Risperidone oral solution 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)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23H 27FN 4O 2 and its molecular weight is 410.49. The structural formula is:

;

Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.

Risperidone is also available as a 1 mg/mL oral solution. Risperidone Oral Solution contains the following inactive ingredients: benzoic acid, sodium hydroxide, sorbitol solution, tartaric acid, and purified water.

Risperidone Oral Solution, USP;1 mg/mL;is supplied in

NDC: 70518-3741-00

NDC: 70518-3741-01

PACKAGING: 10 in 1 BOX

PACKAGING: 2 mL in 1 CUP, UNIT DOSE

Risperidone Oral Solution, USP;1 mg/mL;should be stored at controlled room temperature;20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and freezing.

Light Sensitive:;Store in carton, away from direct sunlight. Keep out of reach of children.

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Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Advise patients using Risperidone oral solution to read the FDA-approved patient labeling (Instructions for Use) for Risperidone oral solution.

Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone.

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, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [ 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)].

Orthostatic Hypotension

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 they should have their CBC monitored while taking risperidone [ see Warnings and Precautions (5.9)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperidone. 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)] .

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperidone therapy 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

Counsel 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, as a potential for interactions [ see Drug Interactions (7)].

Alcohol

Advise patients to avoid alcohol while taking risperidone [ see Drug Interactions (7.2)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperidone. Advise patients that risperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperidone during pregnancy [ see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using risperidone to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (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 risperidone may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible

[ see Use in Specific Populations (8.3)].

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RISPERIDONE ORAL SOLUTION, USP

Read these Instructions for Use before you start using Risperidone Oral Solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important information you need to know before taking Risperidone Oral Solution:

• Take Risperidone Oral Solution exactly as your healthcare provider tells you to take it.
• Each 1 mL contains 1 mg of Risperidone Oral Solution.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose using the oral dosing syringe.
• Always use the oral dosing syringe that comes with Risperidone Oral Solution. Contact your healthcare provider or pharmacist if you lose or damage the oral dosing syringe, or if your carton does not come with one.
• Risperidone Oral Solution can be taken directly from the oral dosing syringe or mixed with water, coffee, orange juice, or low-fat milk. Do not mix Risperidone Oral Solution with cola or tea.

Each Risperidone Oral Solution carton contains:

1 bottle of Risperidone Oral Solution 1 oral dosing syringe

Gather and check supplies:

• Gather the Risperidone Oral Solution bottle and oral dosing syringe.
• Check the expiration date on the bottle. Do not use the bottle of Risperidone Oral Solution if the expiration date has passed.
• Check your dose in mLs as prescribed by your healthcare provider. Find this mL marking on the plunger of the oral dosing syringe. If your dose is more than 3 mL, you will need to divide your dose. Follow the instructions given to you by your healthcare provider or pharmacist on how to divide your dose.

Preparing a dose of Risperidone Oral Solution:

Step 1. Place the Risperidone Oral Solution bottle on a flat surface. Push down on the cap while turning it to the left (counterclockwise) to open the bottle.
Step 2. Push the plunger of the oral dosing syringe all the way down.
Step 3. With the bottle in an upright position, fully insert the oral dosing syringe into the opening of the bottle.
Step 4. Withdraw the prescribed dose of Risperidone Oral Solution from the bottle. Hold down the barrel of the oral dosing syringe with one hand. With your other hand, slowly pull the plunger up until you reach the mL markings on the barrel for the prescribed dose.
Step 5. Remove the oral dosing syringe from the bottle by holding the outer barrel and pulling straight up. Be careful not to push down on the plunger during this step. Check the oral dosing syringe for air bubbles. If you see air bubbles, slowly push the plunger all the way down to return the oral solution into the bottle. Then repeat Step 4 to withdraw the prescribed dose.
Step 6. Risperidone Oral Solution can be mixed with a drink or taken directly from the oral dosing syringe. Mix the dose of Risperidone Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. See Figure 6a. Do not mix Risperidone Oral Solution with cola or tea.
Or To take the Risperidone Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. See Figure 6b.
Step 7. Place the cap back on the Risperidone Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle.
Step 8. Rinse the oral dosing syringe with water after each use. Remove the plunger from the oral dosing syringe barrel. Rinse the oral dosing syringe barrel and plunger with water and let them air dry. When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use. Do not throw away the oral dosing syringe.

Storing Risperidone Oral Solution:

• Store Risperidone Oral Solution at controlled room temperature 20° to 25°C (68° to 77°F).
• Do not freeze Risperidone Oral Solution. Protect from light.
• Keep Risperidone Oral Solution and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 04/2023

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625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Recommended daily dosage:

Initial Dose Target Dose Effective Dose Range
Schizophrenia: adults ( 2.1) 2 mg 4 to 8 mg 4 to 16 mg
Schizophrenia: adolescents ( 2.1) 0.5 mg 3 mg 1 to 6 mg
Bipolar mania: adults ( 2.2) 2 to 3 mg 1 to 6 mg 1 to 6 mg
Bipolar mania: in children and adolescents ( 2.2) 0.5 mg 1 to 2.5 mg 1 to 6 mg
Irritability associated;with autistic disorder ( 2.3)

0.25 mg

(Weight < 20 kg)

0.5 mg

(Weight ≥ 20 kg)

0.5 mg (< 20 kg)

1 mg

(≥ 20 kg)

;0.5 to 3 mg

Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. ( 2.4)
Oral Solution: Can be administered directly from calibrated oral dosing syringe or mixed with beverage (water, coffee, orange juice, or low-fat milk). ( 2.6)

​

Table 1; Recommended Daily Dosage by Indication
; Initial Dose Titration (Increments) ; ; Target Dose ; Effective Dose Range
Schizophrenia: adults ( 2.1) ;2 mg ;1 to 2 mg ;4 to 8 mg ;4 to 16 mg
Schizophrenia:; adolescents ( 2.1) ;0.5 mg ;0.5 to 1 mg ;3 mg ;1 to 6 mg
Bipolar mania: adults ( 2.2) ;2 to 3 mg ;1 mg ;1 to 6 mg ;1 to 6 mg
Bipolar mania: children and adolescents ( 2.2) ;0.5 mg ;0.5 to 1 mg ;1 to 2.5 mg ;1 to 6 mg
Irritability in autistic disorder ( 2.3)

0.25 mg;Can increase to 0.5 mg by Day 4: (body weight less than 20 kg)

0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg)

After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg)

0.5 mg (body weight greater than or equal to 20 kg)

0.5 mg:

(body weight less than 20 kg)

1 mg:

(body weight greater than or equal to 20 kg)

;0.5 to 3 mg

Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

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

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

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table 2.; Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
;Risperidone
; 1 to 8 mg/day ; >8 to 16 mg/day
; Mean change from baseline (mg/dL)
&; n = 748 ; n = 164
;Serum Glucose ;-1.4 ;0.8 ;0.6
; Proportion of patients with shifts

;Serum Glucose

(<140 mg/dL to ≥ 200 mg/dL)

;0.6%

(3/525)

0.4%

(3/702)

0%

(0/158)

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

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3.; Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)

; ; Risperidone
; mg/day
; Mean change from baseline (mg/dL)
; n = 76 ; n = 135
;Serum Glucose ;-1.3 ;2.6
; Proportion of patients with shifts

;Serum Glucose

(<100 mg/dL to ≥126 mg/dL)

;0%

(0/64)

;0.8%

(1/120)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table 4.; Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
; Risperidone
; ; Placebo ; 1 to 8 mg/day ; >8 to16 mg/day
; Mean change from baseline (mg/dL)

Cholesterol

;Change from baseline

; n = 559

;0.6

; n = 742

;6.9

; n = 156

;1.8

Triglycerides

;Change from baseline

; n = 183

;-17.4

; n = 307

;-4.9

; n = 123

;-8.3

Proportion of patients with shifts

Cholesterol

;(<200 mg/dL to ≥240 mg/dL)

;2.7%

(10/368)

;4.3%

(22/516)

;6.3%

(6/96)

Triglycerides

;(<500 mg/dL to ≥500 mg/dL)

;1.1%

(2/180)

;2.7%

(8/301)

;2.5%

(3/121)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5.

Table 5.; Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
Placebo;

; Risperidone

0.5 to 6 mg/day

; Mean change from baseline (mg/dL)

Cholesterol

;Change from baseline

; n = 74

;0.3

; n = 133

;-0.3

LDL

;Change from baseline

; n = 22

;3.7

; n = 22

;0.5

HDL

;Change from baseline

; n = 22

;1.6

; n = 22

;-1.9

Triglycerides

Change from baseline

; n;= 77

;-9

; n = 138

;-2.6

; Proportion of patients with shifts

Cholesterol

;(<170 mg/dL to ≥200 mg/dL)

;2.4%

(1/42)

;3.8%

(3/80)

LDL

;(<110 mg/dL to ≥130 mg/dL)

;0%

(0/16)

;0%

(0/16)

HDL

;(≥40 mg/dL to <40 mg/dL)

;0%

(0/19)

;10%

(2/20)

Triglycerides

;(<150 mg/dL to ≥200 mg/dL)

;1.5%

(1/65)

;7.1%

(8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

Table 6.; Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
; Risperidone
;

;Placebo

(n = 597)

; 1 to 8 mg/day

(n = 769)

; >8 to16 mg/day

(n = 158)

; Weight (kg)

;Change from baseline

;-0.3 ;0.7 ;2.2

; Weight Gain

;≥7% increase from baseline

;2.9% ;8.7% ;20.9%

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7.

Table 7.; Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)

; Placebo

(n = 375)

; Risperidone 0.5 to 6 mg/day

(n = 448)

; Weight (kg)

;Change from baseline

;0.6% ;2%

; Weight Gain

;≥7% increase from baseline

;6.9% ;32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth.

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 events, including stroke, in elderly patients with dementia-related psychosis [ see Warnings and Precautions; ( 5.2 ) ]
Neuroleptic malignant syndrome [ see Warnings and Precautions; ( 5.3 ) ]
Tardive dyskinesia [ see Warnings and Precautions; ( 5.4 ) ]
Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [ see Warnings and Precautions; ( 5.5 ) ]
Hyperprolactinemia [ see Warnings and Precautions; ( 5.6 ) ]
Orthostatic hypotension [ see Warnings and Precautions; ( 5.7 ) ]
Falls [ see Warnings and Precautions ; ( 5.9 ) ]
Potential for cognitive and motor impairment [ see Warnings and Precautions-732c-4032-b401-1fea4ee2cff0">( 5.11 ) ]
Dysphagia [ see Warnings and Precautions; ( 5.12 ) ]
Priapism [ see Warnings and Precautions; ( 5.13 ) ]
Disruption of body temperature regulation [ see Warnings and Precautions; ( 5.14 ) ];

The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [ see Adverse Reactions , Discontinuations Due to Adverse Reactions ( 6.1 )].

The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone 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 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Risperidone oral solution is available in a 1 mg/mL strength.

Risperidone oral solution is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

1.1 Schizophrenia

Risperidone oral solution is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see CLINICAL STUDIES (14.1)].

1.2 Bipolar Mania

Monotherapy

Risperidone oral solution is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see CLINICAL STUDIES (14.2)].

Adjunctive Therapy

Risperidone oral solution adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see CLINICAL STUDIES (14.3)].

1.3 Irritability Associated with Autistic Disorder

Risperidone oral solution is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see CLINICAL STUDIES (14.4)].

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

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperidone is not approved for the treatment of dementia-related psychosis [see BOXED WARNING].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

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

5.3 Neuroleptic Malignant Syndrome

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

If NMS is suspected, immediately discontinue Risperidone Oral Solution and provide symptomatic treatment and monitoring.

5.4 Tardive Dyskinesia

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

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

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

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

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

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

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

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

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to 16 mg/day
Mean change from baseline (mg/dL)
n = 555 n = 748 n = 164
Serum Glucose -1.4 0.8 0.6
Proportion of patients with shifts

Serum Glucose

(<140 mg/dL to ≥ 200 mg/dL)

0.6%

(3/525)

0.4%

(3/702)

0%

(0/158)

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

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)

Risperidone
Placebo 0.5 to 6 mg/day
Mean change from baseline (mg/dL)
n = 76 n = 135
Serum Glucose -1.3 2.6
Proportion of patients with shifts

Serum Glucose

(<100 mg/dL to ≥126 mg/dL)

0%

(0/64)

0.8%

(1/120)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to16 mg/day
Mean change from baseline (mg/dL)

Cholesterol

Change from baseline

n = 559

0.6

n = 742

6.9

n = 156

1.8

Triglycerides

Change from baseline

n = 183

-17.4

n = 307

-4.9

n = 123

-8.3

Proportion of patients with shifts

Cholesterol

(<200 mg/dL to ≥240 mg/dL)

2.7%

(10/368)

4.3%

(22/516)

6.3%

(6/96)

Triglycerides

(<500 mg/dL to ≥500 mg/dL)

1.1%

(2/180)

2.7%

(8/301)

2.5%

(3/121)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5.

Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
Placebo

Risperidone

0.5 to 6 mg/day

Mean change from baseline (mg/dL)

Cholesterol

Change from baseline

n = 74

0.3

n = 133

-0.3

LDL

Change from baseline

n = 22

3.7

n = 22

0.5

HDL

Change from baseline

n = 22

1.6

n = 22

-1.9

Triglycerides

Change from baseline

n = 77

-9

n = 138

-2.6

Proportion of patients with shifts

Cholesterol

(<170 mg/dL to ≥200 mg/dL)

2.4%

(1/42)

3.8%

(3/80)

LDL

(<110 mg/dL to ≥130 mg/dL)

0%

(0/16)

0%

(0/16)

HDL

(≥40 mg/dL to <40 mg/dL)

0%

(0/19)

10%

(2/20)

Triglycerides

(<150 mg/dL to ≥200 mg/dL)

1.5%

(1/65)

7.1%

(8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
Risperidone

Placebo

(n = 597)

1 to 8 mg/day

(n = 769)

>8 to16 mg/day

(n = 158)

Weight (kg)

Change from baseline

-0.3 0.7 2.2

Weight Gain

≥7% increase from baseline

2.9% 8.7% 20.9%

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7.

Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)

Placebo

(n = 375)

Risperidone 0.5 to 6 mg/day

(n = 448)

Weight (kg)

Change from baseline

0.6% 2%

Weight Gain

≥7% increase from baseline

6.9% 32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth.

5.6 Hyperprolactinemia

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

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

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see NONCLINICAL TOXICOLOGY (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.7 Orthostatic Hypotension

Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see DOSAGE AND ADMINISTRATION (2.1, 2.4)].

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

5.8 Falls

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

5.9 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

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

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue risperidone and have their WBC followed until recovery.

5.10 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely.

5.11 Seizures

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.

5.12 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].

5.13 Priapism

Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

DRUG: Risperidone

GENERIC: Risperidone

DOSAGE: SOLUTION

ADMINSTRATION: ORAL

NDC: 70518-3741-0

NDC: 70518-3741-1

COLOR: white

PACKAGING: 2 mL in 1 CUP, UNIT-DOSE

OUTER PACKAGING: 10 in 1 BOX

ACTIVE INGREDIENT(S):

• RISPERIDONE 1mg in 1mL

INACTIVE INGREDIENT(S):

• BENZOIC ACID
• SODIUM HYDROXIDE
• SORBITOL SOLUTION
• TARTARIC ACID
• WATER