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

5.7 Hyperprolactinemia

Like other drugs 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, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

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 in vitro , 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 [see Nonclinical Toxicology (13.1)]. 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.

5.8 Potential for Gastrointestinal Obstruction

Because the paliperidone extended-release tablets is non-deformable and does not appreciably change in shape in the gastrointestinal tract, paliperidone extended-release tablet should ordinarily not be administered to patients with preexisting 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, paliperidone extended-release tablets should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17)].

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 paliperidone (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. Paliperidone 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 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including paliperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Leukopenia, Neutropenia, and Agranulocytosis

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

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 paliperidone 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/mm3) should discontinue paliperidone and have their WBC followed until recovery.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with paliperidone [see Adverse Reactions (6.1, 6.2)]. Antipsychotics, including paliperidone, 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.

5.13 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 paliperidone (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, paliperidone 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.

5.14 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. Paliperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.15 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with paliperidone 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 paliperidone 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 paliperidone 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.

Paliperidone 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 paliperidone, caution should be observed in patients with known cardiovascular disease [see Warnings and Precautions (5.9)].

6. ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

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

The most common adverse reactions in clinical trials in adult in subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone 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 paliperidone 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 paliperidone-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 paliperidone -treated subjects. [See Adverse Reactions (6.4)].

The safety of paliperidone was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone 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 paliperidone at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of paliperidone was evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of paliperidone 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 paliperidone: 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 paliperidone (3-12 mg once daily). Both studies included subjects who received paliperidone 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 paliperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone 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

Table 4 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 paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4. Adverse Reactions Reported by ≥ 2% of Paliperidone –Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose,Placebo-Controlled Clinical Trials *

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily paliperidone 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 [see Clinical Studies (14)]. 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 paliperidone incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting.

Percentage of Patients Paliperidone extended-release Tablets
Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily
Body System or Organ Class Dictionary-Derived Term ( N = 355 ) ( N = 127 ) ( N = 235 ) ( N = 246 ) ( N = 242 )
Total percentage of subjects with adverse reactions 37 48 47 53 59
Cardiac disorders Atrioventricular block first degree Bundle branch block Sinus arrhythmia Tachycardia 1207 23214 01112 23112 1<1<114
Gastrointestinal disorders Abdominal pain upper Dry mouth Salivary hypersecretion 11<1 120 33<1 211 234
General disorders Asthenia Fatigue 11 22 <11 22 22
Nervous system disorders AkathisiaDizziness Extrapyramidal symptoms Headache Somnolence 448127 4610116 357129 84201410 105181411
Vascular disorders Orthostatic hypotension 1 2 1 2 4

Adolescent Patients with Schizophrenia

Table 5 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 paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial *
*
Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone 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.
Percentage of Patients
Paliperidone extended-release tablets
Body System or Organ Class Dictionary-Derived Term Placebo ( N = 51 ) 1 . 5 mg once daily ( N = 54 ) 3 mg once daily ( N = 16 ) 6 mg once daily ( N = 45 ) 12 mg once daily ( N = 35 )
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 Salivary hypersecretion Swollen tongue Vomiting 2 0 0 10 0200 0606 02 0 11 3033
General disorders Asthenia Fatigue 00 0 4 00 22 33
Infections and infestations Nasopharyngitis 2 4 0 4 0
Investigations Weight increased 0 7 6 2 3
Nervous system disorders Akathisia Dizziness Extrapyramidal symptoms Headache Lethargy SomnolenceTongue paralysis 0 0 0 40 4 0 4 2 4 9 0 90 6 6 19 6 0 13 0 11 2 18 4 0 20 0 17 3 23 14 3 263
Psychiatric disorders Anxiety 4 0 0 2 9
Reproductive system and breast disorders AmenorrheaGalactorrhea Gynecomastia 000 0 0 0 6 0 0 0 4 0 0 0 3
Respiratory , thoracic and mediastinal disorders Epistaxis 0 0 0 2 0

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