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RISPERIDONE

Wockhardt USA LLC.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use risperidone oral solution safely and effectively. See full prescribing information for risperidone oral solution. Risperidone Oral Solution for Oral use. Initial U.S. approval:1993BOXED WARNINGWARNING: INCREASED MORTALITY IN ELDERLY PATIENTS   WITH  DEMENTIA-RELATED PSYCHOSISSee full prescribing information for complete boxed warning.Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for patients with dementia-related psychosis. (5.1)RECENT MAJOR CHANGESBoxed Warning 08/2008Warnings and Precautions (5.1) 08/2008Warnings and Precautions, Leucopenia, Neutropenia, and Agranulocytosis (5.8) 09/2009 INDICATIONS AND USAGERisperidone is an atypical antipsychotic agent indicated for: Treatment of schizophrenia in adults (1.1) Alone, or in combination with lithium or valproate, for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults (1.2) Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia, bipolar mania or autistic disorder.(1.1,1.2,1.3) DOSAGE AND ADMINISTRATION Initial Dose Titration Target Dose Effective Dose Range Schizophrenia – adults (2.1) 2 mg/day 1 to 2 mg daily 4 to 8 mg daily 4 to 16 mg / day Bipolar mania- adults (2.2) 2 to 3 mg / day 1 mg daily 1 to 6 mg / day 1 to 6 mg / day DOSAGE FORMS AND STRENGTHS Oral solution: 1 mg/mL (3) CONTRAINDICATIONS Known hypersensitivity to the product (4) WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis. Risperidone is not approved for use in patients with dementia-related psychosis (5.2) Neuroleptic Malignant Syndrome (5.3) Tardive dyskinesia (5.4) Hyperglycemia and diabetes mellitus (5.5) Hyperprolactinemia (5.6) Orthostatic hypotension (5.7) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including risperidone. Patients with a history of a clinically     significant low white blood cell count (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. (5.8) Potential for cognitive and motor impairment (5.9) Seizures (5.10) Dysphagia (5.11) Priapism (5.12) Disruption of body temperature regulation (5.13) Antiemetic Effect (5.14) Suicide (5.15) Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies (5.16) Diseases or conditions that could affect metabolism or hemodynamic responses (5.16) Side EffectsThe most common adverse reactions in clinical trials ≥10% were somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. (6)The most common adverse reactions that were associated with discontinuation from clinical trials were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC., at 1-800-346-6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Due to CNS effects, use caution when administering with other centrally-acting drugs. Avoid alcohol. (7.1) Due to hypotensive effects, hypotensive effects of other drugs with this potential may be enhanced. (7.2) Effects of levodopa and dopamine agonists may be antagonized. (7.3) Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5) Clozapine may decrease clearance of risperidone. (7.6) Fluoxetine and paroxetine increase plasma concentrations of risperidone. (7.10) Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. (7.11) USE IN SPECIFIC POPULATIONS Nursing Mothers: should not breast feed. (8.3) Pediatric Use: safety and effectiveness not established for schizophrenia less than 13 years of age, for bipolar mania less than 10 years of age, and for autistic disorder less than 5 years of age. (8.4) Elderly or debilitated; severe renal or hepatic impairment; predisposition to hypotension or for whom hypotension poses a risk: Lower initial dose (0.5 mg twice daily), followed by increases in dose in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should occur at intervals of at least 1 week. (8.5, 2.4)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

BOXED WARNING

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. 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. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]

RECENT MAJOR CHANGES

Enter section text here

1INDICATIONS AND USAGE

1.1Schizophrenia

Adults
Risperidone oral solution is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)].

Adolescents
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia. Pediatric use information for the treatment of pediatric patients with schizophrenia, 13 to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

1.2Bipolar Mania









1.3Irritability Associated with Autistic Disorder



2DOSAGE AND ADMINISTRATION

2.1Schizophrenia
















2.2Bipolar Mania










2.3Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)

2.4Dosage in Special Populations





2.5Co-Administration of Risperidone Oral Solution with Certain Other Medications



2.6Administration of Risperidone Oral Solution

3DOSAGE FORMS AND STRENGTHS

4CONTRAINDICATIONS

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, risperidone is contraindicated in patients with a known hypersensitivity to the product.

5WARNINGS AND PRECAUTIONS

5.1Increased 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. Risperidone is not approved for the treatment of dementia-related psychosis (see BOXED WARNING).

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


5.3Neuroleptic Malignant Syndrome (NMS)







5.4Tardive Dyskinesia









5.5Hyperglycemia and Diabetes Mellitus



5.6Hyperprolactinemia

2



5.7Orthostatic Hypotension

5.8Leukopenia, Neutropenia, and Agranulocytosis



3

5.9Potential for Cognitive and Motor Impairment

5.10Seizures

5.11Dysphagia


5.12Priapism

5.13Body Temperature Regulation

5.14Antiemetic Effect

5.15Suicide

5.16Use in Patients with Concomitant Illness





2

5.17Monitoring: Laboratory Tests

6ADVERSE REACTIONS



  • 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)]
  • Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
  • Hyperprolactinemia [see Warnings and Precautions (5.6)]
  • Orthostatic hypotension [see Warnings and Precautions (5.7)]
  • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
  • Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
  • Seizures [see Warnings and Precautions (5.10)]
  • Dysphagia [see Warnings and Precautions (5.11)]
  • Priapism [see Warnings and Precautions (5.12)]
  • Disruption of body temperature regulation [see Warnings and Precautions (5.13)]
  • Antiemetic effect [see Warnings and Precautions (5.14)]
  • Suicide [see Warnings and Precautions (5.15)]
  • Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.16)]
  • Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.16)]












6.1Commonly-Observed Side Effects in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia




Table 1. Adverse Reactions in ≥1% of Risperidone -Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials
   Percentage of Patients Reporting Event
Body System
Adverse reaction
 Risperidone
2 to 8 mg per day
(N=366)
 Risperidone
>8 to 16 mg per day
 Placebo
(N=225)
Body as a whole - general disorders


Back pain
 3
 2
 <1
Fatigue
3
 1
 0
Chest pain
3
 1
 2
Fever
 2
 1
 1
Asthenia
1
 1
 <1
Syncope
<1 1
 <1
Edema
 <1 1
 0
Cardiovascular disorders, general


Hypotension postural
 2
 <1 0
Hypotension
<1 1
   0
Central and peripheral nervous system disorders


Parkinsonism*
 12
 17
 6
Dizziness
 10
 4
 2
Dystonia*
 5
 5
 2
Akathisia*
 5
 5
 2
Dyskinesia
 1
 1
 <1
Gastrointestinal system disorders


Dyspepsia
10
 7
 6
Nausea
 9
 4
 4
Constipation
 8
   9
 7
Abdominal pain
 4
 3
0
Mouth dry
4
   <1 <1
Saliva increased
3
 1
 <1
Diarrhea
2
 <1 1
Hearing and vestibular disorders



Earache
 1
 1
   0
Heart rate and rhythm disorders


Tachycardia
 2
 5
 0
Arrhythmia
 0
 1
 0
Metabolic and nutritional disorders


Weight increase
 1
 <1 0
Creatine phosphokinase increased
 <1
 2
 <1
Musculoskeletal system disorders


Arthralgia
  2
 3
 <1
Myalgia
1  0
   0
Platelet, bleeding and clotting disorders


Epistaxis
<1 2
 0
Psychiatric disorders



Anxiety
 16
 12
 11
Somnolence
 14
 5
 4
Anorexia
 2
 0
 <1
Red blood cell disorders


Anemia
<1 1
 0
Reproductive disorders, male


Ejaculation failure
 <1 1
 0
Respiratory system disorders


Rhinitis
 7
 11
 6
Coughing
 3
 3
 3
Upper respiratory tract infection
 2
 3
 <1
Dyspnea
 2
 2
 0
Skin and appendages disorder


Rash
 2
 4
 2
Seborrhea
 <1 2
 0
Urinary system disorders


Urinary tract infection
<1  3
 0
Vision disorders


Vision abnormal
 3
 1
 <1







Table 2. Adverse Reactions in ≥5% of Risperidone -Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial
                                                      Percentage of Patients Reporting Event
                                                                 Risperidone
Body System
Adverse Reaction

1 to 3 mg per day
(N=55)

 4 to 6 mg per day
(N=51)
 Placebo
(N=54)
Central and peripheral nervous system disorders


Parkinsonism*
                   13
                  16
         6
Tremor
                   11
                  10
         6
Dystonia*
                    9
                  18
         7
Dizziness
                    7
                  14
         2
Akathisia*
                   7
                  10
         6
Gastrointestinal system disorders


Saliva increased
                  0
                   10
         2
Psychiatric disorders


Somnolence
                   24
                   12
         4
Anxiety
                    7
                     6
         0


6.2Commonly-Observed Side Effects in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania




Table 3. Adverse Reactions in ≥1% of Risperidone -Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials
Percentage of Patients Reporting Event
Body System
Adverse Reaction
 Risperidone
1 to 6 mg per day (N=448)    
Placebo (N=424)
Body as a whole - general disorders

Fatigue
                               2
              <1
Fever                                1
              <1
Asthenia                                1
              <1
Edema                                1
              <1
Central and peripheral nervous system disorders 

Parkinsonism*
                              20
                6
Dystonia*
                              11
                3
Akathisia*
                               9
                3
Tremor
                               6
                4
Dizziness                                5
               5
Gastrointestinal system disorders

Nausea
                               5
                2
Dyspepsia
                                4
                2
Saliva increased
                               3
              <1
Diarrhea
                                3
                 2
Mouth dry                                1
                 1
Heart rate and rhythm disorders

Tachycardia                                1
              <1
Liver and biliary system disorders 

SGOT increased                                1
              <1
Musculoskeletal disorders

Myalgia
                               2
                 2
Psychiatric disorders

Somnolence
                              12
                 4
Anxiety                                 2
                 2
Reproductive disorders, female

Lactation nonpuerperal
                               1
                 0
Respiratory disorders

Rhinitis
                               2
                 2
Skin and appendages disorders

Acne
                               1
                 0
Vision disorders

Vision abnormal                                2
              <1




Table 4. Adverse Reactions in ≥2% of Risperidone -Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
                  Percentage of Patients Reporting Event
Body System
Adverse Reaction
 Risperidone + Mood Stabilizer
(N=127)
 Placebo + Mood Stabilizer
(N=126)
Body as a whole – general disorders 


Chest pain
                   2
                   2
Fatigue                    2
                   2
Central and peripheral nervous system disorders 

Parkinsonism*
                    9
                   4
Dizziness
                    8
                   2
Dystonia*
                    6
                   3
Akathisia*
                    6
                  0
Tremor                    5
                   2
Gastrointestinal system disorders

Nausea
                   6
                   5
Diarrhea
                   6
                   4
Saliva increased
                   4
                   0
Abdominal pain                    2
                  0
Heart rate and rhythm disorders


Palpitation                    2
                   0
Metabolic and nutritional disorders


Weight increase                    2
                  2
Psychiatric disorders


Somnolence                    12
                   5
Anxiety
                   4
                   2
Respiratory disorders

Pharyngitis
                   5
                   2
Coughing                    3
                   1
Skin and appendages disorders          

Rash
                    2
                   2
Urinary system disorders

Urinary incontinence
                    2
                   1
Urinary tract infection                    2
                   1








Table 5. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
Body System
Adverse Reaction

Risperidone
0.5 to 2.5 mg per day (N=50)
 Risperidone
3 to 6 mg per day (N=61)
 Placebo
(N=58)
Body as a whole - general disorders



Fatigue
                        18
                     30
         3
Central and peripheral nervous system disorders



Dizziness
                        16
                      13
         5
Dystonia*
                          8
                      13
         2
Parkinsonism*
                          2
                        7
         2
Akathisia*                           0
                        7
         2 
Gastrointestinal system disorders 


Abdominal pain
                       18
                     15
         5
Dyspepsia
                       16
                       5
         3
Nausea
                       16
                     13
         7
Vomiting
                       12
                     10
         7
Diarrhea                          8
                       7
         2
Heart rate and rhythm disorders


Tachycardia
                         0
                      5
         2
Psychiatric disorders


Somnolence
                       42
                    56
       19
Appetite increased
                         4
                     7
         2
Anxiety                          0
                     8
         3
Reproductive disorders, female


Lactation nonpuerperal
                         2
                     5
         0
Respiratory system disorders


Rhinitis
                       14
                   13
       10
Dyspnea
                         2
                     5
         0
Skin and appendages disorders



Rash
                          0
                     7
         2
Urinary system disorders


Urinary incontinence
                           0
                      5
         0
Vision disorders



Vision abnormal                          4
                     7
         0




6.3 Commonly-Observed Side Effects in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder



Table 6. Adverse Reactions in ≥5% of Risperidone -Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials
                                                                   Percentage Patients Reporting Event
Body System
Adverse Reaction

Risperidone
0.5 to 4.0 mg per day
(N=76)
 Placebo
(N=80)
Body as a whole - general disorders                            42
         13
Fatigue
                            20
         19
Fever


Central and peripheral nervous system disorders

Dystonia*
                            12
           6
Tremor
                           12
           1
Dizziness
                             9
           3
Parkinsonism*
                              8
           0
Automatism
                              7
           1
Dyskinesia
                             7
           0
Gastrointestinal system disorders


Vomiting
                             25
           21
Saliva increased
                           22
           6
Constipation
                           21
           8
Mouth dry
                           13
           6
Nausea
                             8
           8
Heart rate and rhythm disorders  
  
Tachycardia
                             7
           0
Metabolic and nutritional disorders


Weight increase
                            5
           0
Psychiatric disorders

Somnolence
                           67
         23
Appetite increased
                          49
          19
Anxiety
                          16
          15
Anorexia
                            8
            8
Confusion
                            5
            0
Respiratory system disorders

Rhinitis
                          36
          23
Upper respiratory tract infection
                          34
          15
Coughing
                          24
          18
Skin and appendages disorders


Rash                           11
           8
Urinary system disorders

Urinary incontinence
                          22
         20


6.4 Other Side Effects Observed During the Premarketing Evaluation of Risperidone









































6.5 Discontinuations Due to Side Effects





Table 7. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials
Risperidone
Adverse reaction
 2 to 8 mg/day
(N=366)
 > 8 to 16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
                      1.4%
                             1.0%
          0%
Nausea
                      1.4%
                                0%
          0%
Agitation                       1.1%
                             1.0%
          0%
Parkinsonism
                     0.8%
                                0%
          0%
Somnolence
                     0.8%
                             0.5%
          0%
Dystonia
                      0.5%
                                0%
          0%
Abdominal pain
                      0.5%
                                0%
          0%
Hypotension postural
                      0.3%
                             0.5%
          0%
Tachycardia
                    0.3%
                             0.5%
          0%
Akathisia
                       0%
                              1.0%
          0%









Table 8. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials
                  Risperidone
Adverse reactions
 1 to 6mg/day
(N=448)

 Placebo
(N=424)
Parkinsonism
                        0.4%
                   0%
Somnolence
                        0.2%
                   0%
Dizziness
                         0.2%
                   0%
Dystonia
                        0.2%
                   0%
SGOT increased                         0.2%
                 0.2%
SGPT increased                         0.2%
                 0.2%








6.6Dose Dependency of Side Effects in Clinical Trials





Dose Groups
 Placebo
 Risperidone
2 mg		 Risperidone
6 mg 		Risperidone
10 mg 		Risperidone
  16 mg
Pakinsonism
 1.2
 0.9
 1.8
 2.4
 2.6
EPS Incidence
 11% 15% 16% 20% 31%

Dose Groups
 Risperidone
1 mg
 Risperidone
4 mg		 Risperidone
8 mg 		Risperidone
12 mg 		Risperidone
  16 mg
Pakinsonism
 0.6
 1.7
 2.4
 2.9
 4.1
EPS Incidence
 7% 11% 17% 18% 20%



6.7Changes in Body Weight





6.8Changes in ECG



6.9Postmarketing Experience



7DRUG INTERACTIONS

7.1Centrally-Acting Drugs and Alcohol

7.2Drugs with Hypotensive Effects

7.3Levodopa and Dopamine Agonists

7.4Amitriptyline

7.5Cimetidine and Ranitidine

7.6Clozapine

7.7Lithium

max

7.8Valproate

max

7.9Digoxin

7.10Drugs That Inhibit CYP 2D6 and Other CYP Isozymes









7.11Carbamazepine and Other Enzyme Inducers

7.12Drugs Metabolized by CYP 2D6

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy


2222

22



8.2Labor and Delivery

8.3Nursing Mothers


8.4Pediatric Use






























8.5Geriatric Use






9DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance


9.2Abuse

9.3Dependence

10OVERDOSAGE

Enter section text here

10.1 Human Experience





10.2 Management of Overdosage






11 DESCRIPTION

Risperidone is a psychotropic agent 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 C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:


RISPERIDONE





12 CLINICAL PHARMACOLOGY


12.1 Mechanism of Action

22

221211C1D1A1-512

12.2 Pharmacodynamics

22

12.3 Pharmacokinetics

Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Pharmacokinetic studies showed that risperidone orally disintegrating tablets and risperidone oral solution are bioequivalent to risperidone tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers).

Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.

Distribution
Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each 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 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. 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.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 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 CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 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.

Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions 7.12)].

Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as 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 of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.16)].

Hepatic Impairment
While the pharmacokinetics of 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. Risperidone doses should be reduced in patients with liver disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.16)].

Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Dosage and Administration (2.4)].

Pediatric
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients withschizophrenia, bipolar mania or irritability associated with autistic disorder. Pharmacokinetic information for pediatric patients with schizophrenia, 13 to 17 years of age, bipolar mania, 10 to 17 years old, and irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.


13 NONCLINICAL TOXICOLOGY


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m2(mg/kg) basis at which these tumors occurred.

                                                                           Multiples of Maximum
                                                                           Human Dose in mg/m2
                                                                         (mg/kg)
Tumor Type
 Species
Sex
 Lowest Effect Level
 Highest
No-EffectLevel
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
        rat
        rat
female
female
male
                 0.2 (2.4)
                 0.4 (2.4)
                 6.0 (37.5)

           none
           none
        1.5 (9.4)
Mammary gland neoplasm, Total         rat
 male
                  1.5 (9.4)
        0.4 (2.4)






22









14 CLINICAL STUDIES


14.1 Schizophrenia























14.2 Bipolar Mania - Monotherapy

Adults
The efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow:

  • In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.
  •  In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.


Pediatrics
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with bipolar mania. Clinical trial information for pediatric patients with bipolar mania, 10  to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

14.3 Bipolar Mania – Combination Therapy

The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.

  •  In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.
  •  In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4  to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.


14.4 Irritability Associated with Autistic Disorder

Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with irritability associated with autistic disorder. Clinical trial information for pediatric patients with irritability associated with autistic disorder,5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

16 HOW SUPPLIED/STORAGE AND HANDLING

Risperidone Oral Solution
Risperidone 1 mg/mL Oral Solution (NDC 64679-692-01) is supplied in 30 mL bottles with a calibrated (in milligrams and milliliters) syringe. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.
Storage and Handling
Risperidone 1 mg/mL Oral Solution should be stored at 200-250C (680-770F) [See USP Controlled Room Temperature]. Protect from light and freezing.

Keep out of reach of children

17 PATIENT COUNSELING INFORMATION

17.1 Orthostatic Hypotension

17.2 Interference with Cognitive and Motor Performance

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 [see Warnings and Precautions (5.9)].


17.3 Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

17.4 Nursing

Patients should be advised not to breast-feed an infant if they are taking risperidone [see Use in Specific Populations (8.3)].

17.5 Concomitant Medication

Patients should be advised to inform their physicians 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)].


17.6 Alcohol
















USING YOUR RISPERIDONE ORAL SOLUTION ADAPTER,DISPENSING SYRINGE AND BOTTLE


IMPORTANT
Please read these instructions before using
Risperidone Oral Solution.
  • Push the plastic screw-cap on the bottle down while turning it counter clock-wise. Remove the unscrewed cap (see figure 1).
  • Remove the adapter and dispensing syringe from the plastic pouch provided and fit the adapter properly into the neck of bottle. (see figure 2).
  • Remove the tip cover of dispensing syringe and keep the tip cover in safe place, away from children.      
  • Insert the tip of dispensing syringe in the adapter plug fitted on the bottle neck. (see figure 3)
  • Holding the syringe properly, invert the bottle upside down.
  • While holding the outer barrel of the syringe, pull the plunger up to the level (see marking on side) that equals the dosage prescribed by your physician. (see figure 4).
  • Once the dose is removed, keep the bottle upright holding the outer barrel of the syringe, remove the entire syringe from the bottle, being careful not to depress the plunger prematurely (see figure 5).
  • Empty the entire content of the syringe into 3 to 4 ounces (100 mL) of a beverage by pushing the plunger down inside the syringe barrel. Stir the mixture thoroughly before consuming. Risperidone oral solution is compatible with water, coffee, orange juice, or low-fat milk: IT IS NOT COMPATIBLE with cola or tea.
  • Replace the plastic cap on the bottle by screwing it clock-wise; rinse the empty dispensing syringe thoroughly with water and put the tip cover on the tip of the dispensing syringe (see figure 6).
  • Keep the bottle and syringe in safe place, away from children.

RISPERIDONE




0000





















RISPERIDONE



RISPERIDONE


RISPERIDONE

RISPERIDONE SOLUTION

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:64679-692
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
RISPERIDONE RISPERIDONE 1 mg

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:64679-692-01 30 in 1 BOTTLE

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078744 2009-10-14


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Be sure to consult your doctor before taking any medication!
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