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DRUGS & SUPPLEMENTS
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Invega Sustenna
How often in a day do you take medicine? How many times? |
Invega Sustenna uses
- Warning: increased mortality in elderly patients with dementia-related psychosis
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Drug abuse and dependence
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death .
- Invega Sustenna® is not approved for use in patients with dementia-related psychosis .
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. (5.1)
- Invega Sustenna® is not approved for use in patients with dementia-related psychosis. (5.1)
| Warnings and Precautions (5.8) | 02/2017 |
1 INDICATIONS AND USAGE
Invega Sustenna® (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 Invega Sustenna palmitate extended-release injectable suspension) for at least four months .
Invega Sustenna®, a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month Invega Sustenna palmitate extended-release injectable suspension) for at least four months. (1)
2 DOSAGE AND ADMINISTRATION
- Use Invega Sustenna® only after the patient has been adequately treated with the 1-month Invega Sustenna palmitate extended-release injectable suspension for at least four months.
- Invega Sustenna® should be administered once every 3 months. (2.1)
- For intramuscular injection only. (2.1)
- Each injection must be administered only by a health care professional. (2.1)
- For deltoid injection: For patients weighing less than 90 kg, use the 1-inch 22 gauge thin wall needle. For patients weighing 90 kg or more, use the 1½-inch 22 gauge thin wall needle.
- For gluteal injection: Regardless of patient weight, use the1½-inch 22 gauge thin wall needle.
- Prior to administration, shake the prefilled syringe vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension. (2.1)
- Initiate Invega Sustenna® when the next 1-month Invega Sustenna palmitate dose is scheduled with an Invega Sustenna® dose based on the previous 1-month injection dose as shown below. (2.2)
| If the Last Dose of INVEGA SUSTENNA® is: | Initiate Invega Sustenna® at the Following Dose: |
|---|---|
| Conversion from the INVEGA SUSTENNA® 39 mg dose was not studied. | |
| 78 mg | 273 mg |
| 117 mg | 410 mg |
| 156 mg | 546 mg |
| 234 mg | 819 mg |
- Missed Doses: Missing doses of Invega Sustenna® should be avoided. To manage missed doses on exceptional occasions, refer to the Full Prescribing Information. (2.3)
- Moderate to severe renal impairment (creatinine clearance < 50 mL/min): Invega Sustenna® is not recommended. (2.5)
- Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust dosage and stabilize the patient using INVEGA SUSTENNA®, then transition to Invega Sustenna®. See above table. (2.5)
2.1 Administration Instructions
Invega Sustenna® 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 Sustenna® within 5 minutes of shaking vigorously .
Invega Sustenna® 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 Sustenna® must be administered using only the thin wall needles that are provided in the Invega Sustenna® pack. Do not use needles from the 1-month Invega Sustenna 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 Sustenna® 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 Sustenna® 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 Sustenna®, 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 Sustenna®. Closely monitor and treat the patient with oral supplementation as clinically appropriate until the next scheduled 3-month injection of Invega Sustenna®.
2.2 Schizophrenia
Adults
Invega Sustenna® is to be used only after INVEGA SUSTENNA® 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 Sustenna®.
Initiate Invega Sustenna® when the next 1-month Invega Sustenna palmitate dose is scheduled with an Invega Sustenna® dose based on the previous 1-month injection dose, using the equivalent 3.5-fold higher dose as shown in Table 1. Invega Sustenna® may be administered up to 7 days before or after the monthly time point of the next scheduled Invega Sustenna palmitate 1-month dose.
| If the Last Dose of INVEGA SUSTENNA® is: | Initiate Invega Sustenna® at the Following Dose: |
|---|---|
| Conversion from the INVEGA SUSTENNA® 39 mg dose was not studied. | |
| 78 mg | 273 mg |
| 117 mg | 410 mg |
| 156 mg | 546 mg |
| 234 mg | 819 mg |
Following the initial Invega Sustenna® dose, Invega Sustenna® 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 Sustenna®, the patient's response to an adjusted dose may not be apparent for several months .
2.3 Missed Doses
Dosing Window
Missing doses of Invega Sustenna® 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 Sustenna®, the previously administered Invega Sustenna® 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 Sustenna®, do NOT administer the next dose of Invega Sustenna®. Instead, use the re-initiation regimen shown in Table 2.
| If the Last Dose of Invega Sustenna® was: | Administer INVEGA SUSTENNA®, two doses one week apart (into deltoid muscle) | Then administer Invega Sustenna® (into deltoid | |
|---|---|---|---|
| Day 1 | Day 8 | 1 month after Day 8 | |
| 273 mg | 78 mg | 78 mg | 273 mg |
| 410 mg | 117 mg | 117 mg | 410 mg |
| 546 mg | 156 mg | 156 mg | 546 mg |
| 819 mg | 156 mg | 156 mg | 819 mg |
Missed Dose Longer than 9 Months Since Last Injection
If more than 9 months have elapsed since the last injection of Invega Sustenna®, re-initiate treatment with the 1-month Invega Sustenna palmitate extended-release injectable suspension as described in the prescribing information for that product. Invega Sustenna® can then be resumed after the patient has been adequately treated with the 1-month Invega Sustenna palmitate extended-release injectable suspension for at least 4 months.
2.4 Use with Risperidone or with Oral Invega Sustenna
Since Invega Sustenna is the major active metabolite of risperidone, caution should be exercised when Invega Sustenna® is coadministered with risperidone or oral Invega Sustenna for extended periods of time. Safety data involving concomitant use of Invega Sustenna® with other antipsychotics is limited.
2.5 Dosage Adjustment in Renal Impairment
Invega Sustenna® 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 Invega Sustenna palmitate extended-release injectable suspension, then transition to Invega Sustenna® .
Invega Sustenna® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) .
2.6 Switching from Invega Sustenna® to the 1-Month Invega Sustenna Palmitate Extended-Release Injectable Suspension
For switching from Invega Sustenna® to INVEGA SUSTENNA® (1-month Invega Sustenna palmitate extended-release injectable suspension), the 1-month Invega Sustenna palmitate extended-release injectable suspension should be started 3 months after the last Invega Sustenna® dose, using the equivalent 3.5-fold lower dose as shown in Table 3. The 1-month Invega Sustenna palmitate extended-release injectable suspension should then continue, dosed at monthly intervals.
| If the Last Dose of Invega Sustenna® is: | Initiate |
|---|---|
| 273 mg | 78 mg |
| 410 mg | 117 mg |
| 546 mg | 156 mg |
| 819 mg | 234 mg |
2.7 Switching from Invega Sustenna® to Oral Invega Sustenna Extended-Release Tablets
For switching from Invega Sustenna® to oral Invega Sustenna extended-release tablets, the daily dosing of the Invega Sustenna extended-release tablets should be started 3 months after the last Invega Sustenna® dose and transitioned over the next several months following the last Invega Sustenna® dose as described in Table 4. Table 4 provides dose conversion regimens to allow patients previously stabilized on different doses of Invega Sustenna® to attain similar Invega Sustenna exposure with once daily Invega Sustenna extended-release tablets.
| Weeks Since Last Invega Sustenna® Dose | |||
|---|---|---|---|
| 3 months to 18 weeks | Longer than 18 weeks to 24 weeks | Longer than 24 weeks | |
| Last Invega Sustenna® Dose | Doses of oral Invega Sustenna extended-release tablets | ||
| 273 mg | 3 mg | 3 mg | 3 mg |
| 410 mg | 3 mg | 3 mg | 6 mg |
| 546 mg | 3 mg | 6 mg | 9 mg |
| 819 mg | 6 mg | 9 mg | 12 mg |
2.8 Instructions for Use
| Administer every 3 months | |
| Shake syringe vigorously for at least 15 seconds |
For intramuscular injection only. Do not administer by any other route.
Important
Invega Sustenna® should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.
Invega Sustenna® 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 Sustenna® requires longer and more vigorous shaking than INVEGA SUSTENNA® (1-month Invega Sustenna 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.
Thin Wall Safety Needle Selection
Thin wall safety needles are designed to be used with Invega Sustenna®. Therefore, it is important to only use the needles provided in the Invega Sustenna® kit.
Dose pack contents
| Prefilled Syringe | Thin Wall Safety Needles | ||||
|---|---|---|---|---|---|
1 Select needle
Needle selection is determined by injection area and patient weight.
| If administering a Deltoid injection If patient weighs: Less than 90 kg pink hub | If administering a Gluteal injection If patient weighs: Less than 90 kg yellow hub |
| 90 kg or more yellow hub | 90 kg or more yellow hub |
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.
3 Inject
Inject dose
Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.
Do not administer by any other route.
4 After injection
Secure needle
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.
Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure
3 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 273 mg, 410 mg, 546 mg, and 819 mg Invega Sustenna palmitate.
Extended-release injectable suspension: 273 mg, 410 mg, 546 mg, or 819 mg (3)
4 CONTRAINDICATIONS
Invega Sustenna® is contraindicated in patients with a known hypersensitivity to either Invega Sustenna or risperidone, or to any of the excipients in the Invega Sustenna® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with Invega Sustenna. Invega Sustenna palmitate is converted to Invega Sustenna, which is a metabolite of risperidone.
Known hypersensitivity to Invega Sustenna, risperidone, or to any excipients in Invega Sustenna®. (4)
5 WARNINGS AND PRECAUTIONS
- Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions. Invega Sustenna® is not approved for use in patients with dementia-related psychosis (5.2)
- Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring (5.3)
- QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval (5.4)
- Tardive Dyskinesia: Discontinue drug if clinically appropriate (5.5)
- Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include:
- Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.6)
- Dyslipidemia: Undesirable alterations have been observed. (5.6)
- Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6)
- Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension (5.7)
- Leukopenia, Neutropenia, and Agranulocytosis: Monitor complete blood count in patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors (5.9)
- Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration (5.10)
- Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.11)
- Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.12)
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Invega Sustenna® is not approved for the treatment of patients with dementia-related psychosis .
5.2 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 including fatalities compared to placebo-treated subjects. No studies have been conducted with oral Invega Sustenna, the 1-month Invega Sustenna palmitate extended-release injectable suspension, or Invega Sustenna® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis .
5.3 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 Invega Sustenna. 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 Sustenna®. 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.
5.4 QT Prolongation
Invega Sustenna causes a modest increase in the corrected QT interval. The use of Invega Sustenna 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. Invega Sustenna 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 Invega Sustenna on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral Invega Sustenna in adult patients, and in four fixed-dose efficacy studies and one maintenance study of the 1-month Invega Sustenna palmitate injectable product.
In the Thorough QT study (n=141), the 8 mg dose of immediate-release oral Invega Sustenna (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 Invega Sustenna immediate release (Cmax ss=113 ng/mL) was approximately 2-fold the exposure with the maximum recommended 819 mg dose of Invega Sustenna® 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 Invega Sustenna, 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 Invega Sustenna 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 Sustenna® 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 Sustenna® in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.
5.5 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, Invega Sustenna® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with Invega Sustenna®, drug discontinuation should be considered. Consideration should be given to the long-acting nature of Invega Sustenna®. However, some patients may require treatment with Invega Sustenna® despite the presence of the syndrome.
5.6 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 Sustenna®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of 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 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 Sustenna® in subjects with schizophrenia are presented in Table 5.
| Open-Label Phase (relative to open-label baseline) | Double-Blind Phase (relative to double-blind baseline) | ||
|---|---|---|---|
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| Mean change from baseline (mg/dL) | |||
| n=397 | n=120 | n=138 | |
| Serum Glucose Change from baseline | 1.2 | -1.6 | -1.2 |
| Proportion of Patients with Shifts | |||
| n=397 | n=128 | n=148 | |
| Serum Glucose Normal to High | 2.3% | 2.3% | 4.1% |
| (<100 mg/dL to ≥126 mg/dL) | (9/397) | (3/128) | (6/148) |
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Data from the long-term maintenance trial with Invega Sustenna® in subjects with schizophrenia are presented in Table 6.
| Open-Label Phase (relative to open-label baseline) | Double-Blind Phase (relative to double-blind baseline) | ||
|---|---|---|---|
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| Mean change from baseline (mg/dL) | |||
| Cholesterol | n=400 | n=120 | n=138 |
| Change from baseline | 0.5 | -0.4 | 0.9 |
| LDL | n=396 | n=119 | n=138 |
| Change from baseline | 1.1 | -0.4 | 1.1 |
| HDL | n=397 | n=119 | n=138 |
| Change from baseline | -0.2 | -0.5 | -1.3 |
| Triglycerides | n=400 | n=120 | n=138 |
| Change from baseline | 0.1 | -2.0 | 5.1 |
| Proportion of Patients with Shifts | |||
| Cholesterol Normal to High | 2.0% | 3.9% | 1.4% |
| (<200 mg/dL to ≥240 mg/dL) | (8/400) | (5/128) | (2/148) |
| LDL Normal to High | 0.3% | 0.8% | 0% |
| (<100 mg/dL to ≥160 mg/dL) | (1/396) | (1/127) | (0/148) |
| HDL Normal to Low | 8.6% | 9.4% | 13.5% |
| (≥40 mg/dL to <40 mg/dL) | (34/397) | (12/127) | (20/148) |
| Triglycerides Normal to High | 4.5% | 1.6% | 8.1% |
| (<150 mg/dL to ≥200 mg/dL) | (18/400) | (2/128) | (12/148) |
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 Sustenna® in subjects with schizophrenia are presented in Table 7.
| Open-Label Phase (relative to open-label baseline) | Double-Blind Phase (relative to double-blind baseline) | ||
|---|---|---|---|
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| n=466 | n=142 | n=157 | |
| Weight (kg) Change from baseline | 1.42 | -1.28 | 0.94 |
| Weight Gain ≥ 7% increase from baseline | 15.2% | 0.7% | 9.6% |
5.7 Orthostatic Hypotension and Syncope
Invega Sustenna 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 Invega Sustenna 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 Invega Sustenna palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of Invega Sustenna® during the open-label phase; there were no cases reported during the double-blind phase in either treatment group.
Invega Sustenna® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
5.8 Falls
Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including Invega Sustenna®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
5.9 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 Sustenna®. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count /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 Sustenna® 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 Sustenna® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.
5.10 Hyperprolactinemia
Like other drugs that antagonize dopamine D2 receptors, Invega Sustenna elevates prolactin levels and the elevation persists during chronic administration. Invega Sustenna 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 Sustenna®, 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 Sustenna® group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the Invega Sustenna® group than in the placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the Invega Sustenna® 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 Sustenna® 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%.
5.11 Potential for Cognitive and Motor Impairment
Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with Invega Sustenna® . Antipsychotics, including Invega Sustenna®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that Invega Sustenna therapy does not adversely affect them.
5.12 Seizures
In the long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month Invega Sustenna 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 Sustenna® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
5.13 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Invega Sustenna® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
5.14 Priapism
Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with Invega Sustenna®, priapism has been reported with oral Invega Sustenna during postmarketing surveillance. Severe priapism may require surgical intervention.
5.15 Disruption of Body Temperature Regulation
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Invega Sustenna® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
6 ADVERSE REACTIONS
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
The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 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 Invega Sustenna palmitate extended-release injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of Invega Sustenna® during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of Invega Sustenna® 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 Sustenna® group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of Invega Sustenna® 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 Sustenna® 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 Sustenna®-treated subject and one placebo-treated subject discontinued due to adverse events.
Adverse Reactions Occurring at an Incidence of 2% or More in Invega Sustenna®Treated Patients: The safety profile of Invega Sustenna® was similar to that seen with the 1-month Invega Sustenna extended-release injectable suspension. Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia.
| --- Open Label----- | ------------ Double Blind ------------- | ||
|---|---|---|---|
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| System Organ Class | (N=506) | (N=145) | (N=160) |
| Adverse Reaction Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling. Weight increased includes Weight increased, Waist circumference increased. Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis. Akathisia includes Akasthisia, Restlessness. Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion. | % | % | % |
| Table includes adverse reactions that were reported in 2% or more of subjects in the Invega Sustenna® group during the double-blind phase and which occurred at greater incidence than in the placebo group. | |||
| General disorders and administration site conditions | |||
| Injection site reaction | 12 | 0 | 3 |
| Infections and infestations | |||
| Upper respiratory tract infection | 5 | 4 | 10 |
| Urinary tract infection | <1 | 1 | 3 |
| Metabolism and nutrition disorders | |||
| Weight increased | 10 | 3 | 9 |
| Nervous system disorders | |||
| Akathisia | 5 | 2 | 5 |
| Headache | 7 | 4 | 9 |
| Parkinsonism | 5 | 0 | 4 |
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).
| Percentage of Subjects | |||
|---|---|---|---|
| Open-label Phase | Double-blind Phase | ||
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| Scale | (N=506) % | (N=145) % | (N=160) % |
| Parkinsonism | 6 | 3 | 6 |
| Akathisia | 3 | 1 | 4 |
| Dyskinesia | 1 | 3 | 3 |
| Use of Anticholinergic Medications | 11 | 9 | 11 |
| Percentage of Subjects | |||
|---|---|---|---|
| Open-label Phase | Double-blind Phase | ||
| Invega Sustenna Palmitate | Placebo | Invega Sustenna® | |
| EPS Group | (N=506) % | (N=145) % | (N=160) % |
| Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism | |||
| Hyperkinesia group includes: Akathisia, restlessness | |||
| Dystonia group includes: Blepharospasm, dystonia, muscle spasms | |||
| Overall percentage of subjects with EPS-related adverse events | 10 | 3 | 8 |
| Parkinsonism | 4 | 0 | 4 |
| Hyperkinesia | 5 | 2 | 5 |
| Tremor | 2 | 0 | 1 |
| Dyskinesia | <1 | 1 | 1 |
| Dystonia | 1 | 0 | 1 |
After injection of Invega Sustenna® 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 Sustenna® 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 Invega Sustenna for subjects randomized to Invega Sustenna®.
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 Sustenna® 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 Sustenna® injection.
Subject ratings of injection site pain. Subject evaluations of injection pain during the double-blind phase also were similar for placebo and Invega Sustenna®.
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 Sustenna®
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 Invega Sustenna 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 Invega Sustenna 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 Invega Sustenna
The following is a list of additional adverse reactions that have been reported in clinical trials with oral Invega Sustenna:
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
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Invega Sustenna; 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 Invega Sustenna palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral Invega Sustenna.
Invega Sustenna 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.
7 DRUG INTERACTIONS
Strong CYP3A4/P-glycoprotein inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John's Wort) during a dosing interval for Invega Sustenna®. If administering a strong inducer is necessary, consider managing the patient using Invega Sustenna extended release tablets. (7.2, 12.3)
7.1 Drugs Having Clinically Important Interactions with Invega Sustenna®
Because Invega Sustenna palmitate is hydrolyzed to Invega Sustenna , results from studies with oral Invega Sustenna 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 Sustenna® .
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Drugs with Potential for Inducing Orthostatic Hypotension | Because Invega Sustenna® has the potential for inducing orthostatic hypotension, an additive effect may occur when Invega Sustenna® is administered with other therapeutic agents that have this potential . | Monitor orthostatic vital signs in patients who are vulnerable to hypotension . |
| Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John's Wort) | The concomitant use of Invega Sustenna and strong inducers of CYP3A4 and P-gp may decrease the exposure of Invega Sustenna . | Avoid using CYP3A4 and/or P-gp inducers with Invega Sustenna® during the 3-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using Invega Sustenna extended-release tablets . |
| Levodopa and Other Dopamine Agonists | Invega Sustenna may antagonize the effect of levodopa and other dopamine agonists. | Monitor and manage patient as clinically appropriate. |
7.2 Drugs Having No Clinically Important Interactions with Invega Sustenna®
Based on pharmacokinetic studies with oral Invega Sustenna, no dosage adjustment of Invega Sustenna® is required when administered concomitantly with valproate . Additionally, no dosage adjustment is necessary for valproate when co-administered with Invega Sustenna® .
Pharmacokinetic interaction between lithium and Invega Sustenna® is unlikely.
Invega Sustenna 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 Invega Sustenna metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of Invega Sustenna. Invega Sustenna is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely.
8 USE IN SPECIFIC POPULATIONS
Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure.
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Invega Sustenna®, 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 Sustenna® use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Invega Sustenna has been detected in plasma at very low levels up to 18 months after a single-dose administration of Invega Sustenna®, and the clinical significance of Invega Sustenna® administered before pregnancy or anytime during pregnancy is not known . No teratogenicity was observed when pregnant rats were injected intramuscularly with the 1-month Invega Sustenna 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 Invega Sustenna 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 Invega Sustenna palmitate extended-release injectable suspension.
No treatment-related effects on the offspring were observed when pregnant rats were injected intramuscularly with 1-month Invega Sustenna 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 Invega Sustenna palmitate extended-release injectable suspension on mg/m2 basis.
No increases in fetal abnormalities were observed when Invega Sustenna 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 Invega Sustenna on mg/m2 basis.
In rat reproduction studies with risperidone, which is extensively converted to Invega Sustenna 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).
8.2 Lactation
Invega Sustenna is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. Invega Sustenna has been detected in plasma at very low levels up to 18 months after a single-dose administration of Invega Sustenna®, and the clinical significance on the breastfed infant is not known.
8.4 Pediatric Use
Safety and effectiveness of Invega Sustenna® in patients less than 18 years of age have not been established. Use of Invega Sustenna® is not recommended in pediatric patients because of the potential longer duration of an adverse event compared to shorter-acting products. In clinical trials of oral Invega Sustenna, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.
Juvenile Animal Data
No juvenile animal studies were conducted with the 3-month Invega Sustenna palmitate extended-release injectable suspension.
Juvenile rats administered daily oral doses of Invega Sustenna from days 24 to 73 of age had a reversible impairment of performance in a test of learning and memory in females only. The no-effect dose of 0.63 mg/kg/day produced plasma exposure (AUC) to Invega Sustenna similar to that in adolescents. No other consistent effects on neurobehavior or reproductive development were seen up to the highest dose tested which produced plasma exposure to Invega Sustenna 2 to 3 times that in adolescents.
Juvenile dogs administered for 40 weeks daily oral doses of risperidone, which is extensively metabolized to Invega Sustenna in animals and humans, at 0.31, 1.25, and 5 mg/kg/day, had decreased bone length and density with no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus Invega Sustenna similar to those in children and adolescents receiving the MRHD of 6 mg/day of risperidone. In addition, delayed sexual maturation was seen at all doses in both males and females. All adverse effects showed little or no reversibility in females after a 12-week drug-free recovery period.
The long-term effects of Invega Sustenna on growth and sexual maturation have not been fully evaluated in children and adolescents.
8.5 Geriatric Use
Clinical studies of Invega Sustenna® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, monitor renal function and adjust dosage .
8.6 Renal Impairment
Use of Invega Sustenna® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Use of Invega Sustenna® in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) is based on the previous dose of the 1-month Invega Sustenna palmitate extended-release injectable suspension that the patient was stabilized on prior to initiation of Invega Sustenna® .
8.7 Hepatic Impairment
Invega Sustenna® has not been studied in patients with hepatic impairment. Based on a study with oral Invega Sustenna, no dose adjustment is required in patients with mild or moderate hepatic impairment. Invega Sustenna has not been studied in patients with severe hepatic impairment .
8.8 Patients with Parkinson's Disease or Lewy Body Dementia
Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to Invega Sustenna®. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Invega Sustenna® is not a controlled substance.
9.2 Abuse
Invega Sustenna has not been systematically studied in animals or humans for its potential for abuse.
9.3 Dependence
Invega Sustenna has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
No cases of overdose were reported in premarketing studies with Invega Sustenna palmitate injection. Because Invega Sustenna® is to be administered by health care professionals, the potential for overdosage by patients is low.
While experience with Invega Sustenna overdose is limited, among the few cases of overdose reported in premarketing trials with oral Invega Sustenna, 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 Invega Sustenna.
Invega Sustenna is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.
10.2 Management of Overdosage
Contact a Certified Poison Control Center for the most up to date information on the management of Invega Sustenna and Invega Sustenna® 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 Invega Sustenna.
Consider the prolonged-release characteristics of Invega Sustenna® and the long apparent half-life of Invega Sustenna when assessing treatment needs and recovery.
11 DESCRIPTION
Invega Sustenna® is an atypical antipsychotic. Invega Sustenna® contains Invega Sustenna palmitate. The active ingredient, Invega Sustenna palmitate, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. Invega Sustenna® contains a racemic mixture of (+)- and (-)- Invega Sustenna palmitate. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:
Invega Sustenna palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.
Invega Sustenna® 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 Invega Sustenna palmitate. The drug product hydrolyzes to the active moiety, Invega Sustenna, resulting in dose strengths of 175 mg, 263 mg, 350 mg, and 525 mg of Invega Sustenna, respectively. The inactive ingredients are polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
Invega Sustenna® is provided in a prefilled syringe (cyclic-olefin-copolymer) prefilled with either 175 mg (0.875 mL), 263 mg (1.315 mL), 350 mg (1.75 mL), or 525 mg (2.625 mL) Invega Sustenna (as 273 mg, 410 mg, 546 mg, or 819 mg Invega Sustenna palmitate) suspension with a plunger stopper and tip cap (bromobutyl rubber), a backstop, and 2 types of commercially available needles: a thin walled 22G, 1 ½-inch safety needle and a thin walled 22G, 1-inch safety needle.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Invega Sustenna palmitate is hydrolyzed to Invega Sustenna . The mechanism of action of Invega Sustenna is unknown. It has been proposed that the therapeutic activity of Invega Sustenna in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
12.2 Pharmacodynamics
Invega Sustenna is a centrally active dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2 (5HT2A) receptor antagonist. Invega Sustenna 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. Invega Sustenna has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- Invega Sustenna enantiomers is qualitatively and quantitatively similar in vitro.
12.3 Pharmacokinetics
Absorption and Distribution
Due to its extremely low water solubility, the 3-month formulation of Invega Sustenna palmitate dissolves slowly after intramuscular injection before being hydrolyzed to Invega Sustenna 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 Sustenna®, the plasma concentrations of Invega Sustenna gradually rise to reach maximum plasma concentrations at a median Tmax of 30–33 days. Following intramuscular injection of Invega Sustenna® 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 Sustenna® results in sustained therapeutic concentrations over 3 months. The total and peak exposure of Invega Sustenna following Invega Sustenna® administration was dose-proportional over a 273–819 mg dose range. The mean steady-state peak:trough ratio for a Invega Sustenna® dose was 1.6 following gluteal administration and 1.7 following deltoid administration. Following administration of Invega Sustenna®, the apparent volume of distribution of Invega Sustenna is 1960 L.
The plasma protein binding of racemic Invega Sustenna is 74%.
Following administration of Invega Sustenna®, the (+) and (-) enantiomers of Invega Sustenna 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 Invega Sustenna 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 Invega Sustenna, there is no evidence in vivo that these isozymes play a significant role in the metabolism of Invega Sustenna. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of Invega Sustenna after administration of oral Invega Sustenna between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
The median apparent half-life of Invega Sustenna following Invega Sustenna® 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 Invega Sustenna remaining in the circulation 18 months after dosing of 819 mg Invega Sustenna® 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 Invega Sustenna palmitate injection versus other Invega Sustenna formulations
Invega Sustenna® is designed to deliver Invega Sustenna over a 3-month period, while 1-month Invega Sustenna palmitate injection is administered on a monthly basis. Invega Sustenna®, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-month Invega Sustenna palmitate injection, results in Invega Sustenna exposures similar to those obtained with corresponding monthly doses of 1-month Invega Sustenna palmitate injection and corresponding once daily doses of Invega Sustenna extended-release tablets. The exposure range for Invega Sustenna® is encompassed within the exposure range for the approved dose strengths of Invega Sustenna extended-release tablets.
The between-subject variability for Invega Sustenna pharmacokinetics following delivery from Invega Sustenna® was similar to the variability for Invega Sustenna 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.
Drug Interaction Studies
No specific drug interaction studies have been performed with Invega Sustenna®. The information below is obtained from studies with oral Invega Sustenna.
Effects of other drugs on the exposures of Invega Sustenna® are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean Cmax and AUC values at steady-state was observed. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of Invega Sustenna.
| Figure 1: The effects of other drugs on Invega Sustenna® pharmacokinetics. |
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In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in Invega Sustenna metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of Invega Sustenna; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that Invega Sustenna is a substrate of P-glycoprotein (P-gp) .
In vitro studies in human liver microsomes demonstrated that Invega Sustenna 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, Invega Sustenna is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Invega Sustenna is also not expected to have enzyme inducing properties.
Invega Sustenna is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.
The effects of Invega Sustenna® on the exposures of other drugs are summarized in Figure 2.
After oral administration of Invega Sustenna, the steady-state Cmax and AUC of valproate were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral Invega Sustenna extended-release tablets 3–15 mg/day was added to their existing valproate treatment .
| Figure 2: The effects of Invega Sustenna® on pharmacokinetics of other drugs. |
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Studies in Specific Populations
No specific pharmacokinetic studies have been performed with Invega Sustenna® in specific populations. All the information is obtained from studies with oral Invega Sustenna or is based on the population pharmacokinetic modelling of oral Invega Sustenna and Invega Sustenna®. Exposures of Invega Sustenna in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 .
After oral administration of Invega Sustenna in patients with moderate hepatic impairment, the plasma concentrations of free Invega Sustenna were similar to those of healthy subjects, although total Invega Sustenna exposure decreased because of a decrease in protein binding. Invega Sustenna has not been studied in patients with severe hepatic impairment .
After oral administration of Invega Sustenna in elderly subjects, the Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance .
| Figure 3: Effects of intrinsic factors on Invega Sustenna pharmacokinetics. |
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Based on in vitro studies utilizing human liver enzymes, Invega Sustenna is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of Invega Sustenna. Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with Invega Sustenna®, the trough concentrations were similar between males and females.
Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with Invega Sustenna®, the trough concentrations were similar among normal, overweight, and obese subjects.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
No carcinogenicity studies were conducted with the 3-month Invega Sustenna palmitate extended-release injectable suspension.
The carcinogenic potential of intramuscular injection of 1-month Invega Sustenna 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 of 819 mg of 3-month Invega Sustenna 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 Invega Sustenna palmitate extended-release injectable suspension on mg/m2 basis. A carcinogenicity study in mice has not been conducted with the 1-month Invega Sustenna palmitate extended-release injectable suspension.
Carcinogenicity studies of risperidone, which is extensively converted to Invega Sustenna 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 Invega Sustenna palmitate extended-release injectable suspension.
Invega Sustenna palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test and mouse lymphoma assay. Invega Sustenna was not genotoxic in the in vitro Ames bacterial reverse mutation test, mouse lymphoma assay and the in vivo rat bone marrow micronucleus test.
Impairment of Fertility
No fertility studies were conducted with the 3-month Invega Sustenna palmitate extended-release injectable suspension.
In a rat fertility study orally administered Invega Sustenna increased pre- and post-implantation losses and slightly decreased the number of live embryos at doses up to 2.5 mg/kg/day, a dose which is 2 times the MRHD of 12 mg on mg/m2 basis. This dose also caused slight maternal toxicity but there was no effect on the percentage of treated female rats that became pregnant. Pre- and post- implantation losses, the number of live embryos and maternal toxicity were not affected at 0.63 mg/kg/day, a dose, which is half of the MRHD of 12 mg/day of orally administered Invega Sustenna on mg/m2 basis. The fertility of male rats was not affected at oral doses of Invega Sustenna of up to 2.5 mg/kg/day, which are up to 2 times the MRHD of 12 mg on mg/m2 basis, although sperm count and sperm viability studies were not conducted with Invega Sustenna.
In a sub-chronic study in Beagle dogs with risperidone, which is extensively converted to Invega Sustenna in dogs and humans, all doses tested 0.31 to 5.0 mg/kg/day, which are 0.6 to 10 times the MRHD of 16 mg on mg/m2 basis, resulted in decreases in serum testosterone and decreases in sperm motility and concentration. Serum testosterone and sperm parameters partially recovered, but remained decreased at the last observation two months after treatment was discontinued.
13.2 Animal Toxicology and/or Pharmacology
Injection site toxicity was assessed in minipigs injected intramuscularly with the 3-month Invega Sustenna palmitate extended-release injectable suspension at doses up to 819 mg, which is equal to the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month Invega Sustenna palmitate extended-release injectable suspension. Reversibility of these findings was not examined.
14 CLINICAL STUDIES
The efficacy of Invega Sustenna® for the treatment of schizophrenia in patients who have been adequately treated for at least 4 months with INVEGA SUSTENNA® (1-month Invega Sustenna palmitate extended-release injectable suspension) was evaluated in a long-term double-blind, placebo-controlled randomized-withdrawal trial designed to evaluate time to relapse involving adult subjects who met DSM-IV-TR criteria for schizophrenia.
Patients could enter the study with acute symptoms (if previously treated with oral antipsychotics) or be clinically stable (if treated with long-acting injectable antipsychotics [LAI]). All patients who previously received oral antipsychotics received the Invega Sustenna palmitate 1-month initiation regimen (deltoid injections of 234 mg and 156 mg one week apart), while those patients switching from LAI medication were treated with the 1-month Invega Sustenna palmitate extended-release injectable suspension in place of the next scheduled injection. Specifically:
- For patients entering the study who were already being treated with the 1-month Invega Sustenna palmitate extended-release injectable suspension, their dosing remained unchanged. Patients who were currently receiving the 39 mg dose of 1-month Invega Sustenna palmitate were not eligible to enroll in the study.
- Patients entering the study who were being treated with 25 mg, 37.5 mg, or 50 mg of RISPERDAL CONSTA® (risperidone long-acting injection) were switched to 78 mg, 117 mg, or 156 mg, respectively, of the 1-month Invega Sustenna palmitate administered in the deltoid muscle.
- Patients entering the study who were being treated with any other LAI product were switched to 234 mg of the 1-month Invega Sustenna palmitate administered in the deltoid muscle.
This study consisted of the following three treatment periods:
- A 17-week flexible-dose open-label period with the 1-month Invega Sustenna palmitate (first part of a 29-week open-label stabilization phase). A total of 506 patients entered this phase of the study. Dosing of the 1-month Invega Sustenna palmitate was individualized based on symptom response, tolerability, and previous medication history. Specifically, the dose could be adjusted at the week 5 and 9 injections and the injection site could be deltoid or gluteal. The week 13 dose had to be the same as the week 9 dose. Patients had to be clinically stable at the end of this period before receiving Invega Sustenna® at the week 17 visit. Clinical stability was defined as achieving a PANSS total score <70 at week 17. 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.
- A 12-week open-label treatment period with Invega Sustenna® (second part of a 29-week open-label stabilization phase). A total of 379 patients received a single-dose of Invega Sustenna® which was a 3.5 multiple of the last dose of the 1-month Invega Sustenna palmitate. Patients had to remain clinically stable before entry into the next period (double-blind). Clinical stability was defined as achieving a PANSS total score <70 and scores of ≤ 4 for seven specific PANSS items.
- A variable length double-blind treatment period. In this period, 305 stabilized patients were randomized 1:1 to continue treatment with Invega Sustenna® or placebo until relapse, early withdrawal, or the end of study. Patients were randomized to the same dose of Invega Sustenna® they received during the open-label phase (i.e., 273 mg, 410 mg, 546 mg, or 819 mg) or to placebo administered every 12 weeks. The numbers (%) of patients entering double-blind on each of the dose levels were 6 (4%) for 273 mg, 15 (9%) for 410 mg, 78 (49%) for 546 mg, and 61 (38%) for 819 mg.
The primary efficacy variable was time to first relapse. Relapse was pre-defined as 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.
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 efficacy was demonstrated. The most common reason for relapse observed across both treatment groups was increase in the PANSS total score value, followed by psychiatric hospitalization.
Twenty-three percent (23%) of patients in the placebo group and 7.4% of patients in the Invega Sustenna® group experienced a relapse event. The time to relapse was statistically significantly longer in patients randomized to the Invega Sustenna® group than compared to placebo-treated patients. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4.
An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.
| Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse |
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16 HOW SUPPLIED/STORAGE AND HANDLING
Invega Sustenna® 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 Invega Sustenna 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 Invega Sustenna palmitate kit (NDC 50458-606-01)
410 mg Invega Sustenna palmitate kit (NDC 50458-607-01)
546 mg Invega Sustenna palmitate kit (NDC 50458-608-01)
819 mg Invega Sustenna palmitate kit (NDC 50458-609-01)
Storage and Handling
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.
17 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 Sustenna® .
Hyperprolactinemia
Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of Invega Sustenna®. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males.
Interference with Cognitive and Motor Performance
As Invega Sustenna® 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 Sustenna® 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 (5.14)].
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 Sustenna® may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Invega Sustenna®. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to Invega Sustenna® during pregnancy .
Invega Sustenna® (paliperidone palmitate) Extended-Release Injectable Suspension
INVEGA SUSTENNA®, RISPERDAL®, and RISPERDAL CONSTA® are trademarks of Janssen Pharmaceuticals, Inc.
Product of Ireland
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
© 2015 Janssen Pharmaceutical Companies
| PATIENT INFORMATION Invega Sustenna® (in-VAY-guh TRIN-zuh) (paliperidone palmitate) Extended-Release Injectable Suspension |
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| What is the most important information I should know about Invega Sustenna®? Invega Sustenna® can cause serious side effects, including:
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Invega Sustenna® is used in people who have been treated with INVEGA SUSTENNA® 1 time a month injections for at least 4 months. 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:
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| 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:
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®?
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What should I avoid while receiving Invega Sustenna®?
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| What are the possible side effects of Invega Sustenna®? Invega Sustenna® may cause serious side effects, including:
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| The most common side effects of Invega Sustenna® include: injection site reactions, weight gain, headache, upper respiratory tract infections, feeling restlessness or difficulty sitting still, slow movements, tremors, stiffness and shuffling walk. 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 FDA at 1-800-FDA-1088. |
| General information about the safe and effective use of Invega Sustenna®. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Invega Sustenna® for a condition for which it was not prescribed. Do not give Invega Sustenna® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Invega Sustenna® that is written for health professionals. 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.invegatrinzahcp.com or call 1-800-526-7736. |
| What are the ingredients in Invega Sustenna®? Active ingredient: Invega Sustenna palmitate Inactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 © 2015 Janssen Pharmaceutical Companies |
Invega Sustenna pharmaceutical active ingredients containing related brand and generic drugs:
Invega Sustenna available forms, composition, doses:
Invega Sustenna destination | category:
Invega Sustenna Anatomical Therapeutic Chemical codes:
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References
- Dailymed."INVEGA (PALIPERIDONE) TABLET, EXTENDED RELEASE [JANSSEN PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."PALIPERIDONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- "Paliperidone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Invega Sustenna?Depending on the reaction of the Invega Sustenna after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Invega Sustenna not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Invega Sustenna addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology