Drug Safety-related Labeling Changes (SrLC)

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INVEGA SUSTENNA (NDA-022264)

(PALIPERIDONE PALMITATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/23/2025 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Hyperprolactinemia

Additions and/or revisions underlined:

…

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)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

02/12/2021 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Neuroleptic Malignant Syndrome

(Additions and/or revisions underlined)

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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.

If NMS is suspected, immediately discontinue INVEGA SUSTENNA® and provide symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia

(Additions and/or revisions underlined)

Tardive dyskinesia, a syndrome consisting 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 12 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 with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon 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: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)].

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that INVEGA SUSTENNA® therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7)].

Alcohol

Advise patients to avoid alcohol during treatment with INVEGA SUSTENNA® [see Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA®. Advise patients that INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in a neonate.

01/25/2019 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

 

The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

 

07/27/2018 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

(Additions and/or revisions are underlined)

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) is not approved for the treatment of dementia-related psychosis.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive revisions-please refer to label)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA SUSTENNA® and any potential adverse effects on the breastfed child from INVEGA SUSTENNA® or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to INVEGA SUSTENNA® through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with INVEGA SUSTENNA® may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Juvenile Animal Studies

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  at MRHD of 12 mg/day…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Pregnancy

…Advise patients that INVEGA SUSTENNA®  may cause extrapyramidal and/or withdrawal symptoms in a neonate.  Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA SUSTENNA® during pregnancy.

Lactation

Advise breastfeeding women using INVEGA SUSTENNA® to monitor infants for somnolence,

failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs.

Infertility

Advise females of reproductive potential that INVEGA SUSTENNA® may impair fertility due to

an increase in serum prolactin levels. The effects on fertility are reversible.

12/20/2017 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The safety of INVEGA SUSTENNA was also evaluated in a 15-month, long-term study comparing INVEGA SUSTENNA to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received INVEGA SUSTENNA during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of INVEGA SUSTENNA® was similar to that seen in previous double-blind, placebo- controlled clinical trials in adult subjects with schizophrenia...

06/15/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Hyperprolactinemia

(Additions and/or revisions are underlined)

…

Prolactin data from two long-term, double-blind, placebo-controlled studies with INVEGA SUSTENNA are presented below; one study was in a population of patients with schizophrenia; the second study was in patients with schizoaffective disorder.

 

Schizophrenia

In a long-term maintenance trial of INVEGA SUSTENNA in schizophrenia patients (Study PSY-3001), elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of the patients in the INVEGA SUSTENNA group than those in the placebo group in males (51.9% vs. 29.0%) and in females (50.5% vs. 42.9%). During the double-blind phase, 4 females (4.2%) in the INVEGA SUSTENNA group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the INVEGA SUSTENNA group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.

Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.

 

Schizoaffective Disorder

In a long-term maintenance trial of INVEGA SUSTENNA in patients with schizoaffective disorder (Study SCA-3004), elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in a higher percentage of patients in the INVEGA SUSTENNA group than those in the placebo group in males (55.6% vs. 23.2%) and in females (44.3% vs. 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the INVEGA SUSTENNA group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the INVEGA SUSTENNA group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.

Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% vs. 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

(Additions and/or revisions are underlined)

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. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis.

5.7 Orthostatic Hypotension and Syncope

(Additions and/or revisions are underlined)

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity…

5.9 Leukopenia, Neutropenia, and Agranulocytosis

(Additions and/or revisions are underlined)

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy…

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA SUSTENNA in patients with severe neutropenia (absolute neutrophil count < 1000/mm3) and follow their WBC followed until recovery.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Patient Exposure

The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) with schizophrenia…

 

Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Commonly Observed Adverse Reactions: The most common (at least 5% in any INVEGA SUSTENNA group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.

 

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA SUSTENNA-Treated Patients: Table 10 lists the adverse reactions reported in 2% or more of INVEGA SUSTENNA-treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.

 

Extrapyramidal Symptoms (EPS)

…Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 11), and (5) incidence of spontaneous reports of EPS (Table 12).

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with INVEGA SUSTENNA

(Additions and/or revisions are underlined)

Table 13: Clinically Important Drug Interactions with INVEGA SUSTENNA (Table has been added; please refer to label)

7.2 Drugs Having No Clinically Important Interactions with INVEGA SUSTENNA

(Additions and/or revisions are underlined)

Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA and valproate (including valproic acid and divalproex sodium) is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA SUSTENNA is required when administered with valproate. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA SUSTENNA…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal side effect referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their healthcare provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia.

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur.

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness), and the need for specific monitoring, including blood glucose, lipids, and weight.

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking INVEGA SUSTENNA.

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA SUSTENNA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males.

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism.

Heat Exposure and Dehydration

Counsel patients on the importance of avoiding overheating and dehydration.

Pregnancy

Advise patients that INVEGA SUSTENNA may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA.

PATIENT INFORMATION

(Additions and/or revisions are underlined)

Who should not receive INVEGA SUSTENNA?

Do not receive INVEGA SUSTENNA if you:

• are allergic to paliperidone, paliperidone palmitate, risperidone, or any of the ingredients in INVEGA SUSTENNA…

What should I tell my healthcare provider before receiving INVEGA SUSTENNA?

Before you receive INVEGA SUSTENNA, tell your healthcare provider about all your medical conditions, including if you:

• are pregnant or plan to become pregnant. It is not known if INVEGA SUSTENNA will harm your unborn baby.
• Infants born to women who are treated with INVEGA SUSTENNA may have withdrawal symptoms or other symptoms such as tremors, muscle spasms, abnormal movement of arms and legs, and twitching of eyes.

How will I receive INVEGA SUSTENNA?

• Follow your INVEGA SUSTENNA treatment schedule exactly as your healthcare provider tells you to.

General information about the safe and effective use of INVEGA SUSTENNA

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use INVEGA SUSTENNA for a condition for which it was not prescribed. Do not give INVEGA SUSTENNA to other people, even if they have the same symptoms that you have. It may harm them.

02/23/2017 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Falls

(Newly added subsection)

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA, 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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

• Falls

03/01/2016 (SUPPL-19)

Approved Drug Label (PDF)

4 Contraindications

RISPERDAL/RISPERDAL CONSTA/INVEGA(s) is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the RISPERDAL/RISPERDAL CONSTA/ INVEGA(s) formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.