INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension

INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension

INVEGA HAFYERA™ (paliperidone palmitate)

INVEGA HAFYERA™ 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 (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.

Indications and usage

INVEGA HAFYERA, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

  • A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA) for at least four months or
  • An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA) for at least one three-month cycle.

INVEGA HAFYERA must be administered as a gluteal intramuscular injection by a healthcare professional once every 6 months. Do not administer by any other route

Mechanism of Action

Paliperidone palmitate is hydrolyzed to paliperidone. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, its efficacy in the treatment of schizophrenia could be mediated through a combination of central dopamine D2 and serotonin 5HT2A receptor antagonism.

Dosage and administration

The recommended initial INVEGA HAFYERA dose is based on the previous PP1M dose. Initiate INVEGA HAFYERA when the next PP1M dose is scheduled. INVEGA HAFYERA may be administered up to 1 week before or 1 week after the next scheduled PP1M dose. When switching from PP1M to INVEGA HAFYERA, the two injection cycles immediately preceding the switch should be the same dosage strength before starting INVEGA HAFYERA.

Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP1M* Product

Last Dose of PP1M**Initial Dose of INVEGA HAFYERA
156 mg1,092 mg
234 mg1,560 mg

*PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension

**There are no equivalent doses of INVEGA HAFYERA for 39 mg, 78 mg, or 117 mg doses of a PP1M product, which were not studied

Switching to INVEGA HAFYERA from a PP3M Product: The recommended initial INVEGA HAFYERA dose is based on the previous PP3M dose. Initiate INVEGA HAFYERA when the next PP3M dose is scheduled. INVEGA HAFYERA may be administered up to 2 weeks before or 2 weeks after the next scheduled PP3M dose.

Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP3M* Product

Last Dose of PP3M**Initial Dose of INVEGA HAFYERA
546 mg1,092 mg
819 mg1,560 mg

*PP3M: Every-three-month paliperidone palmitate extended-release injectable suspension

**There are no equivalent doses of INVEGA HAFYERA for the 273 mg or 410 mg doses of a PP3M product, which were not studied

Dosing Window: To avoid a missed dose, patients may be given the injection up to 2 weeks before or 3 weeks after the scheduled 6-month dose.

Missed Dose: If a dose of INVEGA HAFYERA is missed, re-initiate with a PP1M product using the reinitiation regimens

More than 6 Months and 3 Weeks, up to but Less than 8 Months Since Last Dose: If more than 6 months and 3 weeks but less than 8 months have elapsed since the last dose of INVEGA HAFYERA, do not administer the next dose of INVEGA HAFYERA. Instead, use the re-initiation regimen

Re-initiation Regimen for Missed Dose (more than 6 months and 3 weeks, but less than 8 months since last dose)

Last Dose of INVEGA HAFYERAAdminister PP1M Product* into deltoid muscleAdminister INVEGA HAFYERA into gluteal muscle

Day 11 month after Day 1
1,092 mg156 mg1,092 mg
1,560 mg234 mg1,560 mg

*PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension

8 Months Up to and including 11 Months Since Last Dose: If 8 months but up to and including 11 months have elapsed since the last dose of INVEGA HAFYERA, do not administer the next dose of INVEGA HAFYERA. Instead, use the re-initiation regimen

Re-initiation Regimen for Missed Dose (8 months up to and including 11 months since last dose)

Last dose of INVEGA HAFYERAAdminister PP1M Product* into deltoid muscleAdminister INVEGA HAFYERA into gluteal muscle

Day 1 Day 81,092 mg
1,092 mg156 mg 156 mg
1,560 mg156 mg 156 mg1,560 mg

*PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension

More than 11 Months Since Last Dose: If more than 11 months have elapsed since the last dose of INVEGA HAFYERA, re-initiate treatment with a PP1M product as described in the prescribing information for that product. INVEGA HAFYERA can then be resumed after the patient has been adequately treated with a PP1M product for at least 4 months.

Instructions for Preparation and Administration


  • To be prepared and administered by a healthcare provider only.
  • Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider “Instructions for Use” for preparation and administration considerations.
  • For gluteal intramuscular injection only. Do not inject by any other route. As a universal precaution, always wear gloves.
  • Inspect INVEGA HAFYERA for particulate matter and discoloration prior to administration.
  • Do not mix with any other product or diluent.
  • After shaking, INVEGA HAFYERA should appear uniform, thick and milky white.
  • Do not use needles from the PP1M or PP3M products or other commercially-available needles to reduce the risk of blockage.
  • 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 upper-outer quadrant of the gluteal muscle. Future injections should be alternated between the two gluteal muscles.
  • INVEGA HAFYERA™ (paliperidone palmitate). Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds
  • Administer every 6 months
  • For Gluteal Intramuscular injection only.
  • Thin Wall Safety Needle: Thin wall safety needle is designed to be used with INVEGA HAFYERA. Therefore, it is important to only use the needle
    provided in the INVEGA HAFYERA suspension kit.

Prepare for the injection

Pull back plunger
Hold the syringe upright.
Gently pull back the plunger to clear the syringe tip of
any solid product. This will make pressing the plunger
easier during the injection.

Remove air bubbles
Press the plunger carefully until a drop of liquid comes
out of the needle tip.

Slowly inject entire content and confirm
Select and clean a gluteal injection site
Wipe the gluteal site with an alcohol swab and allow it to
dry.

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.

Slowly inject and confirm
Use slow, firm, consistent pressure to press the plunger
completely. This should take approximately 30 seconds.
Continue to press the plunger if you feel resistance.
This is normal.

Contraindications

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

Warnings and precautions

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA HAFYERA is not approved for use in patients with dementia-related psychosis.
  • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities).
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring.
  • QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval.
  • Tardive Dyskinesia: Discontinue treatment if clinically appropriate
  • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain.
  • Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension.
  • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing INVEGA HAFYERA if a clinically significant decline in WBC occurs in the absence of other causative factors.
  • Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration.
  • Potential for Cognitive and Motor Impairment: Use caution when operating machinery.
  • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold

Side effects

  • Blood and lymphatic system disorders: anemia
  • Cardiac disorders: bradycardia, tachycardia
  • Ear and labyrinth disorders: vertigo
  • Gastrointestinal disorders: constipation, nausea, vomiting
  • General disorders and administration site conditions: fatigue
  • Hepatobiliary disorders: transaminases increased
  • Infections and infestations: cystitis, respiratory tract infection, tonsillitis
  • Metabolism and nutritional disorders: decreased appetite, increased appetite, weight decreased
  • Psychiatric disorders: depression
  • Reproductive system and breast disorders: breast pain, menstrual disorder
  • Skin and subcutaneous tissue disorders: rash
  • Vascular disorders: hypertension

Drug interactions

Centrally acting Drugs and Alcohol: INVEGA HAFYERA should be used with caution with other centrally acting drugs and alcohol.

Drugs with Potential for Inducing Orthostatic Hypotension: Because INVEGA HAFYERA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA HAFYERA 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: The concomitant use of INVEGA HAFYERA and strong inducers of CYP3A4 and Pgp may decrease the exposure of paliperidone. Avoid using CYP3A4 and/or P-gp inducers with INVEGA HAFYERA during the 6- month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets. Examples carbamazepine, rifampin, or St. John’s Wort

Levodopa and Other Dopamine Agonists: Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Monitor and manage patient as clinically appropriate.

Use in specific populations

Pregnancy: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. 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. There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA HAFYERA during pregnancy. Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate extended-release injectable suspension. The clinical significance of INVEGA HAFYERA administered before pregnancy or anytime during pregnancy is not known.

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 is 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 HAFYERA, 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 recovered within hours or days without specific treatment; others required prolonged hospitalization.

Lactation: 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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA HAFYERA and any potential adverse effects on the breastfed child from INVEGA HAFYERA or from the mother’s underlying condition.

Pediatric Use: Safety and effectiveness of INVEGA HAFYERA in patients less than 18 years of age have not been established. Use of INVEGA HAFYERA is not recommended in pediatric patients because of the potential longer duration of an adverse event.

Renal Impairment: Use of INVEGA HAFYERA is not recommended for use in patients with mild, moderate, or severe renal impairment (creatinine clearance <90 mL/min) because necessary dosage adjustment is not possible with available strengths of INVEGA HAFYERA

Hepatic Impairment: INVEGA HAFYERA 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.

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 HAFYERA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Overdosage

No cases of overdose were reported in premarketing studies with paliperidone palmitate injection.

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.

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