Dosage & Administration
| Indication | Initiation Dosing (deltoid) | Monthly Maintenance Dose* (deltoid or gluteal) | Maximum Monthly Dose | |
|---|---|---|---|---|
| Day 1 | Day 8 | |||
| Schizophrenia (2.2) | 234 mg | 156 mg | 39–234 mg† | 234 mg |
| Schizoaffective disorder (2.2) | 234 mg | 156 mg | 78–234 mg‡ | 234 mg |
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Invega Sustenna Prescribing Information
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. [see Warnings and Precautions (5.1)] .
INVEGA SUSTENNA (paliperidone palmitate) is indicated for the treatment of:
- Schizophrenia in adults [see Clinical Studies (14.1)].
- Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants [see Clinical Studies (14.2)].
Administration Instructions
Each injection must be administered only by a healthcare professional.
Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration, whenever product and container permit.
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 needles that are provided in the INVEGA SUSTENNA kit.
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, 23 gauge needle is recommended.
- For patients weighing 90 kg or more, the 1½-inch, 22 gauge needle is recommended.
Deltoid injections should be alternated between the two deltoid muscles.
The recommended needle size for administration of INVEGA SUSTENNA into the gluteal muscle is the 1½-inch, 22 gauge needle regardless of patient weight.
Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.
Schizophrenia and Schizoaffective Disorder
For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA.
The recommended dosing of INVEGA SUSTENNA for each approved indication is displayed in Table 1. The recommended initiation of INVEGA SUSTENNA is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.
| Indication | Initiation Dosing (deltoid) | Monthly Maintenance Dose * (deltoid or gluteal) | Maximum Monthly Dose | |
|---|---|---|---|---|
| Day 1 | Day 8 | |||
| ||||
| Schizophrenia | 234 mg | 156 mg | 39–234 mg † | 234 mg |
| Schizoaffective disorder | 234 mg | 156 mg | 78–234 mg ‡ | 234 mg |
Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of INVEGA SUSTENNA should be considered [see Clinical Pharmacology (12.3)] , as the full effect of the dose adjustment may not be evident for several months.
Missed Doses
Avoiding Missed Doses
It is recommended that the second initiation dose of INVEGA SUSTENNA be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.
Management of a Missed Second Initiation Dose
If the target date for the second INVEGA SUSTENNA injection (one week ± 4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient's first injection. In case of a missed second initiation dose follow the dosing instructions provided in Table 2.
| TIMING OF MISSED SECOND INITIATION DOSE | DOSING |
|---|---|
| Less than 4 weeks since first injection | Administer the second initiation dose of 156 mg in the deltoid muscle as soon as possible.
|
| 4 to 7 weeks since first injection | Resume dosing with two injections of 156 mg in the following manner:
|
| More than 7 weeks since first injection | Restart dosing with recommended initiation(see Section 2.2, Table 1) :
|
Management of a Missed Maintenance Dose
In case of a missed maintenance dose follow the dosing instructions provided in Table 3.
| TIMING OF MISSED MAINTENANCE DOSE | DOSING |
|---|---|
| 4 to 6 weeks since last injection | Resume regular monthly dosing as soon as possible at the patient's previously stabilized dose, followed by injections at monthly intervals. |
| More than 6 weeks to 6 months since last injection | Resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first 2 injections should each be 156 mg) in the following manner:
|
| More than 6 months since last injection | Restart dosing with recommended initiation( see Section 2.2, Table 1) :
|
Use with Risperidone or with Oral Paliperidone
Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA SUSTENNA is coadministered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA SUSTENNA with other antipsychotics is limited.
Dosage Adjustments
Patients with Renal Impairment
INVEGA SUSTENNA has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)] .
For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA with a dose of 156 mg on treatment Day 1 and 117 mg on Day 8, both in the deltoid muscle. Follow with the recommended monthly maintenance dose of 78 mg, administered in either the deltoid or gluteal muscle. Adjust monthly maintenance dose based on tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg. The maximum monthly dose is 156 mg for patients with mild renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .
INVEGA SUSTENNA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .
Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers
Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John's Wort) during the 1-month dosing interval for INVEGA SUSTENNA, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to INVEGA SUSTENNA, or concerning concomitant administration with other antipsychotics.
Switching from Oral Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA.
Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with INVEGA SUSTENNA. Recommended initiation of INVEGA SUSTENNA is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle [see Dosage and Administration (2.2)] . Patients previously stabilized on different doses of INVEGA Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with INVEGA SUSTENNA monthly doses as depicted in Table 4.
| Formulation | INVEGA Extended-Release Tablet | INVEGA SUSTENNA Injection |
|---|---|---|
| Dosing Frequency | Once Daily | Once every 4 weeks |
| Dose (mg) | 12 | 234 |
| 9 | 156 | |
| 6 | 117 | |
| 3 | 39–78 |
Switching from Long-Acting Injectable Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA.
When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate INVEGA SUSTENNA therapy in place of the next scheduled injection. INVEGA SUSTENNA should then be continued at monthly intervals. The one-week initiation dosing regimen as described in Section 2.2 is not required. See Table 1 above for recommended monthly maintenance dosing. Based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg). The 39 mg strength was not studied in the long-term schizoaffective disorder study. Monthly maintenance doses can be administered in either the deltoid or gluteal muscle [see Dosage and Administration (2.2)] .
If INVEGA SUSTENNA is discontinued, its prolonged-release characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.
Instructions for Preparation and Administration
Each injection must be administered only by a healthcare professional.
The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle) for intramuscular injection.
INVEGA SUSTENNA is for single use only.
- Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension.
- Select the appropriate needle.
For DELTOID injection:- If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub).
- If the patient weighs 90 kg or more, use the 1 ½-inch 22 gauge needle (needle with gray colored hub).
For GLUTEAL injection:
Use the 1 ½-inch 22 gauge needle (needle with gray colored hub) regardless of patient's weight.
- Hold the syringe with the tip cap pointing up. Remove the rubber tip cap with a gentle twisting motion.
- Peel the safety needle pouch half way open. Grasp the needle sheath using the plastic peel pouch. Hold the syringe pointing up. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leaking prior to administration.
- Pull the needle sheath away from the needle with a straight pull. Do not twist the sheath as the needle may be loosened from the syringe.
- Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.
- Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. Do not administer by any other route.
- After the injection is complete, use either thumb or finger of one hand (h1, h2) or a flat surface (h3) to activate the needle protection system. The needle protection system is fully activated when a 'click' is heard. Discard the syringe with needle appropriately.
| h1 | |
 | |
| h2 | |
 | |
| h3 | |
 | |
INVEGA SUSTENNA is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL, 156 mg/mL, and 234 mg/1.5 mL paliperidone palmitate in single-dose prefilled syringes.
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. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at 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 (see Clinical Considerations) . Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA SUSTENNA, during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 126 days after a single-dose administration of INVEGA SUSTENNA [see Clinical Pharmacology (12.3)] , and the clinical significance of INVEGA SUSTENNA administered before pregnancy or anytime during pregnancy is not known.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. 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.
In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m 2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
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, including INVEGA SUSTENNA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
Data
Human Data
Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.
Animal Data
There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone based on mg/m 2 body surface area.
In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 body surface area.
Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.
In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL package insert).
Lactation
Risk Summary
Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations) . Paliperidone has been detected in plasma in adult subjects up to 126 days after a single-dose administration of INVEGA SUSTENNA [see Clinical Pharmacology (12.3)] , and the clinical significance on the breastfed infant is not known. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INVEGA SUSTENNA and any potential adverse effects on the breastfed child from INVEGA SUSTENNA or from the mother's underlying condition.
Clinical Considerations
Infants exposed to INVEGA SUSTENNA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).
Females and Males of Reproductive Potential
Infertility
Females
Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with INVEGA SUSTENNA may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.10)].
Pediatric Use
Safety and effectiveness of INVEGA SUSTENNA in patients < 18 years of age have not been established.
Juvenile Animal Studies
In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2–3 times those in adolescents.
Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.
The long-term effects of INVEGA SUSTENNA on growth and sexual maturation have not been fully evaluated in children and adolescents.
Geriatric Use
Clinical studies of INVEGA SUSTENNA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)] , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function [see Dosage and Administration (2.5)].
Renal Impairment
Use of INVEGA SUSTENNA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)] .
Hepatic Impairment
INVEGA SUSTENNA has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .
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.
INVEGA SUSTENNA is contraindicated in patients with a known hypersensitivity to either paliperidone 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 paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.