These Highlights Do Not Include All The Information Needed To Use Rykindo®

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, sometimes extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RYKINDO, should be monitored regularly for worsening glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RYKINDO, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RYKINDO, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RYKINDO, should undergo fasting blood glucose testing. In some cases, hyperglycemia resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Pooled data from 3 double-blind, placebo-controlled studies in patients with schizophrenia and 4 double-blind, placebo-controlled monotherapy studies in patients with bipolar mania with oral risperidone are presented in Table 1.

In longer-term, controlled and uncontrolled studies in adult patients, oral risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

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.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RYKINDO, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

During premarketing studies, seizure occurred in 0.3% of patients (5 out of 1, 499 patients) treated with risperidone long-acting injection (intramuscular). Use RYKINDO with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

Priapism has been reported during postmarketing surveillance of other risperidone products. Severe priapism may require surgical intervention.

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 C₂₃H₂₇FN₄O₂ 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.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Antipsychotic drugs, including RYKINDO should be used cautiously in patients at risk for aspiration [see Warnings and Precautions (5.1)].

Safety and effectiveness of RYKINDO have not been established in pediatric patients.

In an open-label study, 57 clinically stable, geriatric patients (≥ 65 years old) with schizophrenia or schizoaffective disorder received risperidone long-acting injection (intramuscular) every 2 weeks for up to 12 months. In general, no differences in the tolerability of risperidone long-acting injection (intramuscular) were observed between otherwise healthy geriatric and younger patients.

Because geriatric patients exhibit a greater tendency for orthostatic hypotension than nonelderly patients, geriatric patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in geriatric patients for whom orthostatic hypotension is a concern [see Warnings and Precautions (5.7) ].

Elderly patients with dementia-related psychosis treated with RYKINDO are at an increased risk of death compared to placebo. RYKINDO is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

The effectiveness of RYKINDO in the treatment of schizophrenia is based on an adequate and well-controlled study with risperidone long-acting injection (intramuscular). The effectiveness of risperidone long-acting injection (intramuscular) was established, in part, on the basis of the established effectiveness of the oral formulation of risperidone as well as in a 12-week, placebo-controlled trial in adult inpatients and outpatients who met the DSM-IV criteria for schizophrenia. The results of the adequate and well-controlled study are presented below.

Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of 25 mg, 50 mg, or 75 mg risperidone long-acting injection (intramuscular) or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral risperidone. Patients who received risperidone long-acting injection (intramuscular) were given doses of oral risperidone (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.

Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of risperidone long-acting injection (intramuscular) (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.

Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.

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.

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)]

• 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)

In patients with renal impairment, titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with RYKINDO [see Dosage and Administration (2.6) ].

Although patients with renal impairment were not studied with RYKINDO, they may have reduced risperidone elimination compared to patients with normal renal function [see Clinical Pharmacology (12.3) ].

RYKINDO^® [ray-KIN-do]

(risperidone)

injection, for gluteal intramuscular use

This Instruction for Use contains information on how to inject RYKINDO^®

Important Information You Need to Know Before Injecting RYKINDO^®

• For gluteal intramuscular injection use only

For gluteal intramuscular injection only. Do not inject by any other route. Alternate injections between the two buttocks.

• Wait 30 minutes

Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes prior to preparation. Do not warm any other way. Prepare medication when you are ready to administer the dose.

• Use components provided

The components in this dose pack are specifically designed for use with RYKINDO. RYKINDO must be reconstituted only in the diluent supplied in the dose pack. Do not substitute ANY components of the dose pack.

• Do not store suspension after reconstitution.

Administer dose as soon as possible after reconstitution to avoid settling.

• Proper dosing

The entire contents of the vial must be administered to ensure the intended dose of RYKINDO is delivered.

• Do not reuse.

RYKINDO^® is for one-time use only. Do not reuse RYKINDO.

The components of the single-dose kit are shown in Figure 1.

Figure1: Single-dose Kit Components

Preparing to Inject RYKINDO^®

Step 1. Take out kit and connect vial adapter to vial

Step 2. Connect prefilled syringe to vial adapter

Step 3. Reconstitute powder

Step 4. Attach needle

Step 5. Inject RYKINDO^®

Storing RYKINDO^®

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.

For product or service related questions, call 1-800-548-9765 or visit www.rykindo.com.

Shandong Luye Pharmaceutical Co., Ltd.

No.15 Chuangye Road, High-tech Zone,

Yantai, Shandong, 264003

China

This Instruction for Use has been approved by the U.S. Food and Drug Administration.

Issued: 05/2023

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT₂), dopamine Type 2 (D₂), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone shows low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT_1C, 5HT_1D, and 5HT_1A receptors; weak affinity (Ki of 620 to 800 nM) for the dopamine D₁ and haloperidol-sensitive sigma site; and no affinity (when tested at concentrations >10^-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

Atypical antipsychotic drugs have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, RYKINDO should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be used. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient treated with RYKINDO, drug discontinuation should be considered. However, some patients may require treatment with RYKINDO despite the presence of the syndrome.

As with other dopamine D₂ receptor antagonists, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients [see Use in Specific Populations (8.3)]. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In patients with hepatic impairment, titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with RYKINDO [see Dosage and Administration (2.6) ].

Although patients with hepatic impairment were not studied in RYKINDO clinical trials, they may have a clinically significant increase in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3) ].

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

The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity could be mediated through a combination of dopamine Type 2 (D₂) and serotonin Type 2 (5HT₂) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3) ]. Antagonism at receptors other than D₂ and 5HT₂ may explain some of the other effects of risperidone.

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemia attack). (5.2)
• Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. (5.3)
• Tardive Dyskinesia: Discontinue treatment if clinically appropriate. (5.4)
• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. (5.5)
• Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. Long-standing hyperprolactinemia, when associated with hypogonadism, can lead to decreased bone density in males and females. (5.6)
• Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood cell counts (CBC) in patients with a history of clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing RYKINDO if clinically significant decline in WBC occurs in the absence of other causative factors. (5.9)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.10)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. (5.11)
• Priapism: Priapism has been reported during postmarketing use of other risperidone products. Severe priapism may require surgical intervention. (5.13)

• 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)

RYKINDO (risperidone) for extended-release injectable suspension, for intramuscular use is available in strengths of 25 mg, 37.5 mg, and 50 mg.

Each strength 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 (20 gauge 2-inch needle with needle protection device).

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.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)

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.

The effectiveness of RYKINDO for the maintenance treatment of bipolar I disorder is based on an adequate and well-controlled study with risperidone long-acting injection (intramuscular). The efficacy of risperidone long-acting injection (intramuscular) was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode. The results of the adequate and well-controlled study are presented below.

A total of 501 patients were treated during a 26-week open-label period with the risperidone long-acting injection (intramuscular) (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-blind treatment with either the same dose of risperidone long-acting injection (intramuscular) or placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving risperidone long-acting injection (intramuscular) monotherapy compared with patients receiving placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar disorder history, subjects entering this study had, on average, more manic episodes than depressive episodes.

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Both hyperthermia and hypothermia have been reported in association with the use of oral risperidone or risperidone long-acting injection (intramuscular). Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use RYKINDO with caution in patients who may experience these conditions.

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) .

RYKINDO may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with risperidone long-acting injection (intramuscular) in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).

RYKINDO should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.

NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue RYKINDO and provide symptomatic treatment and monitoring.

Risperidone long-acting injection (intramuscular) produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.

Risperidone long-acting injection (intramuscular) produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, risperidone long-acting injection (intramuscular) produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. Cellular proliferation was not measured at the low dose or in females in either study.

The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m² basis and is associated with a plasma exposure (AUC) twice the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m² basis). Plasma exposure (AUC) at the no-effect dose was 33% of the expected plasma exposure (AUC) at the IM MRHD.

Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.

The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of Fertility).

The relevance of these findings to humans is unknown.

The effectiveness of RYKINDO as an adjunct to treatment with lithium or valproate for the maintenance treatment of bipolar I disorder is based on an adequate and well-controlled study of risperidone long-acting injection (intramuscular). The results of the adequate and well-controlled study are presented below.

The efficacy of risperidone long-acting injection (intramuscular) was established in a multi-center, randomized, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study.

A total of 240 patients were treated during a 16-week open-label period with risperidone long-acting injection (intramuscular) (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition to continuing their usual treatment for bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first three weeks after the initial injection of risperidone long-acting injection (intramuscular). In the open-label phase, 124 (51.7%) were judged to be stable for at least the last 4 weeks and were randomized to double-blind treatment with either the same dose of risperidone long-acting injection (intramuscular) or placebo in addition to continuing their usual treatment and monitored for relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving adjunctive therapy with risperidone long-acting injection (intramuscular) compared with patients receiving adjunctive therapy with placebo. The relapse types were about half depressive and half manic or mixed episodes.

25 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 25 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-102-11

50 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 50 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-104-11

37.5 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 37.5 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-103-11

• 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

Step 2. Connect prefilled syringe to vial adapter

Step 3. Reconstitute powder

Step 4. Attach Needle

Step 5. Inject RYKINDO

In clinical trial and/or postmarketing experience, leukopenia/neutropenia have been reported in temporal association with antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or past drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Discontinuation of RYKINDO should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue RYKINDO in patients with absolute neutrophil count <1000/mm³ and follow their WBC until recovery.

RYKINDO, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was reported by 5% of patients treated with risperidone long-acting injection (intramuscular) in multiple-dose trials.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with RYKINDO does not affect them adversely.

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.

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.

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.

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) ].

Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to RYKINDO. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

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.

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.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients that was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% versus about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

RYKINDO is not approved for the treatment of dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RYKINDO is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. RYKINDO is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

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)].

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.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, sometimes extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RYKINDO, should be monitored regularly for worsening glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RYKINDO, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RYKINDO, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RYKINDO, should undergo fasting blood glucose testing. In some cases, hyperglycemia resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Pooled data from 3 double-blind, placebo-controlled studies in patients with schizophrenia and 4 double-blind, placebo-controlled monotherapy studies in patients with bipolar mania with oral risperidone are presented in Table 1.

In longer-term, controlled and uncontrolled studies in adult patients, oral risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

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.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RYKINDO, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

During premarketing studies, seizure occurred in 0.3% of patients (5 out of 1, 499 patients) treated with risperidone long-acting injection (intramuscular). Use RYKINDO with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

Priapism has been reported during postmarketing surveillance of other risperidone products. Severe priapism may require surgical intervention.

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 C₂₃H₂₇FN₄O₂ 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.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Antipsychotic drugs, including RYKINDO should be used cautiously in patients at risk for aspiration [see Warnings and Precautions (5.1)].

Safety and effectiveness of RYKINDO have not been established in pediatric patients.

In an open-label study, 57 clinically stable, geriatric patients (≥ 65 years old) with schizophrenia or schizoaffective disorder received risperidone long-acting injection (intramuscular) every 2 weeks for up to 12 months. In general, no differences in the tolerability of risperidone long-acting injection (intramuscular) were observed between otherwise healthy geriatric and younger patients.

Because geriatric patients exhibit a greater tendency for orthostatic hypotension than nonelderly patients, geriatric patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in geriatric patients for whom orthostatic hypotension is a concern [see Warnings and Precautions (5.7) ].

Elderly patients with dementia-related psychosis treated with RYKINDO are at an increased risk of death compared to placebo. RYKINDO is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

The effectiveness of RYKINDO in the treatment of schizophrenia is based on an adequate and well-controlled study with risperidone long-acting injection (intramuscular). The effectiveness of risperidone long-acting injection (intramuscular) was established, in part, on the basis of the established effectiveness of the oral formulation of risperidone as well as in a 12-week, placebo-controlled trial in adult inpatients and outpatients who met the DSM-IV criteria for schizophrenia. The results of the adequate and well-controlled study are presented below.

Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of 25 mg, 50 mg, or 75 mg risperidone long-acting injection (intramuscular) or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral risperidone. Patients who received risperidone long-acting injection (intramuscular) were given doses of oral risperidone (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.

Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of risperidone long-acting injection (intramuscular) (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.

Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.

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.

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)]

• 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)

In patients with renal impairment, titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with RYKINDO [see Dosage and Administration (2.6) ].

Although patients with renal impairment were not studied with RYKINDO, they may have reduced risperidone elimination compared to patients with normal renal function [see Clinical Pharmacology (12.3) ].

RYKINDO^® [ray-KIN-do]

(risperidone)

injection, for gluteal intramuscular use

This Instruction for Use contains information on how to inject RYKINDO^®

Important Information You Need to Know Before Injecting RYKINDO^®

• For gluteal intramuscular injection use only

For gluteal intramuscular injection only. Do not inject by any other route. Alternate injections between the two buttocks.

• Wait 30 minutes

Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes prior to preparation. Do not warm any other way. Prepare medication when you are ready to administer the dose.

• Use components provided

The components in this dose pack are specifically designed for use with RYKINDO. RYKINDO must be reconstituted only in the diluent supplied in the dose pack. Do not substitute ANY components of the dose pack.

• Do not store suspension after reconstitution.

Administer dose as soon as possible after reconstitution to avoid settling.

• Proper dosing

The entire contents of the vial must be administered to ensure the intended dose of RYKINDO is delivered.

• Do not reuse.

RYKINDO^® is for one-time use only. Do not reuse RYKINDO.

The components of the single-dose kit are shown in Figure 1.

Figure1: Single-dose Kit Components

Preparing to Inject RYKINDO^®

Step 1. Take out kit and connect vial adapter to vial

Step 2. Connect prefilled syringe to vial adapter

Step 3. Reconstitute powder

Step 4. Attach needle

Step 5. Inject RYKINDO^®

Storing RYKINDO^®

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.

For product or service related questions, call 1-800-548-9765 or visit www.rykindo.com.

Shandong Luye Pharmaceutical Co., Ltd.

No.15 Chuangye Road, High-tech Zone,

Yantai, Shandong, 264003

China

This Instruction for Use has been approved by the U.S. Food and Drug Administration.

Issued: 05/2023

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT₂), dopamine Type 2 (D₂), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone shows low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT_1C, 5HT_1D, and 5HT_1A receptors; weak affinity (Ki of 620 to 800 nM) for the dopamine D₁ and haloperidol-sensitive sigma site; and no affinity (when tested at concentrations >10^-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

Atypical antipsychotic drugs have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, RYKINDO should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be used. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient treated with RYKINDO, drug discontinuation should be considered. However, some patients may require treatment with RYKINDO despite the presence of the syndrome.

As with other dopamine D₂ receptor antagonists, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients [see Use in Specific Populations (8.3)]. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In patients with hepatic impairment, titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with RYKINDO [see Dosage and Administration (2.6) ].

Although patients with hepatic impairment were not studied in RYKINDO clinical trials, they may have a clinically significant increase in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3) ].

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

The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity could be mediated through a combination of dopamine Type 2 (D₂) and serotonin Type 2 (5HT₂) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3) ]. Antagonism at receptors other than D₂ and 5HT₂ may explain some of the other effects of risperidone.

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemia attack). (5.2)
• Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. (5.3)
• Tardive Dyskinesia: Discontinue treatment if clinically appropriate. (5.4)
• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. (5.5)
• Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. Long-standing hyperprolactinemia, when associated with hypogonadism, can lead to decreased bone density in males and females. (5.6)
• Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood cell counts (CBC) in patients with a history of clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing RYKINDO if clinically significant decline in WBC occurs in the absence of other causative factors. (5.9)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.10)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. (5.11)
• Priapism: Priapism has been reported during postmarketing use of other risperidone products. Severe priapism may require surgical intervention. (5.13)

• 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)

RYKINDO (risperidone) for extended-release injectable suspension, for intramuscular use is available in strengths of 25 mg, 37.5 mg, and 50 mg.

Each strength 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 (20 gauge 2-inch needle with needle protection device).

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.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)

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.

The effectiveness of RYKINDO for the maintenance treatment of bipolar I disorder is based on an adequate and well-controlled study with risperidone long-acting injection (intramuscular). The efficacy of risperidone long-acting injection (intramuscular) was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode. The results of the adequate and well-controlled study are presented below.

A total of 501 patients were treated during a 26-week open-label period with the risperidone long-acting injection (intramuscular) (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-blind treatment with either the same dose of risperidone long-acting injection (intramuscular) or placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving risperidone long-acting injection (intramuscular) monotherapy compared with patients receiving placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar disorder history, subjects entering this study had, on average, more manic episodes than depressive episodes.

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Both hyperthermia and hypothermia have been reported in association with the use of oral risperidone or risperidone long-acting injection (intramuscular). Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use RYKINDO with caution in patients who may experience these conditions.

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) .

RYKINDO may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with risperidone long-acting injection (intramuscular) in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).

RYKINDO should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.

NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue RYKINDO and provide symptomatic treatment and monitoring.

Risperidone long-acting injection (intramuscular) produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.

Risperidone long-acting injection (intramuscular) produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, risperidone long-acting injection (intramuscular) produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. Cellular proliferation was not measured at the low dose or in females in either study.

The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m² basis and is associated with a plasma exposure (AUC) twice the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m² basis). Plasma exposure (AUC) at the no-effect dose was 33% of the expected plasma exposure (AUC) at the IM MRHD.

Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.

The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of Fertility).

The relevance of these findings to humans is unknown.

The effectiveness of RYKINDO as an adjunct to treatment with lithium or valproate for the maintenance treatment of bipolar I disorder is based on an adequate and well-controlled study of risperidone long-acting injection (intramuscular). The results of the adequate and well-controlled study are presented below.

The efficacy of risperidone long-acting injection (intramuscular) was established in a multi-center, randomized, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study.

A total of 240 patients were treated during a 16-week open-label period with risperidone long-acting injection (intramuscular) (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition to continuing their usual treatment for bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first three weeks after the initial injection of risperidone long-acting injection (intramuscular). In the open-label phase, 124 (51.7%) were judged to be stable for at least the last 4 weeks and were randomized to double-blind treatment with either the same dose of risperidone long-acting injection (intramuscular) or placebo in addition to continuing their usual treatment and monitored for relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving adjunctive therapy with risperidone long-acting injection (intramuscular) compared with patients receiving adjunctive therapy with placebo. The relapse types were about half depressive and half manic or mixed episodes.

25 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 25 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-102-11

50 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 50 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-104-11

37.5 mg

Kit

Rykindo^®

(risperiDONE) for extended-release

injectable suspension

KIT CONTENTS:

• One 37.5 mg vial of risperiDONE for extended-release injectable suspension
• One pre-filled syringe containing 2 mL of diluent
• One Vial Adapter
• One 20-gauge 2-inch safety needle for gluteal intramuscular injection only

Do not substitute any components of the kit.

For gluteal intramuscular injection only.

Each injection should be administered by a healthcare professional.

Rx only

Single dose

Store Kit in Refrigerator

(see bottom panel for storage conditions)

PLEASE READ COMPLETE

INSTRUCTIONS PRIOR TO USE.

NDC 72526-103-11

• 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

Step 2. Connect prefilled syringe to vial adapter

Step 3. Reconstitute powder

Step 4. Attach Needle

Step 5. Inject RYKINDO

In clinical trial and/or postmarketing experience, leukopenia/neutropenia have been reported in temporal association with antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or past drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Discontinuation of RYKINDO should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue RYKINDO in patients with absolute neutrophil count <1000/mm³ and follow their WBC until recovery.

RYKINDO, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was reported by 5% of patients treated with risperidone long-acting injection (intramuscular) in multiple-dose trials.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with RYKINDO does not affect them adversely.

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.

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.

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.

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) ].

Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to RYKINDO. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

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.

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.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients that was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% versus about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

RYKINDO is not approved for the treatment of dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RYKINDO is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. RYKINDO is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

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)].

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.