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Invega

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA® (paliperidone) is not approved for the treatment of dementia-related psychosis [see BOXED WARNING].

Cerebrovascular Adverse Reactions, Including Stroke, In Elderly Patients With Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. INVEGA® was not marketed at the time these studies were performed. INVEGA® is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING].

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

QT Prolongation

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of INVEGA® (Cmax ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the INVEGA® 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA® had a QTcLD exceeding 500 msec at any time in any of these three studies.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, INVEGA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA® , drug discontinuation should be considered. However, some patients may require treatment with INVEGA® despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with INVEGA® . Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because INVEGA® was not marketed at the time these studies were performed, it is not known if INVEGA® is associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table 1a: Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

  Placebo INVEGA®
3 mg/day 6 mg/day 9 mg/day 12 mg/day
Serum Glucose Change from baseline Mean change from baseline (mg/dL)
n=322 n=122 n=212 n=234 n=218
0.8 -0.7 0.4 2.3 4.3
Serum Glucose Normal to High( < 100 mg/dL to ≥ 126 mg/dL) Proportion of Patients with Shifts
5.1% 3.2% 4.5% 4.8% 3.8%
(12/236) (3/93) (7/156) (9/187) (6/157)

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52 (n=314).

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with schizophrenia are presented in Table 1b.

Table 1b: Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age) with Schizophrenia

  INVEGA®
Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
Serum Glucose Change from baseline Mean change from baseline (mg/dL)
n=41 n=44 n=11 n=28 n=32
0.8 -1.4 -1.8 -0.1 5.2
Serum Glucose Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Proportion of Patients with Shifts
3% 0% 0% 0% 11%
(1/32) (0/34) (0/9) (0/20) (3/27)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.

Table 2a: Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

  Placebo INVEGA®
3 mg/day 6 mg/day 9 mg/day 12 mg/day
Cholesterol Change from baseline Mean change from baseline (mg/dL)
n=331 n=120 n=216 n=236 n=231
-6.3 -4.4 -2.4 -5.3 -4.0
LDL Change from baseline n=322 n=116 n=210 n=231 n=225
-3.2 0.5 -0.8 -3.9 -2.0
HDL Change from baseline n=331 n=119 n=216 n=234 n=230
0.3 -0.4 0.5 0.8 1.2
Triglycerides Change from baseline n=331 n=120 n=216 n=236 n=231
-22.3 -18.3 -12.6 -10.6 -15.4
Cholesterol Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) Proportion of Patients with Shifts
2.6% (5/194) 2.8% (2/71) 5.6% (7/125) 4.1% (6/147) 3.1% (4/130)
LDL Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) 1.9% (2/105) 0.0% (0/44) 5.0% (3/60) 3.7% (3/81) 0.0% (0/69)
HDL Normal to Low( ≥ 40 mg/dL to < 40 mg/dL) 22.0% (44/200) 16.3% (13/80) 29.1% (39/134) 23.4% (32/137) 20.0% (27/135)
Triglycerides Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) 5.3% (11/208) 11.0% (9/82) 8.8% (12/136) 8.7% (13/150) 4.3% (6/139)

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302).

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with schizophrenia are presented in Table 2b.

Table 2b: Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age) with Schizophrenia

  Placebo INVEGA®
1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
Cholesterol Change from baseline Mean change from baseline (mg/dL)
n=39 n=45 n=11 n=28 n=32
-7.8 -3.3 12.7 3.0 -1.5
LDL Change from baseline n=37 n=40 n=9 n=27 n=31
-4.1 -3.1 7.2 2.4 0.6
HDL Change from baseline n=37 n=41 n=9 n=27 n=31
-1.9 0.0 1.3 1.4 0.0
Triglycerides Change from baseline n=39 n=44 n=11 n=28 n=32
-8.9 3.2 17.6 -5.4 3.9
Cholesterol Normal to High ( < 170 mg/dL to ≥ 200 mg/dL) Proportion of Patients with Shifts
7% (2/27) 4% (1/26) 0% (0/6) 6% (1/18) 11% (2/19)
LDL Normal to High ( < 110 mg/dL to ≥ 130 mg/dL) 3% (1/32) 4% (1/25) 14% (1/7) 0% (0/22) 9% (2/22)
HDL Normal to Low ( ≥ 40 mg/dL to < 40 mg/dL) 14% (4/28) 7% (2/30) 29% (2/7) 13% (3/23) 23% (5/22)
Triglycerides Normal to High( < 150 mg/dL to ≥ 200 mg/dL) 3% (1/34) 5% (2/38) 13% (1/8) 8% (2/26) 7% (2/28)

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia Trials

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.

Table 3a: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

  Placebo
n=323
INVEGA®
3 mg/day
n=112
6 mg/day
n=215
9 mg/day
n=235
12 mg/day
n=218
Weight (kg) Change from baseline -0.4 0.6 0.6 1.0 1.1
Weight Gain ≥ 7% increase from baseline 5% 7% 6% 9% 9%

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302).

Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebo-controlled study and an open-label extension with a median duration of exposure to INVEGA® of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies] from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) are presented in Table 3b.

Table 3b: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age) with Schizophrenia

  Placebo
n=51
INVEGA®
1.5 mg/day
n=54
3 mg/day
n=16
6 mg/day
n=45
12 mg/day
n=34
Weight (kg) Change from baseline 0.0 0.3 0.8 1.2 1.5
Weight Gain ≥ 7% increase from baseline 2% 6% 19% 7% 18%

In the open-label long-term study the proportion of total subjects treated with INVEGA® with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with INVEGA® , weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to INVEGA® in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of INVEGA® -treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

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]. 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.

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 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 nondeformable 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 DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

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.

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.

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

Potential For Cognitive And Motor Impairment

Somnolence was reported in subjects treated with INVEGA® [see ADVERSE REACTIONS]. 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.

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.

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.

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.

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.

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.

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.

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.

Use In Patients With Concomitant Illness

Clinical experience with INVEGA® in patients with certain concomitant illnesses is limited [see CLINICAL PHARMACOLOGY].

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.

Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies of paliperidone have not been performed.

Carcinogenicity studies of risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone on a mg/m² basis (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat micronucleus test.

Impairment of Fertility

In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the maximum recommended human dose on a mg/m² basis.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration. Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

Use In Specific Populations

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/m² basis).

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/m² basis (see risperidone package insert).

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.

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.

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.

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) [see Clinical Studies]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

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 [see CLINICAL PHARMACOLOGY], 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 DOSAGE AND ADMINISTRATION].

Renal Impairment

Dosing must be individualized according to the patient's renal function status [see DOSAGE AND ADMINISTRATION].

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.

Last reviewed on RxList: 5/19/2014
This monograph has been modified to include the generic and brand name in many instances.

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