Save up to 80% by drug discount in your pharmacy with "Pharmacy Near Me - National Drug Discount Card"
You can scan QR Code(just open camera on your phone/scan by application) from the image on prescription drug discount card to save it to your mobile phone. Or just click on image if you're on mobile phone.
| Product NDC Code | 50458-611 | ||||
|---|---|---|---|---|---|
| Drug Name | Invega hafyera |
||||
| Type | Brand | ||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||
| Active Ingredients |
|
||||
| Route | INTRAMUSCULAR | ||||
| Dosage Form | INJECTION, SUSPENSION, EXTENDED RELEASE | ||||
| RxCUI drug identifier | 2570418, 2570419, 2570420, 2570421 |
||||
| Application Number | NDA207946 | ||||
| Labeler Name | Janssen Pharmaceuticals, Inc | ||||
| Packages |
|
||||
| Check if available Online | Get Medication Prices online with Discount |
Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse.
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance INVEGA HAFYERA contains paliperidone, which is not a controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance INVEGA HAFYERA contains paliperidone, which is not a controlled substance. 9.2 Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse. 9.3 Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Overdosage of INVEGA HAFYERA
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Human Experience 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. Management of Overdosage Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA HAFYERA overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone. Consider the extended-release characteristics of INVEGA HAFYERA and the half-life of paliperidone when assessing treatment needs and recovery.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 were upper respiratory tract infection, injection site reaction, weight increased, headache, and parkinsonism. ( 6.1 ) 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 is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 (86.97) days in the INVEGA HAFYERA group and 336.4 (80.89) days in the PP3M group during the double-blind phase: Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial Commonly Observed Adverse Reactions : The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism. Discontinuation of Treatment Due to Adverse Reactions : In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate extended-release injectable suspension group discontinued due to adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients : Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial. Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia Double Blind System Organ Class PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Adverse Reaction Gastrointestinal disorders Diarrhea The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious. Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling. Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper respiratory tract infection includes: Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Viral pharyngitis, Viral upper respiratory tract infection. Back pain includes: Back pain, Neck pain, Spinal pain. Musculoskeletal pain includes: Musculoskeletal pain, Musculoskeletal chest pain, Myalgia, Pain in extremity. Akathisia includes: Akathisia, Restless legs syndrome, Restlessness. Extrapyramidal symptoms includes: blepharospasms, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, musculoskeletal stiffness, muscle rigidity, muscle spasms, oculogyric crisis, Parkinsonism, Parkinsonism rest tremor, reduced facial expression, tardive dyskinesia. Insomnia includes: Insomnia, Initial insomnia, Middle insomnia. Psychosis includes: acute psychosis, delusion, delusion of reference, hallucination (auditory), psychotic disorder, psychotic symptom, and schizophrenia. 1 2 General disorders and administration site conditions Injection site reaction 5 11 Infections and infestations Upper respiratory tract infection 13 12 Urinary tract infection 1 3 Metabolism and nutrition disorders Weight increased 8 9 Musculoskeletal and connective tissue disorders Back pain 1 3 Musculoskeletal pain 1 3 Nervous system disorders Akathisia 4 4 Headache 5 7 Extrapyramidal symptoms 5 7 Psychiatric disorders Psychosis 3 3 Anxiety 0 3 Insomnia 2 3 Demographic Differences An examination of population subgroups in the INVEGA HAFYERA trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone. Extrapyramidal Symptoms (EPS) Data from the randomized double-blind active controlled study provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus Rating Scale 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 8) and (5) incidence of spontaneous reports of EPS (Table 9). Table 8. Extrapyramidal Symptoms (EPS) Assessed by Rating Scales Incidence and Use of Anticholinergic Medication During the Double-blind Phase PP3M PP3M - Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group. Use of Anticholinergic Medication Use of Anti-EPS Medication During the Double-blind Phase 13 15 Parkinsonism Percent of subjects with Simpson-Angus Scale Global Score >0.3(Global Score defined as total sum of items score divided by the number of items). 6 7 Akathisia Percent of subjects with Barnes Akathisia Rating Scale Global Clinical Rating Score ≥2 3 3 Dyskinesia Percent of subjects with a score ≥3 on any of the first seven items or a score ≥2 on two or more of any of the first seven items of the Abnormal Involuntary Movement Scale 1 1 Table 9. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Double-blind Phase EPS Group PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension Parkinsonism group includes: Bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, reduced facial expression Hyperkinesia group includes: Akathisia, restlessness, restless legs syndrome Dyskinesia group includes: Dyskinesia, muscle twitching, tardive dyskinesia Dystonia group includes: Blepharospasm, dystonia, muscle spasms, oculogyric crisis (N=224) % INVEGA HAFYERA (N=478) % Overall percentage of subjects with EPS-related adverse events 9 10 Parkinsonism 4 5 Hyperkinesia 4 4 Tremor 0 <1 Dyskinesia 1 2 Dystonia 1 1 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 . Induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the PP3M group during the double-blind Phase. Investigator evaluation of tenderness was higher for subjects in the INVEGA HAFYERA group versus the 3-month paliperidone palmitate extended-release injectable suspension group (31% vs. 19%) during the double-blind Phase. Active INVEGA HAFYERA medication was given at double-blind baseline and Month 6, while placebo medication was given at the other injection times. Subject ratings of injection site pain . The average score for the subject's evaluation of injection pain on a scale of 0 to 100 was approximately 16 at the open-label Phase end point and approximately 5 in both groups at the double-blind Phase end point. Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA HAFYERA The following additional adverse reactions were identified in the randomized double-blind active controlled study. 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. 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 Additional Adverse Reactions Reported in Clinical Trials with the 1-Month and 3-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month and 3-month paliperidone palmitate extended-release injectable suspensions that are not listed elsewhere: Cardiac disorders : atrioventricular block first degree, bundle branch block, palpitations, postural orthostatic tachycardia syndrome 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, chest discomfort Immune system disorders : hypersensitivity Investigations : electrocardiogram abnormal Metabolism and nutrition disorders : hyperinsulinemia Musculoskeletal and connective tissue disorders : 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, sexual dysfunction Respiratory, thoracic and mediastinal disorders : cough Skin and subcutaneous tissue disorders : drug eruption, eczema, pruritus, pruritus generalized, urticaria Vascular disorders : hypotension, orthostatic hypotension Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone: Cardiac disorders : bundle branch block left, sinus arrhythmia Gastrointestinal disorders : abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions : edema, edema peripheral Immune system disorders : anaphylactic reaction Musculoskeletal and connective tissue disorders : arthralgia, 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, retrograde ejaculation Respiratory, thoracic and mediastinal disorders : nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders : rash papular Vascular disorders : ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) section of the Prescribing Information for those products.
| Double Blind | ||
|---|---|---|
| System Organ Class | PP3M | INVEGA HAFYERA (N=478) % |
| Adverse Reaction | ||
| Diarrhea | 1 | 2 |
| Injection site reaction | 5 | 11 |
| Upper respiratory tract infection | 13 | 12 |
| Urinary tract infection | 1 | 3 |
| Weight increased | 8 | 9 |
| Back pain | 1 | 3 |
| Musculoskeletal pain | 1 | 3 |
| Akathisia | 4 | 4 |
| Headache | 5 | 7 |
| Extrapyramidal symptoms | 5 | 7 |
| Psychosis | 3 | 3 |
| Anxiety | 0 | 3 |
| Insomnia | 2 | 3 |
| PP3M | INVEGA HAFYERA (N=478) % | |
|---|---|---|
| Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group. | ||
| Use of Anticholinergic Medication | 13 | 15 |
| Parkinsonism | 6 | 7 |
| Akathisia | 3 | 3 |
| Dyskinesia | 1 | 1 |
| Double-blind Phase | ||
|---|---|---|
| EPS Group | PP3M | INVEGA HAFYERA (N=478) % |
| 9 | 10 | |
| Parkinsonism | 4 | 5 |
| Hyperkinesia | 4 | 4 |
| Tremor | 0 | <1 |
| Dyskinesia | 1 | 2 |
| Dystonia | 1 | 1 |
INVEGA HAFYERA Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Strong CYP3A4/P-glycoprotein (P-gp) inducers : Avoid using strong CYP3A4 and/or P-gp inducers during a dosing interval for INVEGA HAFYERA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets. ( 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Interactions with INVEGA HAFYERA Because paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 6-month dosing interval and the half-life of INVEGA HAFYERA [see Clinical Pharmacology (12.3) ] . Table 10 presents clinically significant drug interactions with INVEGA HAFYERA. Table 10. Clinically Important Drug Interactions with INVEGA HAFYERA 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 INVEGA HAFYERA. Clinical Recommendation INVEGA HAFYERA should be used with caution with other centrally acting drugs and alcohol. Drugs with Potential for Inducing Orthostatic Hypotension Clinical Rationale 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 [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 INVEGA HAFYERA 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 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 [see Dosage and Administration (2.1) ] . Examples carbamazepine, rifampin, or St. John's Wort 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 INVEGA HAFYERA Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA HAFYERA is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3) ] . Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA HAFYERA [see Clinical Pharmacology (12.3) ] . Pharmacokinetic interaction between lithium and INVEGA HAFYERA is unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely [see Clinical Pharmacology (12.3) ].
| Clinical Rationale | Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA HAFYERA. |
| Clinical Recommendation | INVEGA HAFYERA should be used with caution with other centrally acting drugs and alcohol. |
| Clinical Rationale | 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 |
| Clinical Recommendation | Monitor orthostatic vital signs in patients who are vulnerable to hypotension |
| Clinical Rationale | The concomitant use of INVEGA HAFYERA and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone |
| Clinical Recommendation | 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 |
| Clinical Rationale | Paliperidone may antagonize the effect of levodopa and other dopamine agonists. |
| Clinical Recommendation | Monitor and manage patient as clinically appropriate. |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) ] . 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 D 2 and serotonin 5HT 2A receptor antagonism. 12.2 Pharmacodynamics In vitro , paliperidone acts as an antagonist at the central dopamine D 2 and serotonin 5HT 2A receptors with binding affinities (Ki values) of 1.6–2.8 nM and 0.8–1.2 nM, respectively. Paliperidone also acts as an antagonist at histamine H 1 and α 1 and α 2 adrenergic receptors with binding affinities of 32 nM, 4 nM, and 17 nM, respectively. Paliperidone has no appreciable affinity for cholinergic muscarinic or β 1 - and β 2 -adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar. 12.3 Pharmacokinetics The pharmacokinetics for INVEGA HAFYERA presented below are based on gluteal administration only. INVEGA HAFYERA delivers paliperidone over a 6-month period, compared to the 1-month or 3-month products which are administered every month or every three months, respectively. INVEGA HAFYERA doses of 1,092 mg and 1,560 mg result in paliperidone total exposure ranges that are encompassed within the exposure range for corresponding doses of 1-month paliperidone palmitate injections (PP1M) (156 mg and 234 mg) or corresponding doses of 3-month paliperidone palmitate (PP3M) injections (546 mg and 819 mg, respectively) or to corresponding once daily doses of paliperidone extended-release tablets. However, mean trough concentrations (C trough ) at the end of the dosing interval were approximately 20 – 25% lower for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate. The mean peak concentration (C max ) was higher (1.4 to 1.5-fold) for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate. Inter-subject variability in paliperidone PK parameters for INVEGA HAFYERA ranged from 42 to 48% for AUC 6months and ranged from 56 to 103% for C max . Because of the difference in pharmacokinetic profiles among the four paliperidone products, caution should be exercised when making a direct comparison of their pharmacokinetic properties. Absorption Due to its extremely low water solubility, the 6-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and is predicted to last longer than 18 months. Following gluteal injection(s) of INVEGA HAFYERA at doses of 1,092 or 1,560 mg plasma concentrations of paliperidone rise to reach maximum concentrations at a median T max of 29 to 32 days. The release profile and dosing regimen of INVEGA HAFYERA results in sustained concentrations over 6 months. The total and peak dose-normalized exposures of paliperidone following INVEGA HAFYERA administration were comparable between 1,092 mg and 1,560 mg dose levels. The median steady-state peak:trough ratio for an INVEGA HAFYERA dose is 3.1 and 3.0 following gluteal administration of 1,092 and 1,560 mg respectively. Distribution Following administration of INVEGA HAFYERA, the apparent volume of distribution of paliperidone is 1,960 L. The plasma protein binding of racemic paliperidone is 74%. Elimination Metabolism In a study with oral immediate-release 14 C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14 C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo , none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. Excretion The median apparent half-life of paliperidone following a single INVEGA HAFYERA of either 1,092 or 1,560 mg was 148 and 159 days respectively. the concentration of paliperidone remaining in the circulation 18 months after dosing of 1,560 mg 6-month paliperidone palmitate extended-release injectable suspension stopped is estimated to be 18% of the average steady-state levels. Drug Interaction Studies No specific drug interaction studies have been performed with INVEGA HAFYERA. The information below is obtained from studies with oral paliperidone. Effects of other drugs on the exposures of INVEGA HAFYERA are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max and AUC values at steady-state was observed (see Figure 1 ). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration of paliperidone, a decrease in mean C max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1) ] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. Figure 1: Effects of Other Drugs on INVEGA HAFYERA Pharmacokinetics In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2) ] . Co-administration of a single dose of an oral paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Since no significant effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium extended-release tablets and INVEGA HAFYERA. This interaction has not been studied with INVEGA HAFYERA. In vitro studies in human liver microsomes demonstrated that paliperidone 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, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone 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 HAFYERA on the exposures of other drugs are summarized in Figure 2. After oral administration of paliperidone, the steady-state C max 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 paliperidone extended-release tablets 3–15 mg/day was added to their existing valproate treatment [see Drug Interactions (7.1) ] . Figure 2: Effects of INVEGA HAFYERA on Pharmacokinetics of Other Drugs Figure 1 Figure 2 Specific Populations No specific pharmacokinetic studies have been performed with INVEGA HAFYERA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA HAFYERA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . Geriatric Patients After oral administration of paliperidone in elderly subjects, the C max and AUC increased 1.2-fold compared to young subjects. This may be attributable to age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Figure 3: Effects of Intrinsic factors on Paliperidone Pharmacokinetics Figure 3 Smokers Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Male and Female Patients Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with 6-month paliperidone palmitate extended-release injectable suspension the trough concentrations were similar between males and females. Obese Patients Lower C max was observed in overweight and obese subjects. At apparent steady state with INVEGA HAFYERA, the trough concentrations were similar among normal, overweight, and obese subjects.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) ] . 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 D 2 and serotonin 5HT 2A receptor antagonism.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics In vitro , paliperidone acts as an antagonist at the central dopamine D 2 and serotonin 5HT 2A receptors with binding affinities (Ki values) of 1.6–2.8 nM and 0.8–1.2 nM, respectively. Paliperidone also acts as an antagonist at histamine H 1 and α 1 and α 2 adrenergic receptors with binding affinities of 32 nM, 4 nM, and 17 nM, respectively. Paliperidone has no appreciable affinity for cholinergic muscarinic or β 1 - and β 2 -adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics The pharmacokinetics for INVEGA HAFYERA presented below are based on gluteal administration only. INVEGA HAFYERA delivers paliperidone over a 6-month period, compared to the 1-month or 3-month products which are administered every month or every three months, respectively. INVEGA HAFYERA doses of 1,092 mg and 1,560 mg result in paliperidone total exposure ranges that are encompassed within the exposure range for corresponding doses of 1-month paliperidone palmitate injections (PP1M) (156 mg and 234 mg) or corresponding doses of 3-month paliperidone palmitate (PP3M) injections (546 mg and 819 mg, respectively) or to corresponding once daily doses of paliperidone extended-release tablets. However, mean trough concentrations (C trough ) at the end of the dosing interval were approximately 20 – 25% lower for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate. The mean peak concentration (C max ) was higher (1.4 to 1.5-fold) for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate. Inter-subject variability in paliperidone PK parameters for INVEGA HAFYERA ranged from 42 to 48% for AUC 6months and ranged from 56 to 103% for C max . Because of the difference in pharmacokinetic profiles among the four paliperidone products, caution should be exercised when making a direct comparison of their pharmacokinetic properties. Absorption Due to its extremely low water solubility, the 6-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and is predicted to last longer than 18 months. Following gluteal injection(s) of INVEGA HAFYERA at doses of 1,092 or 1,560 mg plasma concentrations of paliperidone rise to reach maximum concentrations at a median T max of 29 to 32 days. The release profile and dosing regimen of INVEGA HAFYERA results in sustained concentrations over 6 months. The total and peak dose-normalized exposures of paliperidone following INVEGA HAFYERA administration were comparable between 1,092 mg and 1,560 mg dose levels. The median steady-state peak:trough ratio for an INVEGA HAFYERA dose is 3.1 and 3.0 following gluteal administration of 1,092 and 1,560 mg respectively. Distribution Following administration of INVEGA HAFYERA, the apparent volume of distribution of paliperidone is 1,960 L. The plasma protein binding of racemic paliperidone is 74%. Elimination Metabolism In a study with oral immediate-release 14 C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14 C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo , none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. Excretion The median apparent half-life of paliperidone following a single INVEGA HAFYERA of either 1,092 or 1,560 mg was 148 and 159 days respectively. the concentration of paliperidone remaining in the circulation 18 months after dosing of 1,560 mg 6-month paliperidone palmitate extended-release injectable suspension stopped is estimated to be 18% of the average steady-state levels. Drug Interaction Studies No specific drug interaction studies have been performed with INVEGA HAFYERA. The information below is obtained from studies with oral paliperidone. Effects of other drugs on the exposures of INVEGA HAFYERA are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max and AUC values at steady-state was observed (see Figure 1 ). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration of paliperidone, a decrease in mean C max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1) ] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. Figure 1: Effects of Other Drugs on INVEGA HAFYERA Pharmacokinetics In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2) ] . Co-administration of a single dose of an oral paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Since no significant effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium extended-release tablets and INVEGA HAFYERA. This interaction has not been studied with INVEGA HAFYERA. In vitro studies in human liver microsomes demonstrated that paliperidone 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, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone 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 HAFYERA on the exposures of other drugs are summarized in Figure 2. After oral administration of paliperidone, the steady-state C max 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 paliperidone extended-release tablets 3–15 mg/day was added to their existing valproate treatment [see Drug Interactions (7.1) ] . Figure 2: Effects of INVEGA HAFYERA on Pharmacokinetics of Other Drugs Figure 1 Figure 2 Specific Populations No specific pharmacokinetic studies have been performed with INVEGA HAFYERA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA HAFYERA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . Geriatric Patients After oral administration of paliperidone in elderly subjects, the C max and AUC increased 1.2-fold compared to young subjects. This may be attributable to age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Figure 3: Effects of Intrinsic factors on Paliperidone Pharmacokinetics Figure 3 Smokers Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Male and Female Patients Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with 6-month paliperidone palmitate extended-release injectable suspension the trough concentrations were similar between males and females. Obese Patients Lower C max was observed in overweight and obese subjects. At apparent steady state with INVEGA HAFYERA, the trough concentrations were similar among normal, overweight, and obese subjects.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 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. Known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA HAFYERA. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION 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 (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 polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate. INVEGA HAFYERA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 1,092 mg and 1,560 mg paliperidone palmitate. The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 700 mg, and 1,000 mg of paliperidone, 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 (6 mg/mL), sodium hydroxide (5.4 mg/mL), and water for injection. INVEGA HAFYERA is provided in a single-dose prefilled syringe (cyclic-olefin-copolymer) prefilled with either 700 mg (3.5 mL), or 1,000 mg (5.0 mL) paliperidone (as 1,092 mg, or 1,560 mg paliperidone palmitate) suspension with a tip cap, plunger rod, backstop and a thin walled 20G, 1½-inch safety needle. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Administer INVEGA HAFYERA by gluteal injection once every 6 months by a healthcare professional. Do not administer by any other route. ( 2.1 ) See Full Prescribing Information for complete dosing information. ( 2.2 ) Initiate INVEGA HAFYERA when the next once-a-month or every three-month paliperidone palmitate extended-release injectable suspension dose is scheduled. Dose is based on the previous once-a-month or every-three-month product. ( 2.2 ): INVEGA HAFYERA Doses for Adults Adequately Treated with Once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) Switching from the PP1M 39 mg, 78 mg and 117 mg doses was not studied. If the Last Dose of PP1M is: Initiate INVEGA HAFYERA at the Following Dose: 156 mg 1,092 mg 234 mg 1,560 mg INVEGA HAFYERA Doses for Adults Adequately Treated with Every-three-month paliperidone palmitate injectable suspension (PP3M) Switching from the PP3M 273 mg and 410 mg doses was not studied. If the Last Dose of PP3M is: Initiate INVEGA HAFYERA at the Following Dose: 546 mg 1,092 mg 819 mg 1,560 mg Missed Doses: Refer to the Full Prescribing Information. ( 2.3 ) See Full Prescribing Information for important preparation and administration information. ( 2.5 ) Moderate to severe renal impairment (creatinine clearance <50 mL/min): INVEGA HAFYERA is not recommended. ( 2.4 ) Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust dosage and stabilize the patient using PP1M before transitioning to INVEGA HAFYERA, or from PP1M to PP3M before transitioning to INVEGA HAFYERA. See appropriate table above. ( 2.4 ) 2.1 Important Dosage and Administration Information 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 [see Dosage and Administration (2.5) ] . Initiate INVEGA HAFYERA only after adequate treatment has been established with either: A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA), referred to as PP1M, once monthly for at least four months; or An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA), referred to as PP3M, once every three months for at least one three-month injection cycle. See Prescribing Information of the PP1M and PP3M products for the recommended dosage of these products. 2.2 Recommended Dosage for INVEGA HAFYERA Switching to INVEGA HAFYERA from a PP1M Product The recommended initial INVEGA HAFYERA dose is based on the previous PP1M dose (see Table 1 ). 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. Table 1. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP1M PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension Product Last Dose of PP1M 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 [see Clinical Studies (14)] . Initial Dose of INVEGA HAFYERA 156 mg 1,092 mg 234 mg 1,560 mg Switching to INVEGA HAFYERA from a PP3M Product The recommended initial INVEGA HAFYERA dose is based on the previous PP3M dose (see Table 2 ). 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. Table 2. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP3M PP3M: Every-three-month paliperidone palmitate extended-release injectable suspension Product Last Dose of PP3M There are no equivalent doses of INVEGA HAFYERA for the 273 mg or 410 mg doses of a PP3M product, which were not studied [see Clinical Studies (14)] . Initial Dose of INVEGA HAFYERA 546 mg 1,092 mg 819 mg 1,560 mg Dosing Interval and Dosage Adjustments of INVEGA HAFYERA Following the initial dose, administer INVEGA HAFYERA once every 6 months. If needed, dosage adjustment can be made every 6 months between the dose of 1,092 mg to 1,560 mg based on individual response and tolerability. Because of the potential longer duration of INVEGA HAFYERA, the patient's response to an adjusted dose may not be apparent for several months [see Clinical Pharmacology (12.3) ] . 2.3 Missed Doses 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 re-initiation regimens described in Tables 3 and 4. 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 shown in Table 3: Table 3. 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 HAFYERA Administer PP1M Product PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension into deltoid muscle Administer INVEGA HAFYERA into gluteal muscle Day 1 1 month after Day 1 1,092 mg 156 mg 1,092 mg 1,560 mg 234 mg 1,560 mg 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 shown in Table 4: Table 4. Re-initiation Regimen for Missed Dose (8 months up to and including 11 months since last dose) Last dose of INVEGA HAFYERA Administer PP1M Product PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension into deltoid muscle Administer INVEGA HAFYERA into gluteal muscle Day 1 Day 8 1 month after Day 8 1,092 mg 156 mg 156 mg 1,092 mg 1,560 mg 156 mg 156 mg 1,560 mg 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. 2.4 Dosage Recommendations in Patients with Renal Impairment INVEGA HAFYERA 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]), adjust dosage and stabilize the patient using PP1M before transitioning from PP1M to INVEGA HAFYERA, or from PP1M to PP3M before transitioning to INVEGA HAFYERA (see Table 1 ) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. Refer to the Prescribing Information of PP1M or PP3M product for the recommended PP1M or PP3M dosage in patients with mild renal impairment. INVEGA HAFYERA 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) ] . 2.5 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. Incomplete Administration Proper shaking can reduce the likelihood for an incomplete injection. Storing the carton in a horizontal orientation improves the ability to resuspend this highly concentrated product [see How Supplied/Storage and Handling (16) ] . Follow the full instructions for preparation and administration to avoid an incomplete injection. 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 HAFYERA. Closely monitor and treat the patient with oral paliperidone supplementation as clinically appropriate until the next scheduled 6-month injection of INVEGA HAFYERA. See Prescribing Information of the oral paliperidone product for the recommended dosage of these products. Administer every 6 months 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. For Gluteal Intramuscular injection only. Preparation INVEGA HAFYERA requires longer and faster shaking than once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA). INVEGA HAFYERA must be administered by a healthcare professional as a single injection. Do not divide dose into multiple injections. INVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel. Dosing Administer INVEGA HAFYERA once every 6 months . 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. Dose pack contents Prefilled Syringe Thin Wall Safety Needle 20G × 1½" Only use the needle included in this kit 1. Prepare for the injection: this highly concentrated product requires specific steps to resuspend Hold syringe with the tip cap pointing up Syringe tip cap pointing up Shake syringe VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds To ensure complete resuspension shake syringe with: Short, VERY FAST up and down motion Loose wrist Proceed to the next step immediately after shaking. Check suspension for solid product Mixed well Not mixed well STOP Uniform, thick and milky white It is normal to see air bubbles Solid product on sides and top of syringe Uneven mix Thin liquid Product may clog. Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds. Open needle pouch Peel off the pouch cover. Place pouch with the needle inside on a clean surface. Remove syringe tip cap and attach needle Hold the syringe with the tip cap pointing up. Twist and pull off the cap. 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 leakage prior to administration. 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. 2. 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. Do not touch , fan or blow on the injection site after you have cleaned it. 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. Remove needle from the muscle. 3. After the 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 you hear a "click" sound. Dispose of properly and check injection site Dispose of the syringe in an approved sharps container. There may be a small amount of blood or liquid at the injection site. Hold pressure over the skin with a cotton ball or gauze pad until any bleeding stops. Do not rub the injection site. If needed, cover injection site with a bandage. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image
| If the Last Dose of PP1M is: | Initiate INVEGA HAFYERA at the Following Dose: |
|---|---|
| 156 mg | 1,092 mg |
| 234 mg | 1,560 mg |
| If the Last Dose of PP3M is: | Initiate INVEGA HAFYERA at the Following Dose: |
|---|---|
| 546 mg | 1,092 mg |
| 819 mg | 1,560 mg |
| Last Dose of PP1M | Initial Dose of INVEGA HAFYERA |
|---|---|
| 156 mg | 1,092 mg |
| 234 mg | 1,560 mg |
| Last Dose of PP3M | Initial Dose of INVEGA HAFYERA |
|---|---|
| 546 mg | 1,092 mg |
| 819 mg | 1,560 mg |
| Last Dose of INVEGA HAFYERA | Administer PP1M Product | Administer INVEGA HAFYERA into gluteal muscle |
|---|---|---|
| Day 1 | 1 month after Day 1 | |
| 1,092 mg | 156 mg | 1,092 mg |
| 1,560 mg | 234 mg | 1,560 mg |
| Last dose of INVEGA HAFYERA | Administer PP1M Product | Administer INVEGA HAFYERA into gluteal muscle | |
|---|---|---|---|
| Day 1 | Day 8 | 1 month after Day 8 | |
| 1,092 mg | 156 mg | 156 mg | 1,092 mg |
| 1,560 mg | 156 mg | 156 mg | 1,560 mg |
| INVEGA HAFYERA requires | |
| Administer INVEGA HAFYERA | |
| Thin wall safety needle is designed to be used with INVEGA HAFYERA. Therefore, it is important to | |
| |
| Proceed to the next step immediately after shaking. | |
|
|
| Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds. | |
| Peel off the pouch cover. Place pouch with the needle inside on a clean surface. | |||
| Hold the syringe with the tip cap pointing up. Twist and pull off the cap. 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 leakage prior to administration. | |||
| Remove needle from the muscle. | |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS INVEGA HAFYERA is a white to off-white aqueous extended-release injectable suspension for gluteal intramuscular injection in dose strengths of 1,092 mg/3.5 mL and 1,560 mg/5 mL paliperidone palmitate in single-dose prefilled syringes. Extended-release injectable suspension: 1,092 mg/3.5 mL or 1,560 mg/5 mL single-dose prefilled syringes. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE INVEGA HAFYERA, an every-six-month injection, is 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, 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. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.INVEGA HAFYERA paliperidone palmitate CITRIC ACID MONOHYDRATE POLYETHYLENE GLYCOL 4000 SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE INVEGA HAFYERA paliperidone palmitate CITRIC ACID MONOHYDRATE POLYETHYLENE GLYCOL 4000 SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology Injection site toxicity was assessed in minipigs injected intramuscularly with the 6-month paliperidone palmitate extended-release injectable suspension at doses up to 2,115 mg, which is slightly above the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate extended-release injectable suspension. Reversibility of these findings was not examined.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which are ~0.7, 2 and 4 times, respectively, the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at ~2 and 4 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. 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 maximum recommended human dose of risperidone based on mg/m 2 body surface area (see risperidone 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 D 2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.10) ] . Mutagenesis Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test. Impairment of Fertility No fertility studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the oral MRHD of 12 mg based on mg/m 2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at an oral dose of 0.63 mg/kg, which is half of the oral MRHD of 12 mg based on mg/m 2 body surface area. The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the oral MRHD of 12 mg/day based on mg/m 2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg – 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m 2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which are ~0.7, 2 and 4 times, respectively, the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at ~2 and 4 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. 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 maximum recommended human dose of risperidone based on mg/m 2 body surface area (see risperidone 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 D 2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.10) ] . Mutagenesis Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test. Impairment of Fertility No fertility studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the oral MRHD of 12 mg based on mg/m 2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at an oral dose of 0.63 mg/kg, which is half of the oral MRHD of 12 mg based on mg/m 2 body surface area. The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the oral MRHD of 12 mg/day based on mg/m 2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg – 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m 2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after 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 6-month paliperidone palmitate extended-release injectable suspension at doses up to 2,115 mg, which is slightly above the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate extended-release injectable suspension. Reversibility of these findings was not examined.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 3.5 mL Syringe Carton NDC 50458-611-01 Single-dose prefilled syringe. Use entire contents of syringe. INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY Each injection must be administered only by a healthcare professional. Shake before using. CONTENTS: 1 single-dose prefilled syringe and 1 needle (a 20G,1.5-inch thin wall safety needle). Recommended Dosage: See Prescribing Information. Rx only 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. SHIP AND STORE THIS SIDE UP LAY FLAT 1,092 mg/3.5 mL Each single-dose prefilled syringe contains 1,092 mg paliperidone palmitate. 6 MONTHS Administer every 6 months Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds PRINCIPAL DISPLAY PANEL - 3.5 mL Syringe Carton
PRINCIPAL DISPLAY PANEL - 5 mL Syringe Carton NDC 50458-612-01 Single-dose prefilled syringe. Use entire contents of syringe. INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY Each injection must be administered only by a healthcare professional. Shake before using. CONTENTS: 1 single-dose prefilled syringe and 1 needle (a 20G,1.5-inch thin wall safety needle). Recommended Dosage: See Prescribing Information. Rx only 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. SHIP AND STORE THIS SIDE UP LAY FLAT 1,560 mg/5 mL Each single-dose prefilled syringe contains 1,560 mg paliperidone palmitate. 6 MONTHS Administer every 6 months Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds PRINCIPAL DISPLAY PANEL - 5 mL Syringe Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Dosage and Administration ( 2.4 , 2.5 ) 9/2024
| Dosage and Administration ( | 9/2024 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.INVEGA HAFYERA (paliperidone palmitate) Extended-Release Injectable Suspension INVEGA TRINZA ® , 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, USA For patent information: www.janssenpatents.com © 2021 Janssen Pharmaceutical Companies
INVEGA HAFYERA: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.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 [see Warnings and Precautions (5.3) ] . Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.5) ] . 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 [see Warnings and Precautions (5.6) ] . Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7) ] . 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 HAFYERA [see Warnings and Precautions (5.9) ] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA HAFYERA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.10) ]. Interference with Cognitive and Motor Performance As INVEGA HAFYERA 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 HAFYERA therapy does not affect them adversely [see Warnings and Precautions (5.11) ] . 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 [see Warnings and Precautions (5.14) ] . Heat Exposure and Dehydration Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.15) ] . 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 [see Drug Interactions (7) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA HAFYERA. Advise patients that INVEGA HAFYERA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA HAFYERA during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise breastfeeding women using INVEGA HAFYERA to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ] . Infertility Advise females of reproductive potential that INVEGA HAFYERA may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3) ] .
Instructions for use
Information about safe handling and use of the drug product.INSTRUCTIONS FOR USE INVEGA HAFYERA ® in-VAY-guh HAF-ye-RA (paliperidone palmitate) extended-release injectable suspension For Gluteal Intramuscular Injection Only Administer every 6 months Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds Important Shipping and storing the carton in a horizontal orientation improves the ability to resuspend this highly concentrated product. INVEGA HAFYERA must be administered by a healthcare professional as a single injection. Do not divide dose into multiple injections. INVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel. Dosing Administer INVEGA HAFYERA once every 6 months. 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. Dose pack contents Prepare for the injection: this highly concentrated product requires specific steps to resuspend Hold syringe with the tip cap pointing up Shake syringe VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds To ensure complete resuspension shake syringe with: Short, VERY FAST up and down motion Loose wrist Proceed to the next step immediately after shaking. Check suspension for solid product Uniform, thick and milky white It is normal to see air bubbles Solid product on sides and top of syringe Uneven mix Thin liquid Product may clog. Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds. Open needle pouch Peel off the pouch cover. Place pouch with the needle inside on a clean surface. Remove syringe tip cap and attach needle Hold the syringe with the tip cap pointing up. Twist and pull off the cap. 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 leakage prior to administration. 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. Do not touch, fan or blow on the injection site after you have cleaned it. 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. While the needle is in the gluteal muscle, confirm that the entire content of the syringe has been injected. Remove needle from the muscle. After the 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 you hear a "click" sound. Dispose of properly and check injection site Dispose of the syringe in an approved sharps container. There may be a small amount of blood or liquid at the injection site. Hold pressure over the skin with a cotton ball or gauze pad until any bleeding stops. Do not rub the injection site. If needed, cover injection site with a bandage. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 9/2024 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 For patent information: www.janssenpatents.com © 2021 Janssen Pharmaceutical Companies Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image
|
| |
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: September 2024 PATIENT INFORMATION INVEGA HAFYERA ® (in-VAY-guh HAF-ye-RA) (paliperidone palmitate) extended-release injectable suspension What is the most important information I should know about INVEGA HAFYERA? INVEGA HAFYERA may cause serious side effects, including: Increased risk of death in elderly people with dementia-related psychosis. INVEGA HAFYERA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). INVEGA HAFYERA is not for the treatment of people with dementia-related psychosis. What is INVEGA HAFYERA? INVEGA HAFYERA is a prescription medicine given by injection by a healthcare provider 1 time every 6 months and used for the treatment of schizophrenia in adults who have been adequately treated with either: A 1 time each month paliperidone palmitate extended-release injectable suspension for at least 4 months. A 1 time every 3 months paliperidone palmitate extended-release injectable suspension for at least 3 months. It is not known if INVEGA HAFYERA is safe and effective in children under 18 years of age. Do not receive INVEGA HAFYERA if you are allergic to paliperidone palmitate, risperidone, or any of the ingredients in INVEGA HAFYERA. See the end of this Patient Information leaflet for a complete list of ingredients in INVEGA HAFYERA. Before receiving INVEGA HAFYERA, tell your healthcare provider about all your medical conditions, including if you: have had Neuroleptic Malignant Syndrome (NMS) have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome have or have had low levels of potassium or magnesium in your blood have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) have or have had kidney or liver problems have diabetes or have a family history of diabetes have Parkinson's disease or a type of dementia called Lewy Body Dementia have had a low white blood cell count have had problems with dizziness or fainting or are being treated for high blood pressure have or have had seizures or epilepsy are pregnant or plan to become pregnant. It is not known if INVEGA HAFYERA will harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INVEGA HAFYERA. If you become pregnant while receiving INVEGA HAFYERA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Babies born to mothers who receive INVEGA HAFYERA during their third trimester of pregnancy may develop agitation, low muscle tone (floppy baby syndrome) tremors, excessive sleepiness, breathing problems, and feeding problems. Tell your healthcare provider right away if your baby develops any of these symptoms. are breastfeeding or plan to breastfeed. INVEGA HAFYERA can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with INVEGA HAFYERA. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. INVEGA HAFYERA and other medicines may affect each other causing possible serious side effects. INVEGA HAFYERA may affect the way other medicines work, and other medicines may affect how INVEGA HAFYERA works. Your healthcare provider can tell you if it is safe to receive INVEGA HAFYERA with your other medicines. Do not start or stop any medicines during treatment with INVEGA HAFYERA without talking to your healthcare provider first. 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 HAFYERA? Follow your INVEGA HAFYERA treatment schedule exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much INVEGA HAFYERA you will receive and when you will receive it. INVEGA HAFYERA is given as an injection by your healthcare provider into the muscle (intramuscularly) of your buttocks, 1 time every 6 months. What should I avoid while receiving INVEGA HAFYERA? Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you. INVEGA HAFYERA may affect your judgment, thinking, or motor skills. Avoid getting too hot or dehydrated. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. What are the possible side effects of INVEGA HAFYERA? INVEGA HAFYERA may cause serious side effects, including: See " What is the most important information I should know about INVEGA HAFYERA? " Cerebrovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death. Neuroleptic Malignant Syndrome (NMS), a serious condition that can lead to death. Call your healthcare provider or go to your nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: high fever confusion changes in your breathing, pulse, heart rate, and blood pressure stiff muscles sweating Problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms: passing out or feeling like you will pass out dizziness feeling as if your heart is pounding or missing beats Uncontrolled body movements (tardive dyskinesia). INVEGA HAFYERA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving INVEGA HAFYERA. Tardive dyskinesia may also start after you stop receiving INVEGA HAFYERA. Problems with your metabolism such as: high blood sugar (hyperglycemia) and diabetes . Increases in blood sugar can happen in some people who receive INVEGA HAFYERA. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start and regularly during treatment with INVEGA HAFYERA. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with INVEGA HAFYERA: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood. Your healthcare provider should check the fat levels in your blood before you start and regularly during treatment with INVEGA HAFYERA. weight gain. You and your healthcare provider should check your weight before you start and often during treatment with INVEGA HAFYERA. Decreased blood pressure (orthostatic hypotension) and fainting. You may feel lightheaded or faint when you rise too quickly from a sitting or lying position, especially early in treatment or when the dose is changed. Falls. INVEGA HAFYERA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with INVEGA HAFYERA. Increased prolactin levels in your blood (hyperprolactinemia). INVEGA HAFYERA may cause a rise in the blood levels of a hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, a reversible reduction in fertility in females who are able to become pregnant, leakage of milk from the breasts, development of breasts in men, or problems with erection. INVEGA HAFYERA can make you sleepy or dizzy, and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you. Seizures (convulsions). Difficulty swallowing that can cause food or liquid to get into your lungs. Prolonged or painful erection lasting more than 4 hours (priapism). Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours. Problems controlling your body temperature so that you feel too warm. See, " What should I avoid while receiving INVEGA HAFYERA? " The most common side effects of INVEGA HAFYERA include: upper respiratory tract infections weight gain feeling restlessness or difficulty sitting still tremors shuffling walk injection site reactions headache slow movements stiffness These are not all the possible side effects of INVEGA HAFYERA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about INVEGA HAFYERA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about INVEGA HAFYERA that is written for health professionals. What are the ingredients in INVEGA HAFYERA? Active ingredient : paliperidone 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, USA For patent information: www.janssenpatents.com © 2021 Janssen Pharmaceutical Companies For more information, go to www.invegahafyerahcp.com or call 1-800-526-7736.
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: September 2024 | |||
| ||||
| ||||
| ||||
| ||||
| ||||
| ||||
|
| |||
| ||||
|
| |||
| ||||
| ||||
|
| |||
| These are not all the possible side effects of INVEGA HAFYERA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES The efficacy of INVEGA HAFYERA for the treatment of schizophrenia in patients who had previously been stably treated with either PP1M for at least 4 months or PP3M for at least one 3-month injection cycle was evaluated in a randomized, double-blind, active-controlled, interventional, parallel-group, multicenter, non-inferiority study designed to evaluate time to relapse in adults with a DSM-5 diagnosis of schizophrenia. Patients could enter the study if previously treated with PP1M at dosages of 156 or 234 mg, PP3M at dosages of 546 or 819 mg, injectable risperidone at dosages of 50 mg, or any oral antipsychotic with a reason to change (e.g., efficacy, safety, tolerability, or a preference for a long-acting injectable medication) and with a PANSS total score of <70 points. After establishing tolerability with PP1M (at dosages of 156 or 234 mg) or PP3M (at dosages of 546 or 819 mg) and clinical stability, defined by having a PANSS total score of <70 points for the previous 2 assessments prior to the double-blind phase, patients were randomized in a 2:1 ratio to receive INVEGA HAFYERA (478 patients) or PP3M (224 patients). The primary efficacy variable was time to first relapse in the double-blind phase. The primary efficacy analysis was based on the difference in Kaplan-Meier 12-month estimates of percentage of subjects remaining relapse-free between INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. 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: 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 relapse event was experienced by 7.5% and 4.9% of patients in the INVEGA HAFYERA and PP3M treatment groups, respectively, with the Kaplan-Meier estimated difference (INVEGA HAFYERA – PP3M) of 2.9% (95% CI: -1.1 to 6.8). The upper bound of the 95% CI (6.8%) was less than 10%, the prespecified non-inferiority margin. The study demonstrated non-inferiority of INVEGA HAFYERA to PP3M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4. Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse Over Time An evaluation of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race. Figure 4
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use The clinical study of INVEGA HAFYERA 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 substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3) ] . Because elderly patients are more likely to have decreased renal function, INVEGA HAFYERA is not recommended to be used in elderly patients with mild, moderate or severe renal impairment [see Use in Specific Populations (8.6) ] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 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. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies. Juvenile Animal Studies No juvenile animal studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. 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.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA HAFYERA, 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 HAFYERA during pregnancy (see Clinical Considerations ) . 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. [See Clinical Pharmacology (12.3) ] . The clinical significance of INVEGA HAFYERA 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 or when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis. 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 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. 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 No developmental toxicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is ~10 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release injectable suspension 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 oral 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 MRHD. 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 2 body 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA HAFYERA, 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 HAFYERA during pregnancy (see Clinical Considerations ) . 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. [See Clinical Pharmacology (12.3) ] . The clinical significance of INVEGA HAFYERA 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 or when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis. 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 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. 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 No developmental toxicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is ~10 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release injectable suspension 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 oral 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 MRHD. 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 2 body 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. 8.2 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 18 months after a single-dose administration of 3-month paliperidone palmitate extended-release injectable suspension. The clinical significance on the breastfed infant is not known [see Clinical Pharmacology (12.3) ] . 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. Clinical Considerations Infants exposed to INVEGA HAFYERA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of paliperidone (D 2 receptor antagonism), treatment with INVEGA HAFYERA 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) ] . 8.4 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. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies. Juvenile Animal Studies No juvenile animal studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension. 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. 8.5 Geriatric Use The clinical study of INVEGA HAFYERA 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 substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3) ] . Because elderly patients are more likely to have decreased renal function, INVEGA HAFYERA is not recommended to be used in elderly patients with mild, moderate or severe renal impairment [see Use in Specific Populations (8.6) ] . 8.6 Renal Impairment Use of INVEGA HAFYERA is not recommended for use in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min). Use of INVEGA HAFYERA in patients with mild renal impairment (creatinine clearance ≥50 mL/min to <80 mL/min) is based on the patient’s previous dose of PP1M or PP3M before transitioning to INVEGA HAFYERA [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.7 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 [see Clinical Pharmacology (12.3) ] . 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 HAFYERA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING INVEGA HAFYERA ® is available as a white to off-white sterile aqueous extended-release suspension for gluteal intramuscular injection in dose strengths of 1,092 mg/3.5 mL and 1,560 mg/5 mL paliperidone palmitate. The kit contains a single-dose prefilled syringe and a 20G, 1½-inch safety needle. 1,092 mg paliperidone palmitate kit (NDC 50458-611-01) 1,560 mg paliperidone palmitate kit (NDC 50458-612-01) 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. Do not mix with any other product or diluent. Ship and store in a horizontal position. See arrows on product carton for proper orientation.
Storage and handling
Information about safe storage and handling of the drug product.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. Do not mix with any other product or diluent. Ship and store in a horizontal position. See arrows on product carton for proper orientation.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.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 HAFYERA 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. INVEGA HAFYERA is not approved for use in patients with dementia-related psychosis. ( 5.1 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API