INVEGA TRINZA

Dosage Forms And Strengths

INVEGA TRINZA^® is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 273 mg, 410 mg, 546 mg, and 819 mg paliperidone palmitate.

Storage And Handling

INVEGA TRINZA^® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 273 mg, 410 mg, 546 mg, and 819 mg paliperidone palmitate. The kit contains a prefilled syringe and 2 safety needles (a thin walled 22G, 1-inch safety needle and a thin walled 22G, 1½-inch safety needle).

273 mg paliperidone palmitate kit (NDC 50458-606-01)
410 mg paliperidone palmitate kit (NDC 50458-607-01)
546 mg paliperidone palmitate kit (NDC 50458-608-01)
819 mg paliperidone palmitate kit (NDC 50458-609-01)

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted.

Manufactured by: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 © Janssen Pharmaceuticals. Revised: Feb 2017

INVEGA TRINZA^® (paliperidone palmitate), a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA^® (1-month paliperidone palmitate extended-release injectable suspension) for at least four months.

Administration Instructions

INVEGA TRINZA^® should be administered once every 3 months.

Each injection must be administered only by a health care professional.

Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration. It is important to shake the syringe vigorously for at least 15 seconds to ensure a homogeneous suspension. Inject INVEGA TRINZA^® within 5 minutes of shaking vigorously.

INVEGA TRINZA^® is intended for intramuscular use only. Do not administer by any other route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal muscle.

INVEGA TRINZA^® must be administered using only the thin wall needles that are provided in the INVEGA TRINZA^® pack. Do not use needles from the 1-month paliperidone palmitate extended-release injectable suspension pack or other commercially-available needles to reduce the risk of blockage.

Deltoid Injection

The recommended needle size for administration of INVEGA TRINZA^® into the deltoid muscle is determined by the patient’s weight:

• For patients weighing less than 90 kg, the 1-inch, 22 gauge thin wall needle is recommended.
• For patients weighing 90 kg or more, the 1½-inch, 22 gauge thin wall needle is recommended.

Administer into the center of the deltoid muscle. Deltoid injections should be alternated between the two deltoid muscles.

Gluteal Injection

Regardless of patient weight, the recommended needle size for administration of INVEGA TRINZA^® into the gluteal muscle is the 1½-inch, 22 gauge thin wall needle. Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.

Incomplete Administration

To avoid an incomplete administration of INVEGA TRINZA^®, ensure that the prefilled syringe is shaken vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension and ensure the needle does not get clogged during injection.

However, in the event of an incompletely administered dose, do not re-inject the dose remaining in the syringe and do not administer another dose of INVEGA TRINZA^®. Closely monitor and treat the patient with oral supplementation as clinically appropriate until the next scheduled 3month injection of INVEGA TRINZA^®.

Schizophrenia

Adults

INVEGA TRINZA^® is to be used only after INVEGA SUSTENNA^® (1-month paliperidone palmitate extended-release injectable suspension) has been established as adequate treatment for at least four months. In order to establish a consistent maintenance dose, it is recommended that the last two doses of INVEGA SUSTENNA^® be the same dosage strength before starting INVEGA TRINZA^®.

Initiate INVEGA TRINZA^® when the next 1-month paliperidone palmitate dose is scheduled with an INVEGA TRINZA^® dose based on the previous 1-month injection dose, using the equivalent 3.5-fold higher dose as shown in Table 1. INVEGA TRINZA^® may be administered up to 7 days before or after the monthly time point of the next scheduled paliperidone palmitate 1-month dose.

Table 1. INVEGA TRINZA^® may be administered up to 7 days before or after the monthly time point of the next scheduled paliperidone palmitate 1-month dose.

Following the initial INVEGA TRINZA^® dose, INVEGA TRINZA^® should be administered every 3 months. If needed, dose adjustment can be made every 3 months in increments within the range of 273 mg to 819 mg based on individual patient tolerability and/or efficacy. Due to the long-acting nature of INVEGA TRINZA^®, the patient’s response to an adjusted dose may not be apparent for several months.

Missed Doses

Dosing Window

Missing doses of INVEGA TRINZA^® should be avoided. If necessary, patients may be given the injection up to 2 weeks before or after the 3-month time point.

Missed Dose 3½ Months To 4 Months Since Last Injection

If more than 3½ months (up to but less than 4 months) have elapsed since the last injection of INVEGA TRINZA^®, the previously administered INVEGA TRINZA^® dose should be administered as soon as possible, then continue with the 3-month injections following this dose.

Missed Dose 4 Months To 9 Months Since Last Injection

If 4 months up to and including 9 months have elapsed since the last injection of INVEGA TRINZA^®, do NOT administer the next dose of INVEGA TRINZA^®. Instead, use the reinitiation regimen shown in Table 2.

Table 2. Re-initiation Regimen After Missing 4 Months to 9 Months of INVEGA TRINZA^®

Missed Dose Longer Than 9 Months Since Last Injection

If more than 9 months have elapsed since the last injection of INVEGA TRINZA^®, re-initiate treatment with the 1-month paliperidone palmitate extended-release injectable suspension as described in the prescribing information for that product. INVEGA TRINZA^® can then be resumed after the patient has been adequately treated with the 1-month paliperidone palmitate extended-release injectable suspension for at least 4 months.

Use With Risperidone Or With Oral Paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA TRINZA^® is coadministered with risperidone or oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA TRINZA^® with other antipsychotics is limited.

Dosage Adjustment In Renal Impairment

INVEGA TRINZA^® has not been systematically studied in patients with renal impairment. For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula], adjust dosage and stabilize the patient using the 1-month paliperidone palmitate extended-release injectable suspension, then transition to INVEGA TRINZA^®.

INVEGA TRINZA^® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).

Switching From INVEGA TRINZA^® To The 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension

For switching from INVEGA TRINZA^® to INVEGA SUSTENNA^® (1-month paliperidone palmitate extended-release injectable suspension), the 1-month paliperidone palmitate extended-release injectable suspension should be started 3 months after the last INVEGA TRINZA^® dose, using the equivalent 3.5-fold lower dose as shown in Table 3. The 1-month paliperidone palmitate extended-release injectable suspension should then continue, dosed at monthly intervals.

Table 3. Conversion From INVEGA TRINZA^® to INVEGA SUSTENNA^®

Switching From INVEGA TRINZA^® To Oral Paliperidone Extended-Release Tablets

For switching from INVEGA TRINZA^® to oral paliperidone extended-release tablets, the daily dosing of the paliperidone extended-release tablets should be started 3 months after the last INVEGA TRINZA^® dose and transitioned over the next several months following the last INVEGA TRINZA^® dose as described in Table 4. Table 4 provides dose conversion regimens to allow patients previously stabilized on different doses of INVEGA TRINZA^® to attain similar paliperidone exposure with once daily paliperidone extended-release tablets.

Table 4. INVEGA TRINZA^® Doses and Once-Daily Paliperidone Extended-Release Conversion Regimens Needed to Attain Similar Paliperidone Exposures

Instructions For Use

For intramuscular injection only. Do not administer by any other route.

Important

INVEGA TRINZA^® should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.

INVEGA TRINZA^® is intended for intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGA TRINZA^® requires longer and more vigorous shaking than INVEGA SUSTENNA^® (1-month paliperidone palmitate extended-release injectable suspension). Shake the syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within 5 minutes prior to administration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGA TRINZA^®. Therefore, it is important to only use the needles provided in the INVEGA TRINZA^® kit.

Dose pack contents

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown.

Attach needle

With your other hand, hold the syringe by the luer connection and attach it to the safety needle with a gentle clockwise twisting motion.

Do not remove the pouch until the syringe and needle are securely attached.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.

Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.

Do not administer by any other route.

After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device. The needle is secure when a “click” sound is heard.

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Thin wall safety needles are designed specifically for use with INVEGA TRINZA^®. Unused needle should be discarded and not saved for future use.

INVEGA TRINZA^® is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA^® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

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 TRINZA^® is not approved for the treatment of patients with dementia-related psychosis.

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. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, or INVEGA TRINZA^® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

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. Consideration should be given to the long-acting nature of INVEGA TRINZA^®. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

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

QT Prolongation

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

Certain circumstances may increase the risk of the occurrence of 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 paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixed-dose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product.

In the Thorough 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 (QT interval corrected for heart rate using the population specified linear derived method) 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 approximately 2-fold the exposure with the maximum recommended 819 mg dose of INVEGA TRINZA^® administered in the deltoid muscle (predicted median Cmax ss=56 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 four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had 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.

In the long-term maintenance trial of INVEGA TRINZA^® in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA^® in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.

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 TRINZA^® 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 TRINZA^® , drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA^®. However, some patients may require treatment with INVEGA TRINZA^® 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. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA TRINZA^®. 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 hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

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.

Data from the long-term maintenance trial with INVEGA TRINZA^® in subjects with schizophrenia are presented in Table 5.

Table 5. Change in Fasting Glucose from the Long-Term Maintenance Trial with INVEGA TRINZA^® in Subjects with Schizophrenia

Dyslipidemia

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

Data from the long-term maintenance trial with INVEGA TRINZA^® in subjects with schizophrenia are presented in Table 6.

Table 6. Change in Fasting Lipids from the Long-Term Maintenance Trial with INVEGA TRINZA^® in Subjects with Schizophrenia

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 long-term maintenance trial with INVEGA TRINZA^® in subjects with schizophrenia are presented in Table 7.

Table 7. Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from the Long-Term Maintenance Trial with INVEGA TRINZA^® in Subjects with Schizophrenia

Orthostatic Hypotension And Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope was reported in < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. In the long-term maintenance trial, orthostatic hypotension was reported as an adverse event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of INVEGA TRINZA^® during the open-label phase; there were no cases reported during the double-blind phase in either treatment group.

INVEGA TRINZA^® 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.

Falls

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

Leukopenia, Neutropenia, And Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA TRINZA^®. Agranulocytosis has also been reported.

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. In such patients, consider discontinuation of INVEGA TRINZA^® at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

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

In a long-term maintenance trial of INVEGA TRINZA^®, 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 double-blind phase were noted in a higher percentage of males in the INVEGA TRINZA^® group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the INVEGA TRINZA^® group than in the placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the INVEGA TRINZA^® group experienced an adverse reaction of amenorrhea, while no potentially prolactin-related adverse reactions were noted among females in the placebo group. There were no potentially prolactin-related adverse reactions among males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368) were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks after a single injection of INVEGA TRINZA^® at the end of the open-label phase, mean (SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL in females (N=107). During the open-label phases 27% of females and 42% 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 (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse reactions in females. Among males in the open-label phase, no potentially prolactin-related adverse reaction was observed with a rate greater than 3%.

Potential For Cognitive And Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA^®. Antipsychotics, including INVEGA TRINZA^®, 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 long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month paliperidone palmitate extended-release injectable suspension which included four fixed-dose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the 1-month injection 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 TRINZA^® 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. INVEGA TRINZA^® 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 TRINZA^®, 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 TRINZA^® 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

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

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 health care 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 health care 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 .

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose.

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 TRINZA^®.

Hyperprolactinemia

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

Interference With Cognitive And Motor Performance

As INVEGA TRINZA^® has the potential to impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA TRINZA^® therapy does not affect them adversely.

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 [WARNINGS AND PRECAUTIONS].

Heat Exposure And Dehydration

Counsel patients on the importance of avoiding overheating and dehydration.

Concomitant Medication

Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions.

Pregnancy

Advise patients that INVEGA TRINZA^® 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 TRINZA^®. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA TRINZA^® during pregnancy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No carcinogenicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension.

The carcinogenic potential of intramuscular injection of 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which are 0.2, 0.6 and 1 times the maximum recommended human dose (MRHD) of 819 mg of 3-month paliperidone palmitate extended-release injectable suspension on mg/m² basis. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at doses, which are 0.6 and 1 times the MRHD of 819 mg of 3-month paliperidone palmitate extended-release injectable suspension on mg/m² basis. A carcinogenicity study in mice has not been conducted with the 1-month paliperidone palmitate extended-release injectable suspension.

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 for 18 months to mice and for 25 months to rats at daily doses of 0.63, 2.5, and 10 mg/kg/day, which are 0.2 to 3 times in mice and 0.4 to 6 times in rats the MRHD of 16 mg/day of risperidone on mg/m² basis. 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 MRHD of risperidone on mg/m² 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.

Mutagenesis

No mutagenesis studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension.

Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation te

SIDE EFFECTS

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

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

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.

Patient Exposure

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.

Adverse Reactions In A Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial

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

Demographic Differences

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.

Extrapyramidal Symptoms (EPS)

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^®.

Dystonia

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.

Pain Assessment And Local Injection Site Reactions

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.

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of INVEGA TRINZA^®

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

Additional Adverse Reactions Reported In Clinical Trials With The 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension

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

Additional Adverse Reactions Reported In Clinical Trials With Oral Paliperidone

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.

DRUG INTERACTIONS

Drugs Having Clinically Important Interactions With INVEGA TRINZA^®

Because paliperidone palmitate is hydrolyzed to paliperidone , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 3-month dosing interval and long half-life of INVEGA TRINZA^®.

Table 11. Clinically Important Drug Interactions with INVEGA TRINZA^®

Drugs Having No Clinically Important Interactions With INVEGA TRINZA^®

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA TRINZA^® is required when administered concomitantly with valproate. Additionally, no dosage adjustment is necessary for valproate when coadministered with INVEGA TRINZA^®.

Pharmacokinetic Interaction Between Lithium And INVEGA TRINZA^® Is unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely.

Drug Abuse And Dependence

Controlled Substance

INVEGA TRINZA^® (paliperidone) is not a controlled substance.

Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA TRINZA^®, during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data on INVEGA TRINZA^® use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Paliperidone has been detected in plasma at very low levels up to 18 months after a single-dose administration of INVEGA TRINZA^®, and the clinical significance of INVEGA TRINZA^® administered before pregnancy or anytime during pregnancy is not known. No teratogenicity was observed when pregnant rats were injected intramuscularly with the 1-month paliperidone palmitate extended-release injectable suspension during organogenesis at doses up to 250 mg/kg, which is 3 times the maximum recommended human dose (MRHD) of 819 mg of the 3-month paliperidone palmitate injectable suspension on mg/m² basis.

Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. 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

No developmental toxicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension.

No treatment-related effects on the offspring were observed when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-release injectable suspension on mg/m² basis.

No increases in fetal abnormalities were observed when paliperidone was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 8 times the MRHD of 12 mg/day of oral paliperidone on mg/m² basis.

In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, pup deaths increased at oral doses, which are less than the MRHD of risperidone on mg/m² basis (see RISPERDAL^® package insert).

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

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

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.

Patient Exposure

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.

Adverse Reactions In A Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial

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

Demographic Differences

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.

Extrapyramidal Symptoms (EPS)

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^®.

Dystonia

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.

Pain Assessment And Local Injection Site Reactions

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.

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of INVEGA TRINZA^®

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

Additional Adverse Reactions Reported In Clinical Trials With The 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension

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

Additional Adverse Reactions Reported In Clinical Trials With Oral Paliperidone

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.

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.

Paliperidone is a centrally active dopamine Type 2 (D₂) receptor antagonist and a serotonin Type 2 (5HT_2A) 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.

Absorption And Distribution

Due to its extremely low water solubility, the 3-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and lasts for as long as 18 months.

Following a single intramuscular dose of INVEGA TRINZA^®, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 30-33 days. Following intramuscular injection of INVEGA TRINZA^® at doses of 273-819 mg in the deltoid muscle, on average, an 11-12% higher Cmax was observed compared with injection in the gluteal muscle. The release profile and dosing regimen of INVEGA TRINZA^® results in sustained therapeutic concentrations over 3 months. The total and peak exposure of paliperidone following INVEGA TRINZA^® administration was dose-proportional over a 273-819 mg dose range. The mean steady-state peak:trough ratio for a INVEGA TRINZA^® dose was 1.6 following gluteal administration and 1.7 following deltoid administration. Following administration of INVEGA TRINZA^®, the apparent volume of distribution of paliperidone is 1960 L.

The plasma protein binding of racemic paliperidone is 74%.

Following administration of INVEGA TRINZA^®, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7-1.8.

Metabolism And Elimination

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 TRINZA^® administration over the dose range of 273-819 mg ranged from 84-95 days following deltoid injections and 118-139 days following gluteal injections. The concentration of paliperidone remaining in the circulation 18 months after dosing of 819 mg INVEGA TRINZA^® is stopped is estimated to be 3% (following deltoid injection) or 7% (following gluteal injection) of the average steady-state levels.

Long-Acting 3-Month Paliperidone Palmitate Injection Versus Other Paliperidone Formulations

INVEGA TRINZA^® is designed to deliver paliperidone over a 3-month period, while 1-month paliperidone palmitate injection is administered on a monthly basis. INVEGA TRINZA^®, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-month paliperidone palmitate injection, results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-month paliperidone palmitate injection and corresponding once daily doses of paliperidone extended-release tablets. The exposure range for INVEGA TRINZA^® is encompassed within the exposure range for the approved dose strengths of paliperidone extended-release tablets.

The between-subject variability for paliperidone pharmacokinetics following delivery from INVEGA TRINZA^® was similar to the variability for paliperidone extended-release tablets. Because of the difference in median pharmacokinetic profiles among the three formulations, caution should be exercised when making a direct comparison of their pharmacokinetic properties.