Invega Hafyera Drug Information

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 days in the INVEGA HAFYERA group and 336.4 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: the Simpson-Angus Rating Scale Global Score which broadly evaluates parkinsonism, the Barnes Akathisia Rating Scale Global Clinical Rating Score which evaluates akathisia, the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and use of anticholinergic medications to treat EPS (Table 8) and 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

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 section of the Prescribing Information for those products.

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 . 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 . Clinical Recommendation Monitor orthostatic vital signs in patients who are vulnerable to hypotension . 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 . 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 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.

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 . Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA HAFYERA . 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.

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. . 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.

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.

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.

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.