INVEGA HAFYERA

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

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 )

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

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 )

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 1-800-526-7736 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.

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) ].

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.