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Paliperidone Palmitate

FDA Drug Information • Also known as: Erzofri Extended-Release, Invega Hafyera, Invega Sustenna, Invega Trinza

Brand Names
Erzofri Extended-Release, Invega Hafyera, Invega Sustenna, Invega Trinza
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

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. ERZOFRI is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions (5.1) ] . 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. ERZOFRI is not approved for use in patients with dementia-related psychosis. ( 5.1 )

Description

11 DESCRIPTION ERZOFRI (paliperidone palmitate) extended-release injectable suspension contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9 RS )-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 H -pyrido[1,2- a ]pyrimadin-9-yl hexadecanoate. Its molecular formula is C 39 H 57 FN 4 O 4 and its molecular weight is 664.89. The structural formula is: Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in water, and slightly soluble in ethyl acetate. ERZOFRI is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (deliverable volume) in single-dose prefilled syringes: 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1 mL), 234 mg (1.5 mL), and 351 mg (2.25 mL). The drug product hydrolyzes in vivo to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 225 mg of paliperidone, respectively. The inactive ingredients are citric acid monohydrate (5 mg/mL), dibasic sodium phosphate anhydrous (5 mg/mL), monobasic sodium phosphate monohydrate (2.5 mg/mL), polyethylene glycol 4000 (30 mg/mL), polysorbate 20 (12 mg/mL), sodium hydroxide to adjust pH, and water for injection. The drug product pH is 6.5 to 7.5. Chemical Structure

What Is Paliperidone Palmitate Used For?

1 INDICATIONS AND USAGE ERZOFRI is indicated for the treatment of: Schizophrenia in adults . Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants . ERZOFRI is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. ( 1 ) Treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For patients naïve to oral or injectable paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with ERZOFRI. ( 2.1 ) Each injection must be administered by a healthcare professional. ( 2.1 ) Initiate ERZOFRI by intramuscular injection in the deltoid muscle. Following the initial dose, monthly doses can be administered in either the gluteal or deltoid muscle. Do not administer by any other route. ( 2.1 ) Dosage recommendations: Indication Initial Dose (deltoid) Day 1 Monthly Dosage Administered 4 weeks after the first injection. (deltoid or gluteal) Maximum Monthly Dosage Schizophrenia ( 2.1 ) 351 mg 39 mg to 234 mg Recommended monthly dosage for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher monthly doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 234 mg Schizoaffective disorder ( 2.1 ) 351 mg 78 mg to 234 mg Adjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not studied in the long-term schizoaffective disorder study. 234 mg Missed dose: Refer to the Full Prescribing Information. ( 2.2 ) Mild renal impairment: Administer 234 mg on treatment Day 1 in the deltoid muscle. Follow with the recommended monthly maintenance dose of 78 mg, administered in 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 dosage is 156 mg for patients with mild renal impairment. ( 2.4 ) See Full Prescribing Information for important preparation and administration information. ( 2.7 ) 2.1 Recommended Dosage For patients who have never taken oral or injectable paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with ERZOFRI. ERZOFRI must be administered by a healthcare professional as an intramuscular injection. Do not administer ERZOFRI by any other route. For detailed preparation and administration instructions, see Dosage and Administration (2.7) . See Table 1 for dosage recommendations for ERZOFRI in the treatment of schizophrenia in adults or the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants. The initial dosage of ERZOFRI is 351 mg on treatment Day 1 administered in the deltoid muscle. Following the initial dose, monthly doses can be administered in either the deltoid or gluteal muscle [see Clinical Pharmacology (12.3) ] . Table 1: Dosage Recommendations for ERZOFRI Indication Initial Dose (deltoid) Day 1 Monthly Dosage Administered 4 weeks after the first injection. (deltoid or gluteal) Maximum Monthly Dosage Schizophrenia 351 mg 39 mg to 234 mg The recommended monthly dosage for treatment of schizophrenia is 117 mg. Some patients may...

Side Effects (Adverse Reactions)

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 [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Luye Innomind Pharma Shijiazhuang Co., Ltd. at 1-800-548-9765 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. The safety of ERZOFRI for the treatment of schizophrenia in adults and schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon adequate and well-controlled studies of another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). Below is a display of adverse reactions with another PP1M from those adequate and well-controlled studies. Injection site reactions for ERZOFRI presented in this section (see " Pain and Injection Site Reactions with ERZOFRI " below) are based on pharmacokinetic studies. Patient Exposure The data described in this section are derived from a clinical trial database consisting of a total of 3,817 subjects (approximately 1,705 patient-years exposure) with schizophrenia who received at least one dose of PP1M in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3,817 PP1M-treated subjects, 1,293 received PP1M in four fixed-dose, double- blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received PP1M in the maintenance trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive PP1M during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1,675 received PP1M in five non-placebo controlled trials (three noninferiority active- comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoid-gluteal] cross-over trial). One of the 13-week studies included a 234 mg PP1M initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks. The safety of PP1M was also evaluated in a 15-month, long-term study comparing the other PP1M to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received PP1M during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of PP1M was similar to that seen in...

Drug Interactions

7 DRUG INTERACTIONS Drugs that may cause orthostatic hypotension: An additive effect may occur when co-administered with ERZOFRI. ( 7.1 ) Strong CYP3A4 and P-glycoprotein (P-gp) inducers : Avoid using a strong inducer of CYP3A4 and/or P-gp during a dosing interval for ERZOFRI. If concomitant use is necessary, consider using paliperidone extended-release tablets. ( 2.5 , 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Interactions with ERZOFRI Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) ] , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. Table 12 presents clinically significant drug interactions with ERZOFRI. Table 12: Clinically Important Drug Interactions with ERZOFRI Centrally Acting Drugs and Alcohol Clinical Rationale: Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of ERZOFRI. Clinical Recommendation: ERZOFRI should be used with caution in combination with other centrally acting drugs and alcohol [see Adverse Reactions (6.1 , 6.2) ] . Drugs with Potential for Inducing Orthostatic Hypotension Clinical Rationale: Because ERZOFRI has the potential for inducing orthostatic hypotension, an additive effect may occur when ERZOFRI is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.7) ] . Clinical Recommendation: Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7) ] . Strong Inducers of CYP3A4 and P-gp Clinical Rationale: The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) ] . Clinical Recommendation: Avoid using CYP3A4 and/or P-gp inducers with ERZOFRI during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.5) ] . Levodopa and Other Dopamine Agonists Clinical Rationale: Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Clinical Recommendation: Monitor and manage patient as clinically appropriate. 7.2 Drugs Having No Clinically Important Interactions with ERZOFRI Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of ERZOFRI is required when administered with valproate [see Clinical Pharmacology (12.3) ]. Additionally, no dosage adjustment is necessary for valproate when co-administered with ERZOFRI [See Clinical Pharmacology (12.3) ]. Pharmacokinetic interaction between lithium and ERZOFRI is also unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in...

Contraindications

4 CONTRAINDICATIONS ERZOFRI is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the ERZOFRI formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone [see Adverse Reactions (6.1 , 6.2) ] . Known hypersensitivity to paliperidone, risperidone, or to any excipients in ERZOFRI. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ERZOFRI, during pregnancy. Healthcare providers are encouraged to advise patients to register 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 ERZOFRI, during pregnancy (see Clinical Considerations ). Paliperidone has been detected in plasma in adult subjects up to 176 days after a single-dose administration of ERZOFRI [see Clinical Pharmacology (12.3) ] , and the clinical significance of ERZOFRI 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% to 4% and 15% to 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...

Overdosage

10 OVERDOSAGE Human Experience While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. Paliperidone is the major active metabolite of risperidone. Refer to the OVERDOSAGE section of the risperidone prescribing information for overdose experience with risperidone. Management of Overdosage There is no specific antidote to paliperidone. 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. Consider the pharmacokinetic profile of ERZOFRI and the half-life of paliperidone when assessing treatment needs and recovery. Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ERZOFRI ® is provided as a single-use kit containing a single-dose prefilled syringe with a plunger stopper and tip cap. The kit also contains 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle). ERZOFRI is available as a white to off-white aqueous suspension in the following strengths: 39 mg/0.25 mL paliperidone palmitate kit (NDC 72526-105-11) 78 mg/0.5 mL paliperidone palmitate kit (NDC 72526-106-11) 117 mg/0.75 mL paliperidone palmitate kit (NDC 72526-107-11) 156 mg/mL paliperidone palmitate kit (NDC 72526-108-11) 234 mg/1.5 mL paliperidone palmitate kit (NDC 72526-109-11) 351 mg/2.25 mL paliperidone palmitate kit (NDC 72526-110-11) Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not mix with any other product or diluent.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.