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| Product NDC Code | 72526-104 | ||||
|---|---|---|---|---|---|
| Drug Name | Rykindo extended-release microspheres |
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| Type | Brand | ||||
| Dosage Form | KIT | ||||
| RxCUI drug identifier | 402010, 402011, 402012, 706822, 2639732, 2639734, 2639736, 2639738 |
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| Application Number | NDA212849 | ||||
| Labeler Name | Shandong Luye Pharmaceutical Co., Ltd. | ||||
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Rykindo extended-release microspheres
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Human Experience In premarketing experience with oral risperidone, there were eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and EPS. In one case, hyponatremia, hypokalemia, prolonged QT, and widened QRS were observed after a patient took an estimated 240 mg of oral risperidone. In another case, a patient had a seizure after taking an estimated 36 mg of oral risperidone. Postmarketing experience with oral risperidone included reports of acute overdose with estimated doses up to 360 mg. In general, the most frequently reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and EPS. Other postmarketing adverse reactions related to oral risperidone overdose included prolonged QT interval and convulsions. Torsade de pointes was reported in association with combined overdose of oral risperidone and paroxetine. Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be implemented. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe EPS, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome (NMS) [see Warnings and Precautions (5.3) ] Tardive dyskinesia [see Warnings and Precautions (5.4) ] Metabolic changes [see Warnings and Precautions (5.5) ] Hyperprolactinemia [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Dysphagia [see Warnings and Precautions (5.12) ] Priapism [see Warnings and Precautions (5.13) ] Body temperature dysregulation [see Warnings and Precautions (5.14) ] Osteodystrophy and tumors in animals [see Warnings and Precautions (5.15) ] The most common adverse reactions in patients with schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremity, and dry mouth. ( 6 ) The most common adverse reactions in patients with bipolar disorder were (5% in monotherapy trial) weight increased and (≥ 10% in adjunctive therapy trial) tremor and parkinsonism. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Shandong Luye Pharmaceutical Co., Ltd. at 1-800-548-9765 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of RYKINDO for the treatment of schizophrenia in adults and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder in adults is based on adequate and well-controlled studies of risperidone long-acting injection (intramuscular). The data described in this section are derived from a clinical trial database consisting of 2,392 patients exposed to one or more doses of risperidone long-acting injection (intramuscular) for the treatment of schizophrenia. Of these 2,392 patients, 332 patients received risperidone long-acting injection (intramuscular) while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were patients with schizophrenia who received 25 mg or 50 mg risperidone long-acting injection (intramuscular). The conditions and duration of treatment with risperidone long-acting injection (intramuscular) in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. Safety data are also presented from a trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) administered as adjunctive maintenance treatment in patients with bipolar disorder (intramuscular). The most common adverse reactions in clinical trials of risperidone long-acting injection (intramuscular) in patients with schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity, and dry mouth. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials of risperidone long-acting injection (intramuscular) were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the adjunctive treatment trial). Table 4 lists the adverse reactions reported in 2% or more of risperidone long-acting injection-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial. Table 4. Adverse Reactions Occurring in ≥2% of Risperidone Long-acting Injection (intramuscular)-Treated Patients (Adults) with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial Risperidone Long-acting Injection (intramuscular) Placebo System/Organ Class Adverse Reaction 25 mg % 50 mg % % (N=99) (N=103) (N=98) Eye disorders Vision blurred 2 3 0 Gastrointestinal disorders Constipation 5 7 1 Dry mouth 0 7 1 Dyspepsia 6 6 0 Nausea 3 4 5 Toothache 1 3 0 Salivary hypersecretion 4 1 0 General disorders and administration site conditions Fatigue Fatigue includes fatigue and asthenia. 3 9 0 Edema peripheral 2 3 1 Pain 4 1 0 Pyrexia 2 1 0 Infections and infestations Upper respiratory tract infection 2 0 1 Investigations Weight increased 5 4 2 Weight decreased 4 1 1 Musculoskeletal and connective tissue disorders Pain in extremity 6 2 1 Nervous system disorders Headache 15 21 12 Parkinsonism Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. 8 15 9 Dizziness 7 11 6 Akathisia Akathisia includes akathisia and restlessness. 4 11 6 Sedation Sedation includes sedation and somnolence. 5 6 3 Tremor 0 3 0 Syncope 2 1 0 Hypoesthesia 2 0 0 Respiratory, thoracic and mediastinal disorders Cough 4 2 3 Sinus congestion 2 0 0 Skin and subcutaneous tissue disorders Acne 2 2 0 Dry skin 2 0 0 Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder Table 5 lists the adverse reactions reported in 2% or more of risperidone long-acting injection (intramuscular)-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder. Table 5. Adverse Reactions in ≥2% of Adult Patients with Bipolar I Disorder Treated with Risperidone Long-acting Injection (intramuscular) as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Risperidone Long-acting Injection (intramuscular) (N=154) % Placebo (N=149) % Investigations Weight increased 5 1 Nervous system disorders Dizziness 3 1 Vascular disorders Hypertension 3 1 Table 6 lists the adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of risperidone long-acting injection as adjunctive maintenance treatment in patients with bipolar disorder. Table 6. Adverse Reactions Occurring in ≥ 4% of Adult Patients with Bipolar I Disorder Treated with Risperidone Long-acting Injection (intramuscular) as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Risperidone Long-acting Injection (intramuscular) + Treatment as Usual Patients received double-blind risperidone long-acting injection (intramuscular) or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. (N=72) % Placebo + Treatment as Usual (N=67) % General disorders and administration site conditions Gait abnormal 4 0 Infections and infestations Upper respiratory tract infection 6 3 Investigations Weight increased 7 1 Metabolism and nutrition disorders Decreased appetite 6 1 Increased appetite 4 0 Musculoskeletal and connective tissue disorders Arthralgia 4 3 Nervous system disorders Tremor 24 16 Parkinsonism Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. 15 6 Dyskinesia Dyskinesia includes muscle twitching and dyskinesia. 6 3 Sedation Sedation includes sedation and somnolence. 7 1 Disturbance in attention 4 0 Reproductive system and breast disorders Amenorrhea 4 1 Respiratory, thoracic and mediastinal disorders Cough 4 1 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred in < 2% of the risperidone long-acting injection (intramuscular)-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the risperidone long-acting injection (intramuscular) -treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the risperidone long-acting injection (intramuscular)-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in risperidone long-acting injection (intramuscular)-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled, and open-label studies in schizophrenia and bipolar disorder. Blood and lymphatic system disorders: anemia, neutropenia Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain, vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reduced Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall, procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported with Oral Risperidone Additional adverse reactions that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence, include the following: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricular block Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rate increased, eosinophil count increased, WBC count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome (NMS), diabetic coma, head titubation Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listlessness, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Reactions Schizophrenia Approximately 11% (22/202) of risperidone long-acting (intramuscular)-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse reaction, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more risperidone long-acting injection (intramuscular)-treated patients were agitation (3%), depression (2%), anxiety (1%), and akathisia (1%). Bipolar Disorder In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone long-acting injection (intramuscular) monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 risperidone long-acting injection (intramuscular)-treated patients discontinued due to an adverse reaction (hyperglycemia). In the 52-week double-blind phase of the placebo-controlled trial in which risperidone long-acting injection (intramuscular) was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their usual treatment, approximately 4% (3/72) of risperidone long-acting injection (intramuscular)-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in risperidone long-acting injection(intramuscular)-treated patients were hypokinesia (one patient) and tardive dyskinesia (one patient). Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms (EPS) Two methods were used to measure EPS in the 12-week double-blind, placebo-controlled trial comparing three doses of risperidone long-acting injection (intramuscular) (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). The overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg risperidone long-acting injection (intramuscular)was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg risperidone long-acting injection (intramuscular) ( Table 4 ). The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with risperidone long-acting injection (intramuscular) compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group). Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include neck muscle spasms, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Changes in ECG The ECGs of 202 patients with schizophrenia treated with 25 mg or 50 mg risperidone long-acting injection (intramuscular) and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with either risperidone long-acting injection (intramuscular)or placebo. The ECGs of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with risperidone long-acting injection (intramuscular) compared to placebo. The ECGs of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during adjunctive treatment with either risperidone long-acting injection (intramuscular) (25 mg, 37.5 mg, or 50 mg) or placebo in addition to treatment as usual. Pain Assessment and Local Injection Site Reactions The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last dose of risperidone long-acting injection (intramuscular) (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg risperidone long-acting injection (intramuscular) experienced redness, swelling, or induration at the injection site. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to a drug exposure. These adverse reactions include: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during post-approval use of risperidone long-acting injection (intramuscular): cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated. Retinal artery occlusion after use of risperidone long-acting injection (intramuscular) has been reported during postmarketing surveillance. This was reported in the presence of abnormal arteriovenous anastomosis. Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with risperidone long-acting injection (intramuscular) during postmarketing surveillance. Isolated cases required surgical intervention. Very rarely, cases of anaphylactic reaction after administration of risperidone long-acting injection (intramuscular) have been reported during postmarketing experience in patients who previously tolerated oral risperidone. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.
| Risperidone Long-acting Injection (intramuscular) | Placebo | ||
|---|---|---|---|
| System/Organ Class Adverse Reaction | 25 mg % | 50 mg % | % |
| (N=99) | (N=103) | (N=98) | |
| Vision blurred | 2 | 3 | 0 |
| Constipation | 5 | 7 | 1 |
| Dry mouth | 0 | 7 | 1 |
| Dyspepsia | 6 | 6 | 0 |
| Nausea | 3 | 4 | 5 |
| Toothache | 1 | 3 | 0 |
| Salivary hypersecretion | 4 | 1 | 0 |
| Fatigue | 3 | 9 | 0 |
| Edema peripheral | 2 | 3 | 1 |
| Pain | 4 | 1 | 0 |
| Pyrexia | 2 | 1 | 0 |
| Upper respiratory tract infection | 2 | 0 | 1 |
| Weight increased | 5 | 4 | 2 |
| Weight decreased | 4 | 1 | 1 |
| Pain in extremity | 6 | 2 | 1 |
| Headache | 15 | 21 | 12 |
| Parkinsonism | 8 | 15 | 9 |
| Dizziness | 7 | 11 | 6 |
| Akathisia | 4 | 11 | 6 |
| Sedation | 5 | 6 | 3 |
| Tremor | 0 | 3 | 0 |
| Syncope | 2 | 1 | 0 |
| Hypoesthesia | 2 | 0 | 0 |
| Cough | 4 | 2 | 3 |
| Sinus congestion | 2 | 0 | 0 |
| Acne | 2 | 2 | 0 |
| Dry skin | 2 | 0 | 0 |
| System/Organ Class Adverse Reaction | Risperidone Long-acting Injection (intramuscular) (N=154) % | Placebo (N=149) % |
|---|---|---|
| Weight increased | 5 | 1 |
| Dizziness | 3 | 1 |
| Hypertension | 3 | 1 |
| System/Organ Class Adverse Reaction | Risperidone Long-acting Injection (intramuscular) + Treatment as Usual | Placebo + Treatment as Usual |
|---|---|---|
| Gait abnormal | 4 | 0 |
| Upper respiratory tract infection | 6 | 3 |
| Weight increased | 7 | 1 |
| Decreased appetite | 6 | 1 |
| Increased appetite | 4 | 0 |
| Arthralgia | 4 | 3 |
| Tremor | 24 | 16 |
| Parkinsonism | 15 | 6 |
| Dyskinesia | 6 | 3 |
| Sedation | 7 | 1 |
| Disturbance in attention | 4 | 0 |
| Amenorrhea | 4 | 1 |
| Cough | 4 | 1 |
Rykindo extended-release microspheres Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): increase risperidone plasma concentration. ( 2.7 , 7.1 ) Strong CYP3A4 inducers (e.g., carbamazepine): decrease plasma concentrations of risperidone. ( 2.7 , 7.1 ) 7.1 Drugs Having Clinically Significant Interactions with RYKINDO The interactions of RYKINDO with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on studies with oral risperidone. Clinically significant drug interactions with RYKINDO are included in Table 7. Table 7. Clinically Significant Drug Interactions with RYKINDO Strong CYP2D6 Inhibitors Clinical Impact Concomitant use of RYKINDO with strong CYP2D6 inhibitors may increase the plasma concentration of risperidone and lower the concentration of 9-hydroxyrisperidone, a major active metabolite of risperidone [see Clinical Pharmacology (12.3) ] . Intervention When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When a strong CYP2D6 inhibitor is initiated in patients receiving the recommended dose of 25 mg RYKINDO, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. When RYKINDO is initiated in patients already receiving a CYP2D6 inhibitor, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Dosage and Administration (2.7) ] . Strong CYP3A4 Inducers Clinical Impact Co-administration of a strong CYP3A4 inducer with RYKINDO may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RYKINDO ® treatment [see Clinical Pharmacology (12.3) ] . Intervention When initiating therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks because the dose of RYKINDO may need to be adjusted. A dose increase or additional oral risperidone may need to be considered. When discontinuing a strong CYP3A4 inducer, the dosage of RYKINDO should be re-evaluated and decreased, if necessary. Patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned discontinuation of CYP3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RYKINDO and discontinuing from a CYP3A4 enzyme inducer, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials [see Dosage and Administration (2.7) ] . Centrally-Acting Drugs and Alcohol Clinical Impact Nervous system disorders may be exacerbated due to additive pharmacological effects associated with the concomitant use of centrally-acting drugs, including alcohol. Intervention Use caution when RYKINDO is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact Because of its potential for inducing hypotension, RYKINDO may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention Use caution when RYKINDO is administered in combination with other therapeutic agents with hypotensive effects. Dopamine Agonists Clinical Impact RYKINDO may antagonize the effects of levodopa and dopamine agonists. Intervention Caution should be used when RYKINDO is administered in combination with levodopa and dopamine agonists. Methylphenidate Clinical Impact: Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions (6.2) ] . Intervention: Monitor for symptoms of EPS with concomitant use of RYKINDO and methylphenidate. 7.2 Drugs Having No Clinically Important Interactions with RYKINDO Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of RYKINDO ® is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin and CYP2D6 substrates (donepezil and galantamine) when co-administered with RYKINDO [ see Clinical Pharmacology (12.3) ] .
| Concomitant use of RYKINDO with strong CYP2D6 inhibitors may increase the plasma concentration of risperidone and lower the concentration of 9-hydroxyrisperidone, a major active metabolite of risperidone | |
| When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When a strong CYP2D6 inhibitor is initiated in patients receiving the recommended dose of 25 mg RYKINDO, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. When RYKINDO is initiated in patients already receiving a CYP2D6 inhibitor, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied | |
| Co-administration of a strong CYP3A4 inducer with RYKINDO may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RYKINDO® treatment | |
| When initiating therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks because the dose of RYKINDO may need to be adjusted. A dose increase or additional oral risperidone may need to be considered. When discontinuing a strong CYP3A4 inducer, the dosage of RYKINDO should be re-evaluated and decreased, if necessary. Patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned discontinuation of CYP3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RYKINDO and discontinuing from a CYP3A4 enzyme inducer, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials | |
| Nervous system disorders may be exacerbated due to additive pharmacological effects associated with the concomitant use of centrally-acting drugs, including alcohol. | |
| Use caution when RYKINDO is administered in combination with other centrally-acting drugs or alcohol. | |
| Because of its potential for inducing hypotension, RYKINDO may enhance the hypotensive effects of other therapeutic agents with this potential. | |
| Use caution when RYKINDO is administered in combination with other therapeutic agents with hypotensive effects. | |
| RYKINDO may antagonize the effects of levodopa and dopamine agonists. | |
| Caution should be used when RYKINDO is administered in combination with levodopa and dopamine agonists. | |
| Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) | |
| Monitor for symptoms of EPS with concomitant use of RYKINDO and methylphenidate. | |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 (D 2 ) and serotonin Type 2 (5HT 2 ) 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 D 2 and 5HT 2 may explain some of the other effects of risperidone . 12.2 Pharmacodynamics 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 (D 2 ), α1 and α2 adrenergic, and H 1 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 D 1 and haloperidol-sensitive sigma site; and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors. 12.3 Pharmacokinetics Absorption After a single intramuscular injection of RYKINDO, the release profile consists of an initial release of risperidone followed by a stable release phase of 2 to 4 weeks. The median time to peak concentration (T max ) of risperidone and 9-hydroxyrisperidone combined are 14 and 17 days after administration of 25 mg and 50 mg of RYKINDO, respectively. Systemic exposures (AUC 0-t and C max ) of the active moiety increase in a dose proportional manner across the dosing range from 12.5 mg to 50 mg. The combination of the release profile and the dosage regimen (intramuscular injections every 2 weeks) of RYKINDO results in sustained concentrations within the dosing interval (every 2 weeks). Steady-state plasma concentration levels are reached after 2 injections and can be maintained for 2 to 3 weeks after the last injection. Following multiple IM injections (25 mg every two weeks for five consecutive injections) in patients, the geometric mean ratios [RYKINDO to risperidone long-acting injection (intramuscular)] of risperidone and 9-hydroxyrisperidone combined were 102.33% for the C ss-max and 94.08% for the AUC ss-tau , and the 90% CIs of the ratios were within the 80% to 125% range. Distribution The volume of distribution of risperidone is 1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces the other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme CYP2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP2D6, also called debrisoquin hydroxylase, is responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. In a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered in solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life (t ½ ) of active moiety following RYKINDO administration is 3 to 6 days and associated with a monoexponential decline in plasma concentrations after a single dose. This t ½ is related to the erosion of the sterile powder and subsequent absorption of risperidone after RYKINDO intramuscular administration. The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. The elimination phase is completed approximately 6 weeks after the last injection. Specific Populations Patients with Renal Impairment Clearance of the sum of risperidone and 9-hydroxyrisperidone decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects treated with oral risperidone. [see Dosage and Administration (2.6) ] . Patients with Hepatic Impairment While the pharmacokinetics of oral risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not studied in RYKINDO clinical trials, it is recommended that patients with hepatic impairment be carefully titrated on oral risperidone before treatment with RYKINDO [see Dosage and Administration (2.6) ] . Geriatric Patients In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy elderly patients (≥ 65 years old) treated with risperidone long-acting injection (intramuscular) for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients. Racial or Ethnic Groups and Male and Female Patients No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis with risperidone long-acting injection (intramuscular) did not identify important differences in the disposition of risperidone due to gender (whether or not corrected for body weight) or race. Drug Interaction Studies Clinical Studies The interactions of RYKINDO with co-administration of other drugs have not been systematically evaluated in humans. The drug interaction data provided in this section is based primarily on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone and total active moiety as well as the effects of risperidone on the exposures of other drugs are summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone and Total Active Moiety Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent 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 effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Dosage and Administration (2.8) and Drug Interactions (7.1) ] . Moderate CYP3A4 Inhibitor (Erythromycin) There was no significant interaction between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine were not affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RYKINDO treatment [see Dosage and Administration (2.8) and Drug Interactions (7.1) ] . Amitriptyline, Cimetidine, Ranitidine, Clozapine Clinically meaningful pharmacokinetic interaction between RYKINDO and other drugs, such as amitriptyline, cimetidine, ranitidine and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9- hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9- hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Drugs Metabolized by CYP2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, RYKINDO ® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action 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 (D 2 ) and serotonin Type 2 (5HT 2 ) 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 D 2 and 5HT 2 may explain some of the other effects of risperidone .
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics 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 (D 2 ), α1 and α2 adrenergic, and H 1 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 D 1 and haloperidol-sensitive sigma site; and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption After a single intramuscular injection of RYKINDO, the release profile consists of an initial release of risperidone followed by a stable release phase of 2 to 4 weeks. The median time to peak concentration (T max ) of risperidone and 9-hydroxyrisperidone combined are 14 and 17 days after administration of 25 mg and 50 mg of RYKINDO, respectively. Systemic exposures (AUC 0-t and C max ) of the active moiety increase in a dose proportional manner across the dosing range from 12.5 mg to 50 mg. The combination of the release profile and the dosage regimen (intramuscular injections every 2 weeks) of RYKINDO results in sustained concentrations within the dosing interval (every 2 weeks). Steady-state plasma concentration levels are reached after 2 injections and can be maintained for 2 to 3 weeks after the last injection. Following multiple IM injections (25 mg every two weeks for five consecutive injections) in patients, the geometric mean ratios [RYKINDO to risperidone long-acting injection (intramuscular)] of risperidone and 9-hydroxyrisperidone combined were 102.33% for the C ss-max and 94.08% for the AUC ss-tau , and the 90% CIs of the ratios were within the 80% to 125% range. Distribution The volume of distribution of risperidone is 1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces the other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme CYP2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP2D6, also called debrisoquin hydroxylase, is responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. In a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered in solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life (t ½ ) of active moiety following RYKINDO administration is 3 to 6 days and associated with a monoexponential decline in plasma concentrations after a single dose. This t ½ is related to the erosion of the sterile powder and subsequent absorption of risperidone after RYKINDO intramuscular administration. The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. The elimination phase is completed approximately 6 weeks after the last injection. Specific Populations Patients with Renal Impairment Clearance of the sum of risperidone and 9-hydroxyrisperidone decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects treated with oral risperidone. [see Dosage and Administration (2.6) ] . Patients with Hepatic Impairment While the pharmacokinetics of oral risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not studied in RYKINDO clinical trials, it is recommended that patients with hepatic impairment be carefully titrated on oral risperidone before treatment with RYKINDO [see Dosage and Administration (2.6) ] . Geriatric Patients In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy elderly patients (≥ 65 years old) treated with risperidone long-acting injection (intramuscular) for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients. Racial or Ethnic Groups and Male and Female Patients No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis with risperidone long-acting injection (intramuscular) did not identify important differences in the disposition of risperidone due to gender (whether or not corrected for body weight) or race. Drug Interaction Studies Clinical Studies The interactions of RYKINDO with co-administration of other drugs have not been systematically evaluated in humans. The drug interaction data provided in this section is based primarily on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone and total active moiety as well as the effects of risperidone on the exposures of other drugs are summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone and Total Active Moiety Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent 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 effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Dosage and Administration (2.8) and Drug Interactions (7.1) ] . Moderate CYP3A4 Inhibitor (Erythromycin) There was no significant interaction between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine were not affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RYKINDO treatment [see Dosage and Administration (2.8) and Drug Interactions (7.1) ] . Amitriptyline, Cimetidine, Ranitidine, Clozapine Clinically meaningful pharmacokinetic interaction between RYKINDO and other drugs, such as amitriptyline, cimetidine, ranitidine and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9- hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9- hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Drugs Metabolized by CYP2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, RYKINDO ® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS RYKINDO is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Known hypersensitivity to risperidone, paliperidone, or to any components in RYKINDO. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION RYKINDO contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.5 g/mol. The structural formula is: Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. RYKINDO is provided as a single-dose kit consisting of: a vial containing a white to almost white powder, a pre-filled syringe containing 2 mL of a colorless, clear diluent, a vial adapter, and a needle (a 20 gauge 2-inch needle with needle protection device). The vial contains a white to almost white sterile powder containing risperidone. The powder consists of risperidone, mannitol (5.38 mg/100 mg risperidone), polylactide-co-glycolide (PLGA) 5050 (24.2 mg/100 mg risperidone) and polylactide-co-glycolide (PLGA) 7525 (96.7 mg/100 mg risperidone). The diluent is a sterile, clear, colorless, 2 mL solution. The diluent contains: 1.10 mg/mL citric acid monohydrate, 1.02 mg/mL dibasic sodium phosphate anhydrous, 1 mg/mL polysorbate 80, 6 mg/mL sodium carboxymethyl cellulose, 6 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 12.5 mg, 25 mg, 37.5 mg, or 50 mg. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 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. A starting dose of 12.5 mg may be appropriate for some patients. ( 2.6 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.8 ) 2.1 General Administration Information For patients who have never taken oral risperidone, establish tolerability with oral risperidone prior to initiating RYKINDO. RYKINDO should be administered every 2 weeks by intramuscular (IM) gluteal injection. Each injection should be administered by a health care professional. Do not administer by any other route. Alternate injections between the two buttocks. Do not combine two different dose strengths of RYKINDO in a single administration. For detailed preparation and administration instructions, see Dosage and Administration (2.8) . 2.2 Dosage Recommendations for the Treatment of Schizophrenia The recommended dosage of RYKINDO for the treatment of schizophrenia is 25 mg every 2 weeks. Administer the first dose of RYKINDO along with 7 days of oral risperidone. Patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg every 2 weeks. No additional benefit was observed with dosages greater than 50 mg of risperidone long-acting injection (intramuscular); however, a higher incidence of adverse reactions was observed. Dose titration should not be made more frequently than every 4 weeks. 2.3 Dosage Recommendations for Maintenance Treatment of Bipolar I Disorder The recommended dosage of RYKINDO for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder is 25 mg every 2 weeks. Administer the first dose of RYKINDO along with 7 days of oral risperidone. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. Dose titration should not be made more frequently than every 4 weeks. 2.4 Patients Currently Receiving Risperidone Long-acting Injection 2-week Intramuscular Formulation (e.g., Risperdal Consta) The RYKINDO dose for patients receiving a risperidone long-acting injection (intramuscular) every two week formulation (e.g., Risperdal Consta) should be the same as that of the previous treatment. The first injection of RYKINDO should be given 4 weeks (no later than 5 weeks) after the last injection of the previous treatment. Supplementation with oral risperidone is not recommended [see Clinical Pharmacology (12.3) ] . Titration should not be made more frequently than every 4 weeks. 2.5 Reinitiation of Treatment in Patients Previously Discontinued There are no data to specifically address reinitiation of treatment. When restarting patients who have had an interval off treatment with RYKINDO, the previously established dosage should be reinitiated if there has been no change in the patient's general medical condition. Supplementation with oral risperidone is also required. 2.6 Dosage Recommendations for Patients with Renal or Hepatic Impairment Patients with renal or hepatic impairment should be treated with titrated oral risperidone prior to initiating treatment with RYKINDO [see Use in Specific Populations (8.6 , 8.7) and Clinical Pharmacology (12.3) ] . The recommended starting dose is 0.5 mg oral risperidone twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral risperidone is well tolerated, RYKINDO 25 mg can be administered every 2 weeks with oral supplementation for 7 days following the first injection [see Dosing and Administration (2.2 , 2.3) ] . In some patients, slower titration may be appropriate. Alternatively, a starting dose of RYKINDO 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. 2.7 Dosage Recommendations for Concomitant Use of RYKINDO with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Co-administration of carbamazepine and other CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RYKINDO treatment. The risperidone dose needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.1) ]. At the initiation of therapy with carbamazepine or other known CYP3A4 hepatic enzyme inducers, patients should be closely monitored during the first 1 to 2 months because the dose of RYKINDO may need to be adjusted. A dose increase, or additional oral risperidone, needs to be considered. On discontinuation of carbamazepine or other CYP3A4 hepatic enzyme inducers, the dosage of RYKINDO should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RYKINDO between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RYKINDO and discontinuing from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates either lowering the RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. 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 RYKINDO dose to 12.5 mg or interruption of RYKINDO treatment. When RYKINDO is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Drug Interactions (7.1) ]. 2.8 Preparation and Administration Instructions Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider "Instructions for Use" for additional preparation and administration considerations. For gluteal intramuscular injection only. Do not inject by any other route. Alternate injections between the two buttocks. Allow package to come to room temperature for at least 30 minutes prior to preparation. Prepare medication when you are ready to administer the dose. The components in the single-dose kit are shown in Figure 1. Figure 1. Single-dose Kit Components Step 1. Take out kit and connect vial adapter to vial Wait 30 minutes Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting. Do not warm any other way. Remove cap from vial Flip off colored cap from vial. Wipe top of the gray stopper with an alcohol swab. Allow to air dry. Do not remove gray rubber stopper. Prepare vial adapter Hold sterile blister as shown. Peel back and remove paper backing. Do not remove vial adapter from blister. Do not touch spike tip at any time. This will result in contamination. Connect vial adapter to vial Place vial on a hard surface and hold by the base. Center vial adapter over the gray rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial. Step 2. Connect prefilled syringe to vial adapter Remove sterile blister Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination. Use proper grip Hold by the LUER-LOK ADAPTER at the tip of the syringe. Do not hold syringe by the glass barrel during assembly. Remove cap Holding the transparent LUER-LOK ADAPTER, unscrew the translucent gray cap Do not snap or cut off the translucent gray cap Do not touch syringe tip. This will result in contamination. The unscrewed cap can be discarded. Connect syringe to vial adapter Hold vial adapter by skirt to keep stationary. Hold syringe by the LUER-LOK ADAPTER then turn it to connect with the luer opening of the vial adapter Do not hold the glass syringe barrel. This may cause the LUER-LOK ADAPTER to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break. Step 3. Reconstitute powder Inject diluent Inject entire amount of diluent from syringe into the vial. Suspend Powder in diluent Continuing to hold down the plunger rod, shake vigorously for at least 30 seconds , as shown. Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in color. Immediately proceed to the next step so suspension does not settle. Transfer suspension to syringe Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. Remove vial adapter Hold LUER-LOK ADAPTER on the syringe and unscrew from vial adapter. Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. Discard both vial and vial adapter appropriately. Step 4. Attach Needle Take out needle Take out needle for gluteal injection. Attach needle Peel blister pouch open part way and use to grasp the base of the needle, as shown. Holding the LUER-LOK ADAPTER on the syringe, attach syringe to needle luer connection with a firm clockwise twisting motion until snug. Do not touch needle luer opening. This will result in contamination. Resuspend Powder Fully remove the blister pouch. Just before injection, shake syringe vigorously for 20 to 30 seconds until there is no deposition of powder, as some settling will have occurred. Step 5. Inject RYKINDO Remove transparent needle protector Move the needle safety device back towards the syringe, as shown. Then hold the LUER-LOK ADAPTER on syringe and carefully pull the transparent needle protector straight off. Do not twist transparent needle protector, as the luer connection may loosen. Remove air bubbles Hold syringe upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air. Inject Immediately inject entire contents of syringe intramuscularly into the upper-outer quadrant of the gluteal muscle of the patient. Secure needle in safety device Using one hand, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. Properly dispose of syringes Check to confirm needle safety device is fully engaged. Discard in an approved sharps container. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS RYKINDO (risperidone) for extended-release injectable suspension, for intramuscular use is available in strengths of 12.5 mg, 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). For extended-release injectable suspension: 12.5 mg, 25 mg, 37.5 mg, and 50 mg. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE RYKINDO is indicated: for the treatment of schizophrenia in adults as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults RYKINDO is an atypical antipsychotic indicated: for the treatment of schizophrenia in adults. ( 1 ) as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Rykindo extended-release microspheres Risperidone Rykindo extended-release microspheres Risperidone Risperidone Risperidone POLY(DL-LACTIC-CO-GLYCOLIC ACID), (75:25; 140000 MW) POLY(DL-LACTIC-CO-GLYCOLIC ACID), (50:50; 46000 MW) MANNITOL Diluent Diluent CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS POLYSORBATE 80 CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED SODIUM CHLORIDE SODIUM HYDROXIDE WATER Rykindo extended-release microspheres Risperidone Rykindo extended-release microspheres Risperidone Risperidone Risperidone POLY(DL-LACTIC-CO-GLYCOLIC ACID), (75:25; 140000 MW) POLY(DL-LACTIC-CO-GLYCOLIC ACID), (50:50; 46000 MW) MANNITOL Diluent Diluent CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS POLYSORBATE 80 CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED SODIUM CHLORIDE SODIUM HYDROXIDE WATER Rykindo extended-release microspheres Risperidone Rykindo extended-release microspheres Risperidone Risperidone Risperidone POLY(DL-LACTIC-CO-GLYCOLIC ACID), (75:25; 140000 MW) POLY(DL-LACTIC-CO-GLYCOLIC ACID), (50:50; 46000 MW) MANNITOL Diluent Diluent CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS POLYSORBATE 80 CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED SODIUM CHLORIDE SODIUM HYDROXIDE WATER Rykindo extended-release microspheres Risperidone Rykindo extended-release microspheres Risperidone Risperidone Risperidone POLY(DL-LACTIC-CO-GLYCOLIC ACID), (75:25; 140000 MW) POLY(DL-LACTIC-CO-GLYCOLIC ACID), (50:50; 46000 MW) MANNITOL Diluent Diluent CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS POLYSORBATE 80 CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED SODIUM CHLORIDE SODIUM HYDROXIDE WATER
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Oral Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas, endocrine pancreatic adenomas, and mammary gland adenocarcinomas. Table 8 summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 8. Summary of Tumor Occurrence at Multiples of the MRHD MRHD = maximum recommended human dose on a mg/ m 2 (mg/kg) basis with Oral Risperidone Dosing in Mice and Rats Tumor Type Species Sex Multiples of the MRHD in mg/m 2 (mg/kg) Lowest Effect Level Highest No-Effect Level Pituitary adenomas Mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas Rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas Mouse Female 0.2 (2.4) None Rat Female 0.4 (2.4) None Rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm (total) Rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels by 5- to 6- fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms were found in rodents after chronic administration of other antipsychotic drugs. These neoplasms were considered to be prolactin-mediated. The clinical relevance of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ]. Carcinogenesis - Intramuscular Risperidone was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with intramuscular (IM) injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m 2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m 2 basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m 2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m 2 basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD. Dopamine D 2 receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels by 5- to 6-fold in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month treatment with risperidone every 2 weeks IM. Increases in the incidence of pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and may be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo micronucleus test in mice, and the sex-linked recessive lethal test in Drosophila . In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for risperidone long-acting injection (intramuscular). Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses between 0.1 and 3 times the oral maximum recommended human dose (MRHD of 16 mg/day) based on a mg/m 2 body surface area. The effect appeared to be in females since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses between 0.6 and 10 times the oral MRHD on a mg/m 2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm values partially recovered but remained decreased after treatment discontinuation. A no-effect dose could not be determined in either rat or dog.
| Tumor Type | Species | Sex | Multiples of the MRHD in mg/m2 (mg/kg) | |
|---|---|---|---|---|
| Lowest Effect Level | Highest No-Effect Level | |||
| Pituitary adenomas | Mouse | Female | 0.75 (9.4) | 0.2 (2.4) |
| Endocrine pancreas adenomas | Rat | Male | 1.5 (9.4) | 0.4 (2.4) |
| Mammary gland adenocarcinomas | Mouse | Female | 0.2 (2.4) | None |
| Rat | Female | 0.4 (2.4) | None | |
| Rat | Male | 6.0 (37.5) | 1.5 (9.4) | |
| Mammary gland neoplasm (total) | Rat | Male | 1.5 (9.4) | 0.4 (2.4) |
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Oral Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas, endocrine pancreatic adenomas, and mammary gland adenocarcinomas. Table 8 summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 8. Summary of Tumor Occurrence at Multiples of the MRHD MRHD = maximum recommended human dose on a mg/ m 2 (mg/kg) basis with Oral Risperidone Dosing in Mice and Rats Tumor Type Species Sex Multiples of the MRHD in mg/m 2 (mg/kg) Lowest Effect Level Highest No-Effect Level Pituitary adenomas Mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas Rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas Mouse Female 0.2 (2.4) None Rat Female 0.4 (2.4) None Rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm (total) Rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels by 5- to 6- fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms were found in rodents after chronic administration of other antipsychotic drugs. These neoplasms were considered to be prolactin-mediated. The clinical relevance of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ]. Carcinogenesis - Intramuscular Risperidone was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with intramuscular (IM) injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m 2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m 2 basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m 2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m 2 basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD. Dopamine D 2 receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels by 5- to 6-fold in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month treatment with risperidone every 2 weeks IM. Increases in the incidence of pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and may be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo micronucleus test in mice, and the sex-linked recessive lethal test in Drosophila . In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for risperidone long-acting injection (intramuscular). Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses between 0.1 and 3 times the oral maximum recommended human dose (MRHD of 16 mg/day) based on a mg/m 2 body surface area. The effect appeared to be in females since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses between 0.6 and 10 times the oral MRHD on a mg/m 2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm values partially recovered but remained decreased after treatment discontinuation. A no-effect dose could not be determined in either rat or dog.
| Tumor Type | Species | Sex | Multiples of the MRHD in mg/m2 (mg/kg) | |
|---|---|---|---|---|
| Lowest Effect Level | Highest No-Effect Level | |||
| Pituitary adenomas | Mouse | Female | 0.75 (9.4) | 0.2 (2.4) |
| Endocrine pancreas adenomas | Rat | Male | 1.5 (9.4) | 0.4 (2.4) |
| Mammary gland adenocarcinomas | Mouse | Female | 0.2 (2.4) | None |
| Rat | Female | 0.4 (2.4) | None | |
| Rat | Male | 6.0 (37.5) | 1.5 (9.4) | |
| Mammary gland neoplasm (total) | Rat | Male | 1.5 (9.4) | 0.4 (2.4) |
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 12.5 mg Kit Carton 12.5 mg Kit Rykindo ® (risperiDONE) for extended-release injectable suspension KIT CONTENTS: One 12.5 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 72526-101-11 Principal Display Panel - 12.5 mg Kit Carton
PRINCIPAL DISPLAY PANEL - 25 mg Kit Carton 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 Principal Display Panel - 25 mg Kit Carton
PRINCIPAL DISPLAY PANEL - 37.5 mg Kit Carton 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 Principal Display Panel - 37.5 mg Kit Carton
PRINCIPAL DISPLAY PANEL - 50 mg Kit Carton 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 Principal Display Panel - 50 mg Kit Carton
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.RYKINDO is manufactured by: Shandong Luye Pharmaceutical Co., Ltd. Yantai, Shandong Province, China
Rykindo extended-release microspheres: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3) ] . Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4) ] . Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5) ] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of RYKINDO. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.6) ] . Orthostatic Hypotension and Syncope Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7) ] . Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while being treated with RYKINDO [see Warnings and Precautions (5.9) ] . Potential for Cognitive and Motor Impairment Inform patients that RYKINDO has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that treatment with RYKINDO does not affect them adversely [see Warnings and Precautions (5.10) ] . Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.13) ] . Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14) ] . Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7) ] . Alcohol Advise patients to avoid alcohol during treatment with RYKINDO [see Drug Interactions (7.1) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with RYKINDO. Advise patients that RYKINDO may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to RYKINDO during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using RYKINDO to monitor infants for somnolence, failure to thrive, jitteriness, and EPS (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Infertility Advise females of reproductive potential that RYKINDO may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3) ].
Instructions for use
Information about safe handling and use of the drug product.INSTRUCTIONS FOR USE 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 Wait 30 minutes Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting. Do not warm any other way. Remove cap from vial Flip off colored cap from vial. Wipe top of the gray stopper with an alcohol swab. Allow to air dry. Do not remove gray rubber stopper. Prepare vial adapter Hold sterile blister as shown. Peel back and remove paper backing. Do not remove vial adapter from blister. Do not touch spike tip at any time. This will result in contamination. Connect vial adapter to vial Place vial on a hard surface and hold by the base. Center vial adapter over the gray rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial. Step 2. Connect prefilled syringe to vial adapter Remove sterile blister Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination. Use proper grip Hold by the LUER-LOK ADAPTER at the tip of the syringe. Do not hold syringe by the glass barrel during assembly. Remove cap Holding the transparent LUER-LOK ADAPTER, unscrew the translucent gray cap. Do not snap or cut off the translucent gray cap. Do not touch syringe tip. This will result in contamination. The unscrewed cap can be discarded. Connect syringe to vial adapter Hold vial adapter by skirt to keep stationary. Hold syringe by the LUER-LOK ADAPTER then turn it to connect with the luer opening of the vial adapter. Do not hold the glass syringe barrel. This may cause the LUER-LOK ADAPTER to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break. Step 3. Reconstitute powder Inject diluent Inject entire amount of diluent from syringe into the vial. Suspend powder in diluent Continuing to hold down the plunger rod, shake vigorously for at least 30 seconds , as shown. Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in color. Immediately proceed to the next step so suspension does not settle. Transfer suspension to syringe Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. Remove vial adapter Hold the LUER-LOK ADAPTER on the syringe and unscrew from vial adapter. Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. Discard both vial and vial adapter appropriately. Step 4. Attach needle Take out needle Take out needle for gluteal injection. Attach needle Peel blister pouch open part way and use to grasp the base of the needle, as shown. Holding the LUER-LOK ADAPTER on the syringe, attach syringe to needle luer connection with a firm clockwise twisting motion until snug. Do not touch needle luer opening. This will result in contamination. Resuspend powder Fully remove the blister pouch. Just before injection, shake syringe vigorously for 20 to 30 seconds until there is no deposition of powder, as some settling will have occurred. Step 5. Inject RYKINDO ® Remove transparent needle protector Move the needle safety device back towards the syringe, as shown. Then hold the LUER-LOK ADAPTER on syringe and carefully pull the transparent needle protector straight off. Do not twist transparent needle protector, as the luer connection may loosen. Remove air bubbles Hold syringe upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air. Inject Immediately inject entire contents of syringe intramuscularly into the upper outer quadrant of the gluteal muscle of the patient. Do not administer by any other route. Secure needle in safety device Using one hand, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. Avoid needle stick injury: Do not use two hands. Do not intentionally disengage or mishandle the needle safety device. Do not attempt to straighten the needle or engage the safety device if the needle is bent or damaged. Properly dispose of syringes Check to confirm needle safety device is fully engaged. Discard in an approved sharps container. 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 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Schizophrenia 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. 14.2 Bipolar Disorder - Monotherapy 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. 14.3 Bipolar Disorder - Adjunctive Therapy 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.
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use 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) ].
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of RYKINDO have not been established in pediatric patients. Juvenile Animal Toxicity Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to childhood through adolescence in humans) at doses of 0.31, 1.25, or 5 mg/kg/day (1.2, 3.4, or 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area). Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUCs of risperidone and 9-hydroxyrisperidone combined that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. Juvenile rats treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females) with a no-effect dose of 0.63 mg/kg/day (0.5 times the MRHD of 6 mg/day for children). This dose produced plasma AUCs of risperidone and 9-hydroxyrisperidone combined that were approximately half the AUCs observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen in juvenile rats given up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUCs of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6mg/day of children.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RYKINDO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RYKINDO, during pregnancy (see Clinical Considerations ) . Risperidone has been detected in plasma in adult subjects up to 6 weeks after a single-dose of RYKINDO [see Clinical Pharmacology (12.3) ] . The clinical significance of RYKINDO administered before or during pregnancy is unknown. Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the MRHD based on mg/m 2 body surface area. Increased incidence of stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the MRHD based on mg/m 2 body surface area. Learning was impaired in the offspring of dams dosed at 0.6-times the MRHD and offspring mortality increased at maternal doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms (including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not show a clear association between antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI: 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI: 0.88-1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day or 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in the offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD. In a rat cross-fostering study, the number of live offspring was decreased, the number of stillbirths was increased, and the offspring birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced for offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD and the only dose tested in the study.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RYKINDO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RYKINDO, during pregnancy (see Clinical Considerations ) . Risperidone has been detected in plasma in adult subjects up to 6 weeks after a single-dose of RYKINDO [see Clinical Pharmacology (12.3) ] . The clinical significance of RYKINDO administered before or during pregnancy is unknown. Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the MRHD based on mg/m 2 body surface area. Increased incidence of stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the MRHD based on mg/m 2 body surface area. Learning was impaired in the offspring of dams dosed at 0.6-times the MRHD and offspring mortality increased at maternal doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms (including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not show a clear association between antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI: 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI: 0.88-1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day or 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in the offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD. In a rat cross-fostering study, the number of live offspring was decreased, the number of stillbirths was increased, and the offspring birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced for offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD and the only dose tested in the study. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant doses ranging between 2.3% and 4.7% of the maternal weight-adjusted dose. There are reports of sedation, failure to thrive, jitteriness, and EPS (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations ) . Risperidone has been detected in the plasma in adult subjects up to 6 weeks after a single-dose of RYKINDO [see Clinical Pharmacology (12.3) ] , and the clinical significance on the breastfed infant is not known. There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RYKINDO and any potential adverse effects on the breastfed child from RYKINDO or from the mother's underlying condition. Clinical Considerations Infants exposed to RYKINDO through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and EPS (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with RYKINDO may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.6) and Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness of RYKINDO have not been established in pediatric patients. Juvenile Animal Toxicity Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to childhood through adolescence in humans) at doses of 0.31, 1.25, or 5 mg/kg/day (1.2, 3.4, or 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area). Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUCs of risperidone and 9-hydroxyrisperidone combined that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. Juvenile rats treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females) with a no-effect dose of 0.63 mg/kg/day (0.5 times the MRHD of 6 mg/day for children). This dose produced plasma AUCs of risperidone and 9-hydroxyrisperidone combined that were approximately half the AUCs observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen in juvenile rats given up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUCs of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6mg/day of children. 8.5 Geriatric Use 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) ]. 8.6 Renal Impairment 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) ] . 8.7 Hepatic Impairment 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) ] . 8.8 Patients with Parkinson's Disease or Dementia with Lewy Bodies 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.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RYKINDO (risperidone) for extended-release injectable suspension, for intramuscular use is, when fully mixed, a white suspension, available in strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg. It 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). RYKINDO 12.5-mg kit: (NDC 72526-101-11): A white to almost white powder provided in a vial with an orange flip-off cap (NDC 72526-201-01); a pre-filled syringe containing 2 mL of a colorless, clear diluent (NDC 72526-801-01); a needle; and a vial adapter. RYKINDO: 25-mg kit (NDC 72526-102-11): A white to almost white powder provided in a vial with a green flip-off cap (NDC 72526-202-01); a pre-filled syringe containing 2 mL of a colorless, clear diluent (NDC 72526-801-01); a needle; and a vial adapter. RYKINDO: 37.5-mg kit: (NDC 72526-103-11): A white to almost white powder provided in a vial with a purple flip-off cap (NDC 72526-203-01); a pre-filled syringe containing 2 mL of a colorless, clear diluent (NDC 72526-801-01); a needle; and a vial adapter. RYKINDO 50-mg kit: (NDC 72526-104-11): A white to almost white powder provided in a vial with a blue flip-off cap (NDC 72526-204-01); a pre-filled syringe containing 2 mL of a colorless, clear diluent (NDC 72526-801-01); a needle; and a vial adapter. 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.
Storage and handling
Information about safe storage and handling of the drug product.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.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RYKINDO is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning . Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RYKINDO is not approved for use in patients with dementia-related psychosis. ( 5.1 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API