Paliperidone Palmitate Extended-Release Injectable Suspension

Dosage Forms And Strengths

INVEGA SUSTENNA® is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.

INVEGA SUSTENNA® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate. The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).

39 mg paliperidone palmitate kit (NDC 50458-560-01)
78 mg paliperidone palmitate kit (NDC 50458-561-01)
117 mg paliperidone palmitate kit (NDC 50458-562-01)
156 mg paliperidone palmitate kit (NDC 50458-563-01)
234 mg paliperidone palmitate kit (NDC 50458-564-01)

Storage And Handling

Store at room temperature (25°C, 77°F); excursions between 15°C and 30°C (between 59°F and 86°F) are permitted.

Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. Revised: Feb 2017

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Paliperidone palmitate is hydrolyzed to paliperidone [see Pharmacokinetics]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2 (5HT2A) receptor antagonist. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β1-and β2-adrenergic receptors. The pharmacological activity of the (+)-and (-)-paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

Pharmacokinetics

Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.

Following intramuscular injection of single doses (39 mg -234 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA SUSTENNA® results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA SUSTENNA® administration was dose-proportional over a 39 mg-234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an INVEGA SUSTENNA® dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.

Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6-1.8.

Based on a population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.

In a study with oral immediate-release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

The median apparent half-life of paliperidone following INVEGA SUSTENNA® single-dose administration over the dose range of 39 mg -234 mg ranged from 25 days -49 days.

INVEGA SUSTENNA® is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. The initiation regimen for INVEGA SUSTENNA® (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.

In general, overall initiation plasma levels with INVEGA SUSTENNA® were within the exposure range observed with 6-12 mg extended-release oral paliperidone. The use of the INVEGA SUSTENNA® initiation regimen allowed patients to stay in this exposure window of 6-12 mg extended-release oral paliperidone even on trough pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from INVEGA SUSTENNA® was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.

Drug Interaction Studies

In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available, and the clinical relevance is unknown.

In a drug interaction study, co-administration of oral paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing valproate treatment [see DRUG INTERACTIONS].

While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies did not demonstrate decreased elimination by these isozymes; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a P-gp substrate [see DRUG INTERACTIONS].

Co-administration of oral paliperidone extended-release 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-gp, at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration [see DRUG INTERACTIONS].

Co-administration of a single dose of oral paliperidone extended-release 12 mg tablet with divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with INVEGA SUSTENNA® , a clinically significant interaction would not be expected between divalproex sodium and INVEGA SUSTENNA® intramuscular injection [see DRUG INTERACTIONS].

Paliperidone is metabolized to a limited extent by CYP2D6. In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone extended-release was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Specific Populations

INVEGA SUSTENNA® has not been systematically studied in patients with renal impairment. Based on a limited number of observations with INVEGA SUSTENNA® in subjects with mild renal impairment and pharmacokinetic simulations, the dose of INVEGA SUSTENNA® should be reduced in patients with mild renal impairment; INVEGA SUSTENNA® is not recommended in patients with moderate or severe renal impairment. Although INVEGA SUSTENNA® was not studied in patients with moderate or severe renal impairment, the disposition of a single oral dose paliperidone 3 mg extended-release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

INVEGA SUSTENNA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), no dose adjustment is required in patients with mild or moderate hepatic impairment. In the study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations].

No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and DOSAGE AND ADMINISTRATION].

No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed between Japanese and Caucasians.

No dosage adjustment is recommended based on gender, although slower absorption was observed in females in a population pharmacokinetic analysis.

No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Clinical Studies

The efficacy of INVEGA SUSTENNA® was established in the following adequate and well-controlled trials:

• Four short-term, fixed-dose trials and one maintenance trial in adults with schizophrenia as monotherapy [see Schizophrenia]
• One long-term, flexible-dose maintenance trial in adults with schizoaffective disorder as monotherapy or as adjunctive therapy to a mood stabilizer or antidepressant [see Schizoaffective Disorder]

Schizophrenia

The efficacy of INVEGA SUSTENNA® in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of INVEGA SUSTENNA® in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies, i.e., at a weekly interval for the initial two doses and then every 4 weeks for maintenance.

Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.

In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of INVEGA SUSTENNA® (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA® were superior to placebo in improving the PANSS total score.

In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of INVEGA SUSTENNA® (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of INVEGA SUSTENNA® was superior to placebo in improving the PANSS total score.

In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of INVEGA SUSTENNA® (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA® were superior to placebo in improving the PANSS total score.

In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of INVEGA SUSTENNA® (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of INVEGA SUSTENNA® were superior to placebo in improving PANSS total score.

A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 13.

Table 13: Schizophrenia Short-term Studies

The efficacy of INVEGA SUSTENNA® in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed-dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of INVEGA SUSTENNA® they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized patients were randomized to either INVEGA SUSTENNA® or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was ≤ 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with INVEGA SUSTENNA® compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the INVEGA SUSTENNA® group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of INVEGA SUSTENNA®. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the INVEGA SUSTENNA® group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

Figure 1: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5)

Schizoaffective Disorder

The efficacy of INVEGA SUSTENNA® in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSMIV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received INVEGA SUSTENNA® either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers.

This study included a 13-week, open-label, flexible-dose (INVEGA SUSTENNA® 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score ≥ 4 on ≥ 3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms ≥ 16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years) and 53.5% were male. The mean scores at open-label enrollment of PANSS total was 85.8 (range 42 to 128), HAM-D-21 was 20.4 (range 3 to 43), YMRS was 18.6 (range 0 to 50), and CGI-SSCA was 4.4 (range 2 to 6).

After the 13-week open-label flexible-dose INVEGA SUSTENNA® treatment, 432 subjects met stabilization criteria (PANSS total score ≤ 70, YMRS ≤ 12, and HAM-D-21 ≤ 12) and continued into the 12-week open-label fixed-dose stabilization period.

A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of INVEGA SUSTENNA® or to placebo in the 15-month, double-blind, maintenance period. For the 164 subjects who were randomized to INVEGA SUSTENNA®, dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to relapse. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of ≥ 6 (if the score was ≤ 4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: ≥ 25% increase (if the score at randomization was > 45) or ≥ 10-point increase (if the score at randomization was ≤ 45) in total PANSS score; a score of ≥ 5 (if the score was ≤ 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of ≥ 2 points (if the score was 1 [not ill] to 3 [mildly ill] at randomization) or increase of ≥ 1 point (if the score was ≥ 4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score.

There was a statistically significant difference in time to relapse between the treatment groups in favor of INVEGA SUSTENNA®. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 2.

Figure 2: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1)

Table 14 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy vs. adjunctive therapy), and by symptom type at the first occurrence of relapse.

Table 14: Summary of Relapse Rates (SAff Study 1).

INVEGA SUSTENNA®
(In-VEY-guh Suss-TEN-uh)
(paliperidone palmitate) Extended-Release Injectable Suspension

Read this Patient Information carefully before you receive INVEGA SUSTENNA and each time you receive it. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about INVEGA SUSTENNA?

INVEGA SUSTENNA can cause serious side effects, including:

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). INVEGA SUSTENNA is not for treating dementia-related psychosis.

What is INVEGA SUSTENNA?

INVEGA SUSTENNA is a prescription medicine given by injection by a health care professional and used to treat:

• schizophrenia
• schizoaffective disorder either alone or with other medicines such as mood stabilizers or antidepressants

It is not known if INVEGA SUSTENNA is safe and effective in children under 18 years of age.

Who should not receive INVEGA SUSTENNA?

Do not receive INVEGA SUSTENNA if you:

• are allergic to paliperidone, risperidone, or any of the ingredients in INVEGA SUSTENNA. See the end of this Patient Information leaflet for a complete list of 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:

• have had Neuroleptic Malignant Syndrome (NMS)
• have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome
• have or have had low levels of potassium or magnesium in your blood
• have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)
• have or have had kidney or liver problems
• have diabetes or have a family history of diabetes
• have had a low white blood cell count
• have had problems with dizziness or fainting or are being treated for high blood pressure
• have or have had seizures or epilepsy
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if INVEGA SUSTENNA will harm your unborn baby.
• are breastfeeding or plan to breastfeed. INVEGA SUSTENNA can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will receive INVEGA SUSTENNA or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine.

How will I receive INVEGA SUSTENNA?

• Take INVEGA SUSTENNA exactly as your healthcare provider tells you to.
• Your healthcare provider will tell you how much INVEGA SUSTENNA you will receive and when you will receive it.
• INVEGA SUSTENNA is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks.
• When you receive your first dose of INVEGA SUSTENNA you will need to get a second dose 1 week later. After that you will only need to get a dose 1 time a month.

What should I avoid while receiving INVEGA SUSTENNA?

• INVEGA SUSTENNA may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA SUSTENNA affects you.
• Avoid getting overheated or dehydrated.

What are the possible side effects of INVEGA SUSTENNA?

INVEGA SUSTENNA may cause serious side effects, including:

• See “What is the most important information I should know about INVEGA SUSTENNA?”
• stroke in elderly people (cerebrovascular problems) that can lead to death
• Neuroleptic Malignant Syndrome (NMS). NMS is a rare but very serious problem that can happen in people who receive INVEGA SUSTENNA. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have any of these symptoms:
  • high fever
  • severe muscle stiffness
  • confusion
  • loss of consciousness
  • changes in your breathing, heartbeat and blood pressure
• problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms:
  • passing out or feeling like you will pass out
  • dizziness
  • feeling as if your heart is pounding or missing beats
• uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)
• metabolic changes. Metabolic changes may include high blood sugar (hyperglycemia), diabetes mellitus and changes in the fat levels in your blood (dyslipidemia), and weight gain.
• low blood pressure and fainting
• changes in your blood cell counts
• high level of prolactin in your blood (hyperprolactinemia). INVEGA SUSTENNA may cause a rise in the blood levels of a hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, leakage of milk from the breasts, development of breasts in men, or problems with erection
• problems thinking clearly and moving your body
• seizures
• difficulty swallowing that can cause food or liquid to get into your lungs
• prolonged or painful erection lasting more than 4 hours. Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours.
• problems with control of your body temperature especially when you exercise a lot or spend time doing things that make you warm. It is important for you to drink water to avoid dehydration.

The most common side effects of INVEGA SUSTENNA include:

• injection site reactions
• sleepiness or drowsiness
• dizziness
• feeling of inner restlessness or needing to be constantly moving
• abnormal muscle movements, including tremor (shaking), shuffling, uncontrolled involuntary movements, and abnormal movements of your eyes

Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of INVEGA SUSTENNA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

General information about the safe and effective use of INVEGA SUSTENNA.

This Patient Information leaflet summarizes the most important information about INVEGA SUSTENNA. If you would like more information, talk with your healthcare provider.

You can ask your healthcare provider or pharmacist for more information that is written for healthcare professionals. For more information, go to www.invegasustenna.com or call 1-800-526-7736.

What are the ingredients in INVEGA SUSTENNA?

Active ingredient: paliperidone palmitate

Inactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection

Human Experience

No cases of overdose were reported in premarketing studies with paliperidone palmitate injection. Because INVEGA TRINZA® is to be administered by health care professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

Management Of Overdosage

Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA TRINZA® overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.

Consider the prolonged-release characteristics of INVEGA TRINZA® and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

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

• Increased mortality in elderly patients with dementia-related psychosis [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• QT prolongation [see WARNINGS AND PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic changes [see WARNINGS AND PRECAUTIONS]
• Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA® during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA® and 145 subjects received placebo during the double-blind placebo-controlled phase. The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA® group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA® concomitantly with other oral antipsychotics.

Commonly Observed Adverse Reactions:

The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA® group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.

Discontinuation of Treatment Due to Adverse Events:

The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the double-blind phase, no INVEGA TRINZA®-treated subject and one placebo-treated subject discontinued due to adverse events.

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA®-Treated Patients:

The safety profile of INVEGA TRINZA® was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia.

Table 8. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA®-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia

An examination of population subgroups in the long-term maintenance trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.

Data from the long-term maintenance trial provided information regarding 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 9), and (5) incidence of spontaneous reports of EPS (Table 10).

Table 9. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication

Table 10. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term

After injection of INVEGA TRINZA® in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common. After injection of INVEGA TRINZA® in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness.

An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to INVEGA TRINZA®.

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Investigator ratings of injection site. Redness and swelling were observed in 2% or less of subjects in the INVEGA TRINZA® and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe). There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to INVEGA TRINZA® injection.

Subject ratings of injection site pain

Subject evaluations of injection pain during the double-blind phase also were similar for placebo and INVEGA TRINZA®.

Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain. Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.

The following additional adverse reactions were identified in the long-term maintenance trial. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) occurred at an incidence lower than that of placebo-treated patients.

Cardiac disorders: tachycardia

Gastrointestinal disorders: nausea, vomiting

Metabolism and nutrition disorders: hyperinsulinemia

Psychiatric disorders: anxiety

The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month paliperidone palmitate extended-release injectable suspension:

Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome

Ear and labyrinth disorders: vertigo

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache

General disorders and administration site conditions: asthenia, fatigue

Immune system disorders: hypersensitivity

Investigations: electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, increased appetite

Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope

Psychiatric disorders: agitation, nightmare

Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria

Vascular disorders: hypertension

The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction

General disorders and administration site conditions: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, torticollis, trismus

Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: hypotension, ischemia

Postmarketing Experience

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, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) sections of the package inserts for those products.

Read the entire FDA prescribing information for Invega Trinza (Paliperidone Palmitate Extended-release Injectable Suspension)