RYKINDO EXTENDED-RELEASE MICROSPHERES

RYKINDO contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.5 g/mol. The structural formula is: Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. RYKINDO is provided as a single-dose kit consisting of: a vial containing a white to almost white powder, a pre-filled syringe containing 2 mL of a colorless, clear diluent, a vial adapter, and a needle (a 20 gauge 2-inch needle with needle protection device). The vial contains a white to almost white sterile powder containing risperidone. The powder consists of risperidone, mannitol (5.38 mg/100 mg risperidone), polylactide-co-glycolide (PLGA) 5050 (24.2 mg/100 mg risperidone) and polylactide-co-glycolide (PLGA) 7525 (96.7 mg/100 mg risperidone). The diluent is a sterile, clear, colorless, 2 mL solution. The diluent contains: 1.10 mg/mL citric acid monohydrate, 1.02 mg/mL dibasic sodium phosphate anhydrous, 1 mg/mL polysorbate 80, 9 mg/mL sodium carboxymethyl cellulose, 7.5 mg/mL sodium chloride, 0.54 mg/mL sodium hydroxide, and water. RYKINDO (risperidone) for extended-release injectable suspension, for intramuscular use is, when fully mixed, a white suspension, available in strengths of 25 mg, 37.5 mg, or 50 mg. Chemical Structure

RYKINDO is indicated: for the treatment of schizophrenia in adults as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults RYKINDO is an atypical antipsychotic indicated: for the treatment of schizophrenia in adults. ( 1 ) as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults. ( 1 )

Establish tolerability with oral risperidone prior to initiating treatment with RYKINDO . ( 2.1 ) Administer RYKINDO by intramuscular (IM) injection in the gluteal muscle by a healthcare provider. Do not administer by any other route. ( 2.1 ) Recommended dosage of RYKINDO is 25 mg intramuscular (IM) every 2 weeks. Patients not responding to 25 mg may benefit from 37.5 mg or 50 mg. Dosage titration should not be made more frequently than every 4 weeks. The maximum recommended dosage should not exceed 50 mg every 2 weeks. ( 2.2 , 2.3 ) Administer the first dose of RYKINDO along with 7 days of oral risperidone. ( 2.2 , 2.3 ) Renal or Hepatic Impairment: Titrate with oral risperidone up to at least 2 mg prior to initiating treatment with RYKINDO. ( 2.6 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.8 ) 2.1 General Administration Information For patients who have never taken oral risperidone, establish tolerability with oral risperidone prior to initiating RYKINDO. RYKINDO should be administered every 2 weeks by intramuscular (IM) gluteal injection. Each injection should be administered by a health care professional. Do not administer by any other route. Alternate injections between the two buttocks. Do not combine two different dose strengths of RYKINDO in a single administration. For detailed preparation and administration instructions, see Dosage and Administration (2.8) . 2.2 Dosage Recommendations for the Treatment of Schizophrenia The recommended dosage of RYKINDO for the treatment of schizophrenia is 25 mg every 2 weeks. Administer the first dose of RYKINDO along with 7 days of oral risperidone. Patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg every 2 weeks. No additional benefit was observed with dosages greater than 50 mg of risperidone long-acting injection (intramuscular); however, a higher incidence of adverse reactions was observed. Dose titration should not be made more frequently than every 4 weeks. 2.3 Dosage Recommendations for Maintenance Treatment of Bipolar I Disorder The recommended dosage of RYKINDO for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder is 25 mg every 2 weeks. Administer the first dose of RYKINDO along with 7 days of oral risperidone. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. Dose titration should not be made more frequently than every 4 weeks. 2.4 Patients Currently Receiving Risperidone Long-acting Injection 2-week Intramuscular Formulation (e.g., Risperdal Consta) The RYKINDO dose for patients receiving a risperidone long-acting injection (intramuscular) every two week formulation (e.g., Risperdal Consta) should be the same as that of the previous treatment. The first injection of RYKINDO should be given 4 weeks (no later than 5 weeks) after the last injection of the previous treatment. Supplementation with oral risperidone is not recommended [see Clinical Pharmacology (12.3) ] . Titration should not be made more frequently than every 4 weeks. 2.5 Reinitiation of Treatment in Patients Previously Discontinued There are no data to specifically address reinitiation of treatment. When restarting patients who have had an interval off treatment with RYKINDO, the previously established dosage should be reinitiated if there has been no change in the patient's general medical condition. Supplementation with oral risperidone is also required. 2.6 Dosage Recommendations for Patients with Renal or Hepatic Impairment Patients with renal or hepatic impairment should be treated with titrated oral risperidone prior to initiating treatment with RYKINDO [see Use in Specific Populations (8.6 , 8.7) and Clinical Pharmacology (12.3) ] . The recommended starting dose is 0.5 mg oral risperidone twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral risperidone is well tolerated, RYKINDO 25 mg can be administered every 2 weeks with oral supplementation for 7 days following the first injection [see Dosing and Administration (2.2 , 2.3) ] . In some patients, slower titration may be appropriate. 2.7 Dosage Recommendations for Concomitant Use of RYKINDO with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Co-administration of carbamazepine and other CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RYKINDO treatment. The risperidone dose needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.1) ]. At the initiation of therapy with carbamazepine or other known CYP3A4 hepatic enzyme inducers, patients should be closely monitored during the first 1 to 2 months because the dose of RYKINDO may need to be adjusted. A dose increase, or additional oral risperidone, needs to be considered. On discontinuation of carbamazepine or other CYP3A4 hepatic enzyme inducers, the dosage of RYKINDO should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RYKINDO and discontinuing from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates either lowering the dose to 12.5 mg, in which case a different risperidone long-acting injection intramuscular formulation should be used, or interruption of RYKINDO treatment. Fluoxetine and paroxetine, CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5 to 2.8-fold and 3 to 9-fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly when co-administering fluoxetine or paroxetine. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RYKINDO. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RYKINDO it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates either lowering the dose to 12.5 mg, in which case a different risperidone long-acting injection intramuscular formulation should be used, or interruption of RYKINDO treatment. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Drug Interactions (7.1) ]. 2.8 Preparation and Administration Instructions Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider "Instructions for Use" for additional preparation and administration considerations. For gluteal intramuscular injection only. Do not inject by any other route. Alternate injections between the two buttocks. Allow package to come to room temperature for at least 30 minutes prior to preparation. Prepare medication when you are ready to administer the dose. The components in the single-dose kit are shown in Figure 1. Figure 1. Single-dose Kit Components Step 1. Take out kit and connect vial adapter to vial Wait 30 minutes Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting. Do not warm any other way. Remove cap from vial Flip off colored cap from vial. Wipe top of the gray stopper with an alcohol swab. Allow to air dry. Do not remove gray rubber stopper. Prepare vial adapter Hold sterile blister as shown. Peel back and remove paper backing. Do not remove vial adapter from blister. Do not touch spike tip at any time. This will result in contamination. Connect vial adapter to vial Place vial on a hard surface and hold by the base. Center vial adapter over the gray rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial. Step 2. Connect prefilled syringe to vial adapter Remove sterile blister Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination. Use proper grip Hold by the LUER-LOK ADAPTER at the tip of the syringe. Do not hold syringe by the glass barrel during assembly. Remove cap Holding the transparent LUER-LOK ADAPTER, unscrew the translucent gray cap Do not snap or cut off the translucent gray cap Do not touch syringe tip. This will result in contamination. The unscrewed cap can be discarded. Connect syringe to vial adapter Hold vial adapter by skirt to keep stationary. Hold syringe by the LUER-LOK ADAPTER then turn it to connect with the luer opening of the vial adapter Do not hold the glass syringe barrel. This may cause the LUER-LOK ADAPTER to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break. Step 3. Reconstitute powder Inject diluent Inject entire amount of diluent from syringe into the vial. Suspend Powder in diluent Continuing to hold down the plunger rod, shake vigorously for at least 30 seconds , as shown. Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in color. Immediately proceed to the next step so suspension does not settle. Transfer suspension to syringe Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. Remove vial adapter Hold LUER-LOK ADAPTER on the syringe and unscrew from vial adapter. Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. Discard both vial and vial adapter appropriately. Step 4. Attach Needle Take out needle Take out needle for gluteal injection. Attach needle Peel blister pouch open part way and use to grasp the base of the needle, as shown. Holding the LUER-LOK ADAPTER on the syringe, attach syringe to needle luer connection with a firm clockwise twisting motion until snug. Do not touch needle luer opening. This will result in contamination. Resuspend Powder Fully remove the blister pouch. Just before injection, shake syringe vigorously for 20 to 30 seconds until there is no deposition of powder, as some settling will have occurred. Step 5. Inject RYKINDO Remove transparent needle protector Move the needle safety device back towards the syringe, as shown. Then hold the LUER-LOK ADAPTER on syringe and carefully pull the transparent needle protector straight off. Do not twist transparent needle protector, as the luer connection may loosen. Remove air bubbles Hold syringe upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air. Inject Immediately inject entire contents of syringe intramuscularly into the upper-outer quadrant of the gluteal muscle of the patient. Secure needle in safety device Using one hand, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. Properly dispose of syringes Check to confirm needle safety device is fully engaged. Discard in an approved sharps container. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

RYKINDO is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Known hypersensitivity to risperidone, paliperidone, or to any components in RYKINDO. ( 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 (NMS) [see Warnings and Precautions (5.3) ] Tardive dyskinesia [see Warnings and Precautions (5.4) ] Metabolic changes [see Warnings and Precautions (5.5) ] Hyperprolactinemia [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) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Dysphagia [see Warnings and Precautions (5.12) ] Priapism [see Warnings and Precautions (5.13) ] Body temperature dysregulation [see Warnings and Precautions (5.14) ] Osteodystrophy and tumors in animals [see Warnings and Precautions (5.15) ] The most common adverse reactions in patients with schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremity, and dry mouth. ( 6 ) The most common adverse reactions in patients with bipolar disorder were (5% in monotherapy trial) weight increased and (≥ 10% in adjunctive therapy trial) tremor and parkinsonism. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Shandong Luye Pharmaceutical Co., Ltd. at 1-800-548-9765 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of RYKINDO for the treatment of schizophrenia in adults and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder in adults is based on adequate and well-controlled studies of risperidone long-acting injection (intramuscular). The data described in this section are derived from a clinical trial database consisting of 2,392 patients exposed to one or more doses of risperidone long-acting injection (intramuscular) for the treatment of schizophrenia. Of these 2,392 patients, 332 patients received risperidone long-acting injection (intramuscular) while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were patients with schizophrenia who received 25 mg or 50 mg risperidone long-acting injection (intramuscular). The conditions and duration of treatment with risperidone long-acting injection (intramuscular) in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. Safety data are also presented from a trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) administered as adjunctive maintenance treatment in patients with bipolar disorder (intramuscular). The most common adverse reactions in clinical trials of risperidone long-acting injection (intramuscular) in patients with schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity, and dry mouth. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials of risperidone long-acting injection (intramuscular) were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the adjunctive treatment trial). Table 4 lists the adverse reactions reported in 2% or more of risperidone long-acting injection-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial. Table 4. Adverse Reactions Occurring in ≥2% of Risperidone Long-acting Injection (intramuscular)-Treated Patients (Adults) with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial Risperidone Long-acting Injection (intramuscular) Placebo System/Organ Class Adverse Reaction 25 mg % 50 mg % % (N=99) (N=103) (N=98) Eye disorders Vision blurred 2 3 0 Gastrointestinal disorders Constipation 5 7 1 Dry mouth 0 7 1 Dyspepsia 6 6 0 Nausea 3 4 5 Toothache 1 3 0 Salivary hypersecretion 4 1 0 General disorders and administration site conditions Fatigue Fatigue includes fatigue and asthenia. 3 9 0 Edema peripheral 2 3 1 Pain 4 1 0 Pyrexia 2 1 0 Infections and infestations Upper respiratory tract infection 2 0 1 Investigations Weight increased 5 4 2 Weight decreased 4 1 1 Musculoskeletal and connective tissue disorders Pain in extremity 6 2 1 Nervous system disorders Headache 15 21 12 Parkinsonism Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. 8 15 9 Dizziness 7 11 6 Akathisia Akathisia includes akathisia and restlessness. 4 11 6 Sedation Sedation includes sedation and somnolence. 5 6 3 Tremor 0 3 0 Syncope 2 1 0 Hypoesthesia 2 0 0 Respiratory, thoracic and mediastinal disorders Cough 4 2 3 Sinus congestion 2 0 0 Skin and subcutaneous tissue disorders Acne 2 2 0 Dry skin 2 0 0 Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder Table 5 lists the adverse reactions reported in 2% or more of risperidone long-acting injection (intramuscular)-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder. Table 5. Adverse Reactions in ≥2% of Adult Patients with Bipolar I Disorder Treated with Risperidone Long-acting Injection (intramuscular) as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Risperidone Long-acting Injection (intramuscular) (N=154) % Placebo (N=149) % Investigations Weight increased 5 1 Nervous system disorders Dizziness 3 1 Vascular disorders Hypertension 3 1 Table 6 lists the adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of risperidone long-acting injection as adjunctive maintenance treatment in patients with bipolar disorder. Table 6. Adverse Reactions Occurring in ≥ 4% of Adult Patients with Bipolar I Disorder Treated with Risperidone Long-acting Injection (intramuscular) as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Risperidone Long-acting Injection (intramuscular) + Treatment as Usual Patients received double-blind risperidone long-acting injection (intramuscular) or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. (N=72) % Placebo + Treatment as Usual (N=67) % General disorders and administration site conditions Gait abnormal 4 0 Infections and infestations Upper respiratory tract infection 6 3 Investigations Weight increased 7 1 Metabolism and nutrition disorders Decreased appetite 6 1 Increased appetite 4 0 Musculoskeletal and connective tissue disorders Arthralgia 4 3 Nervous system disorders Tremor 24 16 Parkinsonism Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. 15 6 Dyskinesia Dyskinesia includes muscle twitching and dyskinesia. 6 3 Sedation Sedation includes sedation and somnolence. 7 1 Disturbance in attention 4 0 Reproductive system and breast disorders Amenorrhea 4 1 Respiratory, thoracic and mediastinal disorders Cough 4 1 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred in < 2% of the risperidone long-acting injection (intramuscular)-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the risperidone long-acting injection (intramuscular) -treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the risperidone long-acting injection (intramuscular)-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in risperidone long-acting injection (intramuscular)-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled, and open-label studies in schizophrenia and bipolar disorder. Blood and lymphatic system disorders: anemia, neutropenia Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain, vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reduced Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall, procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported with Oral Risperidone Additional adverse reactions that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence, include the following: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricular block Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rate increased, eosinophil count increased, WBC count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome (NMS), diabetic coma, head titubation Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listlessness, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Reactions Schizophrenia Approximately 11% (22/202) of risperidone long-acting (intramuscular)-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse reaction, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more risperidone long-acting injection (intramuscular)-treated patients were agitation (3%), depression (2%), anxiety (1%), and akathisia (1%). Bipolar Disorder In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 risperidone long-acting injection (intramuscular)-treated patients discontinued due to an adverse reaction (hyperglycemia). In the 52-week double-blind phase of the placebo-controlled trial in which risperidone long-acting injection (intramuscular) was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their usual treatment, approximately 4% (3/72) of risperidone long-acting injection (intramuscular)-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in risperidone long-acting injection(intramuscular)-treated patients were hypokinesia (one patient) and tardive dyskinesia (one patient). Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms (EPS) Two methods were used to measure EPS in the 12-week double-blind, placebo-controlled trial comparing three doses of risperidone long-acting injection (intramuscular) (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). The overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg risperidone long-acting injection (intramuscular)was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg risperidone long-acting injection (intramuscular) ( Table 4 ). The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with risperidone long-acting injection (intramuscular) compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group). 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 neck muscle spasms, 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. Changes in ECG The ECGs of 202 patients with schizophrenia treated with 25 mg or 50 mg risperidone long-acting injection (intramuscular) and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with either risperidone long-acting injection (intramuscular)or placebo. The ECGs of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with risperidone long-acting injection (intramuscular) compared to placebo. The ECGs of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during adjunctive treatment with either risperidone long-acting injection (intramuscular) (25 mg, 37.5 mg, or 50 mg) or placebo in addition to treatment as usual. Pain Assessment and Local Injection Site Reactions The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last dose of risperidone long-acting injection (intramuscular) (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg risperidone long-acting injection (intramuscular) experienced redness, swelling, or induration at the injection site. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to a drug exposure. These adverse reactions include: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during post-approval use of risperidone long-acting injection (intramuscular): cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated. Retinal artery occlusion after use of risperidone long-acting injection (intramuscular) has been reported during postmarketing surveillance. This was reported in the presence of abnormal arteriovenous anastomosis. Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with risperidone long-acting injection (intramuscular) during postmarketing surveillance. Isolated cases required surgical intervention. Very rarely, cases of anaphylactic reaction after administration of risperidone long-acting injection (intramuscular) have been reported during postmarketing experience in patients who previously tolerated oral risperidone. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): increase risperidone plasma concentration. ( 2.7 , 7.1 ) Strong CYP3A4 inducers (e.g., carbamazepine): decrease plasma concentrations of risperidone. ( 2.7 , 7.1 ) 7.1 Drugs Having Clinically Significant Interactions with RYKINDO The interactions of RYKINDO with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on studies with oral risperidone. Clinically significant drug interactions with RYKINDO are included in Table 7. Table 7. Clinically Significant Drug Interactions with RYKINDO Strong CYP2D6 Inhibitors Clinical Impact Concomitant use of RYKINDO with strong CYP2D6 inhibitors may increase the plasma concentration of risperidone and lower the concentration of 9-hydroxyrisperidone, a major active metabolite of risperidone [see Clinical Pharmacology (12.3) ] . Intervention When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When a strong CYP2D6 inhibitor is initiated in patients receiving the recommended dose of 25 mg RYKINDO, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates either lowering the dose to 12.5 mg, in which case a different risperidone long-acting injection intramuscular formulation should be used, or interruption of RYKINDO treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Dosage and Administration (2.7) ] . Strong CYP3A4 Inducers Clinical Impact Co-administration of a strong CYP3A4 inducer with RYKINDO may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RYKINDO ® treatment [see Clinical Pharmacology (12.3) ] . Intervention When initiating therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks because the dose of RYKINDO may need to be adjusted. A dose increase or additional oral risperidone may need to be considered. When discontinuing a strong CYP3A4 inducer, the dosage of RYKINDO should be re-evaluated and decreased, if necessary. Patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned discontinuation of CYP3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RYKINDO and discontinuing from a CYP3A4 enzyme inducer, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg, in which case a different risperidone long-acting injection intramuscular formulation should be used, or interruption of RYKINDO treatment. [see Dosage and Administration (2.7) ] . Centrally-Acting Drugs and Alcohol Clinical Impact Nervous system disorders may be exacerbated due to additive pharmacological effects associated with the concomitant use of centrally-acting drugs, including alcohol. Intervention Use caution when RYKINDO is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact Because of its potential for inducing hypotension, RYKINDO may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention Use caution when RYKINDO is administered in combination with other therapeutic agents with hypotensive effects. Dopamine Agonists Clinical Impact RYKINDO may antagonize the effects of levodopa and dopamine agonists. Intervention Caution should be used when RYKINDO is administered in combination with levodopa and dopamine agonists. Methylphenidate Clinical Impact: Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions (6.2) ] . Intervention: Monitor for symptoms of EPS with concomitant use of RYKINDO and methylphenidate. 7.2 Drugs Having No Clinically Important Interactions with RYKINDO Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of RYKINDO ® is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin and CYP2D6 substrates (donepezil and galantamine) when co-administered with RYKINDO [ see Clinical Pharmacology (12.3) ] .

Storage and Handling Store kit in refrigerator at 2° to 8°C (36° to 46°F). Protect from light. If refrigeration is unavailable, RYKINDO can be stored in its unopened original packaging at temperatures not exceeding 77°F (25°C) for no more than 7 days prior to administration. After removal from the refrigerator, use RYKINDO within 7 days or discard.