12 14
Gastrointestinal disorders
Abdominal pain upper 1 1 3 2 2
Dry mouth 1 2 3 1 3
Salivary hypersecretion <1 0 <1 1 4
General disorders
Asthenia 1 2 <1 2 2
Fatigue 1 2 1 2 2
Nervous system disorders
Akathisia 4 4 3 8 10
Dizziness 4 6 5 4 5
Extrapyramidal symptoms 8 10 7 20 18
Headache 12 11 12 14 14
Somnolence 7 6 9 10 11
Vascular disorders
Orthostatic hypotension 1 2 1 2 4

Adolescent Patients with Schizophrenia

lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12–17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with INVEGA in any of the dose groups, and for which the incidence in INVEGA -treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 5 ® ®

Table 5. Adverse Reactions Reported by ≥ 2% of INVEGA -Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial ® *
Percentage of Patients
INVEGA ®
Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily
Body System or Organ Class (N=51) (N=54) (N=16) (N=45) (N=35)
Dictionary-Derived Term
*
Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling. ®
Total percentage of subjects with adverse reactions 43 37 50 58 74
Cardiac disorders
Tachycardia 0 0 6 9 6
Eye disorders
Vision blurred 0 0 0 0 3
Gastrointestinal disorders
Dry mouth 2 0 0 0 3
Salivary hypersecretion 0 2 6 2 0
Swollen tongue 0 0 0 0 3
Vomiting 10 0 6 11 3
General disorders
Asthenia 0 0 0 2 3
Fatigue 0 4 0 2 3
Infections and infestations
Nasopharyngitis 2 4 0 4 0
Investigations
Weight increased 0 7 6 2 3
Nervous system disorders
Akathisia 0 4 6 11 17
Dizziness 0 2 6 2 3
Extrapyramidal symptoms 0 4 19 18 23
Headache 4 9 6 4 14
Lethargy 0 0 0 0 3
Somnolence 4 9 13 20 26
Tongue paralysis 0 0 0 0 3
Psychiatric disorders
Anxiety 4 0 0 2 9
Reproductive system and breast disorders
Amenorrhea 0 0 6 0 0
Galactorrhea 0 0 0 4 0
Gynecomastia 0 0 0 0 3
Respiratory, thoracic and mediastinal disorders
Epistaxis 0 0 0 2 0

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