Recommended Topic Related To:

Invega Sustenna

"Jan. 7, 2011 -- Many people taking powerful psychiatric medications that increase their risk of weight gain and diabetes are prescribed those drugs when there's little evidence that they will get any benefit from them, a new study shows.

"...

Invega Sustenna

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA® SUSTENNA® (paliperidone palmitate) is not approved for the treatment of patients with 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. Oral paliperidone and INVEGA® SUSTENNA® were not marketed at the time these studies were performed and are not approved for the treatment of patients with dementia-related psychosis [see 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. Reference ID: 3495576 12 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 Torsades 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 oral 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 (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of INVEGA® SUSTENNA® administered in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). 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.

In the three fixed-dose efficacy studies of oral paliperidone extended release, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).

In the four fixed-dose efficacy studies of INVEGA® SUSTENNA® , no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

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® SUSTENNA® 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® SUSTENNA® , drug discontinuation should be considered. However, some patients may require treatment with INVEGA® SUSTENNA® 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® SUSTENNA® . 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 treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because INVEGA® SUSTENNA® was not marketed at the time these studies were performed, it is not known if INVEGA® SUSTENNA® is associated with this 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 four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 2.

Table 2: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia

Placebo INVEGA® SUSTENNA®
39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga
Mean change from baseline (mg/dL)
n=367 n=86 n=244 n=238 n=110 n=126 n=115
Serum Glucose Change from baseline -1.3 1.3 3.5 0.1 3.4 1.8 -0.2
  Proportion of Patients with Shifts
Serum Glucose Normal to 4.6% 6.3% 6.4% 3.9% 2.5% 7.0% 6.6%
High ( < 100 mg/dL to > 126mg/dL) (11/241) (4/64) (11/173) (6/154) (2/79) (6/86) (5/76)
a Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [See Clinical Studies].

In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA® SUSTENNA® was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).

Dyslipidemia

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

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 3.

Table 3: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia

Placebo INVEGA® SUSTENNA®
39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga
Cholesterol Change from baseline Mean change from baseline (mg/dL)
n=366 n=89 n=244 n=232 n=105 n=119 n=120
-6.6 -6.4 -5.8 -7.1 -0.9 -4.2 9.4
LDL Change from baseline n=275 n=80 n=164 n=141 n=104 n=117 n=108
-6.0 -4.8 -5.6 -4.8 0.9 -2.4 5.2
HDL Change from baseline n=286 n=89 n=165 n=150 n=105 n=118 n=115
0.7 2.1 0.6 0.3 1.5 1.1 0.0
Triglycerides Change from baseline n=366 n=89 n=244 n=232 n=105 n=119 n=120
-16.7 7.6 -9.0 -11.5 -14.1 -20.0 11.9
Cholesterol Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) Proportion of Patients with Shifts
3.2% 2.0% 2.0% 2.1% 0% 3.1% 7.1%
(7/222) (1/51) (3/147) (3/141) (0/69) (2/65) (6/84)
LDL Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) 1.1% 0% 0% 0% 0% 0% 0%
(1/95) (0/29) (0/67) (0/46) (0/41) (0/37) (0/44)
HDL Normal to Low( ≥ 40 mg/dL to < 40 mg/dL) 13.8% 14.8% 9.6% 14.2% 12.7% 10.5% 16.0%
(28/203) (9/61) (11/115) (15/106) (9/71) (8/76) (13/81)
Triglycerides Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) 3.6% 6.1% 9.2% 7.2% 1.3% 3.7% 10.7%
(8/221) (3/49) (14/153) (10/139) (1/79) (3/82) (9/84)
a Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [See Clinical Studies].

In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA® SUSTENNA® was associated with a mean change in (a) total cholesterol of -1.2 mg/dL at Week 29 (n=112) and +0.1 mg/dL at Week 53 (n=100); (b) LDL of -2.7 mg/dL at Week 29 (n=107) and -2.3 mg/dL at Week 53 (n=89); (c) HDL of -0.8 mg/dL at Week 29 (n=112) and -2.6 mg/dL at Week 53 (n=98); and (d) triglycerides of +16.2 mg/dL at Week 29 (n=112) and +37.4 mg/dL at Week 53 (n=100).

Weight Gain

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

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 4.

Table 4. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia

Placebo INVEGA®SUSTENNA®
39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga
Weight (kg) n=451 n=116 n=280 n=267 n=137 n=144 n=145
Change from baseline Weight Gain -0.4 0.4 0.8 1.4 0.4 0.7 1.4
≥ 7% increase from baseline 3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1%
a Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [See Clinical Studies].

In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA® SUSTENNA® was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).

Orthostatic Hypotension And Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with INVEGA® SUSTENNA® in the recommended dose range of 39 mg to 234 mg in the four fixeddose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of INVEGA® SUSTENNA® -treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies were similar to those observed in the short-term studies.

INVEGA® SUSTENNA® 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® , an oral form of 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 INVEGA® SUSTENNA® 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® SUSTENNA® and have their WBC followed until recovery.

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 Cognitive And Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA® SUSTENNA® [see ADVERSE REACTIONS]. Antipsychotics, including INVEGA® SUSTENNA® , 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

In the four fixed-dose double-blind placebo-controlled studies, < 1% (1/1293) of subjects treated with INVEGA® SUSTENNA® in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with < 1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.

Like other antipsychotic drugs, INVEGA® SUSTENNA® 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® SUSTENNA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA® SUSTENNA® , priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption Of 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® SUSTENNA® 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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Physicians are advised to discuss the following issues with patients for whom they prescribe INVEGA® SUSTENNA® .

Orthostatic Hypotension

Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see WARNINGS AND PRECAUTIONS].

Interference With Cognitive And Motor Performance

As INVEGA® SUSTENNA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA® SUSTENNA® therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with INVEGA® SUSTENNA® [see Use In Specific Populations].

Nursing

Inform patients and caregivers that INVEGA® SUSTENNA® is present in human breast milk; there is a potential for serious adverse reactions in nursing infants. Advise patients that the decision whether to discontinue nursing or to discontinue the drug should take into account the importance of the drug to the patient [see Use In Specific Populations].

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions [see DRUG INTERACTIONS].

Alcohol

Patients should be advised to avoid alcohol while taking INVEGA® SUSTENNA® [see DRUG INTERACTIONS].

Heat Exposure And Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which is 0.6, 2, and 4 times, respectively, the maximum recommended human 234 mg dose of INVEGA® SUSTENNA® on a mg/m² body surface area basis. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 47 mg and 94 mg/kg/month. A carcinogenicity study in mice has not been conducted with paliperidone palmitate.

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, 2.5, 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 body surface area basis (see RISPERDAL® 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-receptor antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

Paliperidone palmitate showed no genotoxic potential in the Ames reverse mutation test or the mouse lymphoma assay. 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

Fertility studies of paliperidone palmitate have not been performed.

In a study of fertility conducted with orally administered paliperidone, the percentage of treated female rats that became pregnant was not affected at doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and post-implantation loss were 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 (12 mg/day) of orally administered paliperidone (INVEGA® ) on a mg/m² body surface area 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

Risk Summary

Adequate and well controlled studies with INVEGA® SUSTENNA® have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. INVEGA® SUSTENNA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization.

Data

Human Data

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. 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.

Animal Data

There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 250 mg/kg, which is 10 times the maximum recommended human 234 mg dose of INVEGA® SUSTENNA® on a mg/m² body surface area basis.

In studies in pregnant rats and rabbits in which paliperidone was given orally during the period of organogenesis, there were no increases in fetal abnormalities up to the highest doses tested (10 mg/kg/day in rats and 5 mg/kg/day in rabbits, which are each 8 times the maximum recommended human dose of 12 mg/day of orally administered paliperidone [INVEGA® ] on a mg/m² body surface area basis).

In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, increases in pup deaths were seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m² body surface area basis (see RISPERDAL® package insert).

Labor And Delivery

The effect of INVEGA® SUSTENNA® on labor and delivery in humans is unknown.

Nursing Mothers

In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of INVEGA® SUSTENNA® in patients < 18 years of age have not been established.

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

Geriatric Use

Clinical studies of INVEGA® SUSTENNA® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with 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

Use of INVEGA® SUSTENNA® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

INVEGA® SUSTENNA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment.

Patients With Parkinson's Disease Or Lewy Body Dementia

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA® SUSTENNA® . Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

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

Warnings
Precautions
A A A

Invega Sustenna - User Reviews

Invega Sustenna User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Invega Sustenna sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Emotional Wellness

Get tips on therapy and treatment.