HIGHLIGHTS OF PRESCRIBING INFORMATION
`do not include all the information
`These highlights
`needed to use
`RISPERDAL safely and effectively. See full prescribing information
`RISPERDAL".
`RISPKRDAL" (risperidone)
`tablets, for oral use
`RISPKRDAL" (risperidone) oral solution
`RISPERDAL M-TAB" (risperidone) orally disintegrating
`Initial U.S. Approval: 1993
`
`tablets
`
`for
`
`WARNING:
`
`INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RFI,ATKB PSYCHOSIS
`See full prescribing infbrmation for complete boxed warning.
`treated with
`~Elderly patients with dementia-related
`psychosis
`drugs are at an increased risk of death.
`antipsychotic
`~RISPKRBAI,"is not approved for use in patients with dementia-related
`psychosis. (5.1)
`--------------INDICATIONS AND USAGE--------------
`RISPERDAL's an atypical antipsychotic
`indicated for:
`(1.1)
`~ Treatment of schizophrenia
`for the
`or adjunctive
`therapy with lithium or valproate,
`~ As monotherapy
`treatment of acute manic or mixed episodes associated with Bipolar I
`Disorder (1.2)
`~ Treatment of irritability associated with autistic disorder (1.3)
`------------DOSAGE AND ADMINISTRATION------------
`S Recommended
`daily dosage:
`Initiul Dose
`
`Turget
`Dose
`
`El'I'ective
`Dose Range
`
`Schizophrenia
`: adults (2.1)
`
`Schizophrenia
`: adolescents
`(-'.I)
`Bipolar
`mania: Adults
`(2 2)
`Bipolar
`mania:
`in
`children and
`adolescents
`(2.2)
`Irritability
`dssocldted
`with autistic
`disorder (2.3)
`
`2 mg
`
`0.5 mg
`
`2 to 3 mg
`
`0.5 mg
`
`0.25 mg
`(Weight <
`20 kg)
`
`4 to 8 mg
`
`4 to 16 mg
`
`3 mg
`
`I to 6 mg
`
`I to6mg
`
`I to6mg
`
`I to 2.5
`mg
`
`I to 6 mg
`
`0.5 mg
`(<20 kg)
`
`0.5 to 3 mg
`
`I mg
`(>20 kg)
`
`0.5 mg
`(Weight
`>20 kg)
`in Adults: Usc a lower starting dose of
`~ Scvcrc Renal or Hepatic Impairment
`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
`pipette or
`from calibrated
`directly
`mixed with beverage (water, coffee, orange juice, or low-fat milk). (2.6)
`~ M-TAB Orally Disintegrating Tablets: Open the blister only when ready to
`tongue. Can be swallowed
`place tablet under
`and immediately
`administer,
`liquid. (2.7)
`with or without
`——————————DOSAGE FORMS AND STRENGTHS ———————————
`'ablets: 0.25 mg, 0.5 mg, I mg, 2 mg, 3 mg, and 4 mg (3)
`I mg per ml. (3)
`~ Oral solution:
`tablets: 0.5 mg,
`I mg, 2 mg, 3 mg, and 4 mg (3)
`~ Orally disintegrating
`———————————————-CONTRAINDICATIONS ———————————————-
`to RISPERDAL '4)
`~ Known hypersensitivity
`
`-------------WARNINGS AND PRECAUTIONS----------
`Cerebrovascular
`stroke,
`in elderly patients with
`including
`events,
`psychosis: RISPERDAL's not. approved I'or use in
`dementia-related
`psychosis. (5.2)
`patients with dementia-related
`Neuroleptic Malignant Syndrome: Manage with immediate
`of RISPERDAL" and close momtonng.
`(5.3)
`discontinuation
`Tardive dyskinesia: Consider discontinuing RISPERDAL'f clinically
`indicated. (5.4)
`drugs have bccn associated
`Metabolic Changes: Atypical antipsychotic
`with metabolic changes that may increase cardiovascular/
`risk. These metabolic changes include hyperglycemia,
`cerebrovascular
`and weight. guin. (5.5)
`dyslipidemiu,
`o Hjpcrglyccmia
`and Diabetes Mellitu»r Monitor
`for
`patients
`of
`including
`polyuria,
`polydipsia,
`hyperglycemia
`symptoms
`and weakness. Monitor glucose regularly
`in patients with
`polyphagia,
`diabetes or at risk for diabetes. (5.5)
`o Dy»lipidemia: Undesirable
`have been observed in patients
`alterations
`(5.5)
`treated with atypical antipsychotics.
`o Weight Gain: Significant weight
`gain has been reported. Monitor
`weight gain. (5.5)
`Prolactin clcvations occur and persist during
`Hypcrprolactincmia:
`(5.6)
`chronic administration.
`Orthostatic hypotension: For patients at risk, consider a lower starting
`dose and slower titration. (5.7)
`Perform complete blood
`and Agranulocytosis:
`Leukopenia, Neutropenia,
`counts in patients with a history of clinically significant
`low white blood
`cell count (WBC). Consider discontinuing RISPERDAL'f a clinically
`significant decline in WBC occurs in the absence of other causative
`factors. (5.8)
`for cognitivc and motor impairment: Usc caution when
`Potential
`(5.9)
`operating machinery.
`I lse cautiously in patients with a history of seizures or with
`Seizures:
`(5.10)
`conditions
`lower the seizure threshold.
`that
`———————————————ADVERSE REACTIONS ———————————————
`trials ()5"lo and twice placebo)
`The most common adverse reactions in clinical
`tremor, sedation, dizziness, anxiety,
`akathisia, dystonia,
`were parkinsonism,
`blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort,
`constipation,
`dyspepsia, diarrhea,
`salivary hypersecretion,
`dry mouth,
`rash, nasal congestion, upper
`increased weight,
`mcreased appetite,
`fatigue,
`respiratory tract infection, nasopharyngitis,
`pain. (6)
`and pharyngolaryngeal
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Inc. at I-800-JANSSEN (1-800-526-7736) or FDA at I-
`Pharmaceuticals,
`8UU-I'DA-IU88 or www fda.govlmedwatch
`-DRUG INTERACTIONS ——————————————
`'arbamazepine
`and other enzyme inducers decrease plasma concentrations
`Increase the RISPFRDAI." dose up to double the patient'
`of risperidone.
`usual dose. Titrate slowly. (7.1)
`and other CYP 2D6 enzyme inhibitors
`~ Fluoxetine, paroxetine,
`increase
`plasma concentrations of risperidone. Reduce the initial dose. Do not
`exceed a final dose of 8 mg per day of RISPERDAL". (7.1)
`------------USE IN SPECIFIC POPULATIONS------------
`'regnancy: Based on animal data, may cause fetal harm. (8.1)
`~ Nursing Mothers: Discontinue drug or nursing,
`taking into consideration
`the importance of drug to the mother. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: X/201X
`
`Reference ID: 3495570
`
`VNDA 02700183
`
`Vanda Exhibit 2039 - Page 1
`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS"
`
`2.5
`2.6
`2.7
`
`INCREASED MORTALITY IN ELDERLY PATIENTS
`WARNING:
`WITH DEMENTIA-RELATED PSYCHOSIS
`INDICATIONS AND USAGE
`1.1
`Schizophrenia
`1.2
`Bipolar Mania
`1.3
`Irritability Associated with Autistic Disorder
`DOSAGE AND ADMINISTRATION
`2.1
`Schizophrenia
`2.2
`Bipolar Mania
`2.3
`Irritability Associated with Autistic Disorder—
`(Children and Adolescents)
`Pediatrics
`Dosing in Patients with Severe Renal or Hepatic
`Impairment
`Dose Adjustments
`for Specific Drug Interactions
`of RISPERDAL Oral Solution
`Administration
`Directions for Use of RISPERDAL M-TAB
`Orally Disintegrating Tablets
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with
`Dementia-Related
`Psychosis
`Cerebrovascular Adverse Reactions,
`Including
`Stroke,
`in Elderly Patients with Dementia-
`Related Psychosis
`5.3
`Neuroleptic Malignant Syndrome
`5.4
`Tardive Dyskinesia
`5.5
`Metabolic Changes
`5.6
`Hyperprolactinemia
`5.7
`Orthostatic Hypotension
`5.8
`Leukopenia, Neutropenia,
`and Agranulocytosis
`5.9
`Potential
`for Cognitive and Motor Impairment
`5.10
`Seizures
`5.11 Dysphagia
`5.12
`Priapism
`5.13 Body Temperature Regulation
`5.14
`Patients with Phenylketonuria
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Experience
`Postmarketing
`DRUG INTERACTIONS
`7.1
`Pharmacokinetic-related
`7.2
`Pharmacodynamic-related
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`
`Interactions
`Interactions
`
`8.5
`8.6
`8.7
`8.8
`
`9
`
`Geriatric Use
`Renal
`Impairment
`Hepatic Impairment
`Patients with Parkinson's Disease or Lewy Body
`Dementia
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse
`9.3
`Dependence
`10 OVERDOSAGE
`10.1
`Human Experience
`10.2 Management
`of Overdosage
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Fertility
`13.2
`Animal Toxicology
`14 CLINICAL STUDIES
`14.1
`Schizophrenia
`Bipolar Mania - Monotherapy
`14.2
`Bipolar Mania —Adjunctive Therapy with Lithium
`14.3
`or Valproate
`14.4
`Irritability Associated with Autistic Disorder
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1
`How Supplied
`16.2
`Storage and Handling
`PATIENT COUNSELING INFORMATION
`17.1 Orthostatic Hypotension
`17.2
`Interference with Cognitive and Motor
`Performance
`17.3
`Pregnancy
`17.4
`Nursing
`17.5
`Concomitant Medication
`17.6 Alcohol
`17.7
`Phenylketonurics
`17.8 Metabolic Changes
`17.9
`Tardive Dyskinesia
`
`Impairment of
`
`17
`
`~Sections or subsections omitted from thc full prescribing
`listed
`
`information
`
`arc not
`
`Reference ID: 3495570
`
`VNDA 02700184
`
`Vanda Exhibit 2039 - Page 2
`
`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING:
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
`RELATED PSYCHOSIS
`drugs are at an
`treated with antipsychotic
`Elderly patients with dementia-related
`psychosis
`increased risk of death. RISPERDAL (risperidone)
`is not approved for the treatment of
`(5.1)J
`/See 8'arnings and Precaations
`patients with dementia-related
`psychosis.
`
`INDICATIONS AND USAGE
`1
`1.1 Schizophrenia
`of schizophrenia.
`RISPERDAL
`Efficacy was
`for
`is indicated
`treatment
`the
`(risperidone)
`(ages 13 to 17 years),
`established in 4 short-term trials in adults, 2 short-term trials in adolescents
`in adults jsee Clitiical Studies (14.1)j.
`and one long-term maintenance
`trial
`
`1.2 Bipolar Mania
`Monothera
`RISPERDAL's 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
`(ages 10 to 17 years) jsee Clinical Studies (14.2)j.
`in children and adolescents
`trial
`
`Ad unctive Thera
`for the treatment of
`RISPERDAL adjunctive
`therapy with lithium or valproate
`is indicated
`acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established
`in
`in adults jsee Clinical Studies (14.3)j.
`one short-term trial
`1.3 Irritability Associated with Autistic Disorder
`for the treatment of irritability
`RISPERDAL is indicated
`associated with autistic
`disorder,
`including symptoms of aggression towards others, deliberate
`self-injuriousness,
`temper
`tantrums,
`changing moods. Efficacy was established
`in 3 short-term trials
`in children
`and
`and quickly
`jsee Clinical Studies (14.4)j.
`(ages 5 to 17 years)
`adolescents
`
`2 DOSAGE AND ADMINISTRATION
`
`Reference ID: 3495570
`
`VNDA 02700185
`
`Vanda Exhibit 2039 - Page 3
`
`

`
`Table 1.Recommended Daily Dosage by Indication
`Initial Dose
`
`adults
`
`Schizophrenia:
`(2.1)
`Schizophrenia:
`adolescents
`(2.2)
`Bipolar mania: adults
`(2.2)
`Bipolar mania:
`children and
`adolescents
`(2.2)
`Irritability in autistic
`(2.3)
`disorder
`
`2 mg
`
`0.5 mg
`
`2 to 3 mg
`
`0.5 mg
`
`Titration
`(Increments)
`1 to 2 mg
`
`0 5 to 1 mg
`
`1 mg
`
`0 5 to 1 mg
`
`0.25 mg
`Can increase to
`0.5 mg by Day 4:
`less
`(body weight
`than 20 kg)
`
`0.5 mg
`Can increase to
`1 mg by Day 4:
`(body weight
`than or
`greater
`to 20 kg)
`equal
`
`After Day 4, at
`intervals of) 2
`weeks:
`0.25 mg
`less
`(body weight
`than 20 kg)
`
`0.5 mg
`(body weight
`than or
`greater
`to 20 kg)
`equal
`
`Effective Dose
`Range
`4to16mg
`
`1 to 6 mg
`
`1 to 6 mg
`
`1 to 6 mg
`
`0.5 to 3 mg
`
`Target Dose
`
`4toit mg
`
`3 mg
`
`1 to 6 mg
`
`1 to 2.5 mg
`
`0.5 mg:
`less
`(body weight
`than 20 kg)
`
`1 mg:
`(body weight
`than or
`greater
`to 20 kg)
`equal
`
`in Adults: use a lower starting dose of 0.5 mg twice daily.
`Severe Renal and Hepatic Impairment
`May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.
`
`Schizophrenia
`
`2.1
`Adults
`Initial Dose
`Usual
`RISPERDAL'an be administered
`Initial dosing is 2 mg per day. May
`once or twice daily.
`intervals of 24 hours or greater,
`in increments of 1 to 2 mg per day, as
`increase the dose at
`dose of 4 to 8 mg per day. In some patients,
`slower titration may be
`to a recommended
`tolerated,
`in a range of 4 ing to 16 ing per day. However,
`appropriate. Efficacy has been deinonstrated
`doses above 6 mg per day for twice daily dosing were not demonstrated
`to be more efficacious
`than lower doses, were associated with more extrapyramidal
`and other adverse effects,
`symptoms
`the efficacy
`In a single study supporting
`once-daily dosing,
`and are generally not recommended.
`for 8 mg than for 4 mg. The safety of doses above 16 mg per day
`results were generally stronger
`trials jsee Clinical Studies (14.1)j.
`has not been evaluated in clinical
`
`Adolescents
`The initial dose is 0.5 mg once daily,
`administered
`as a single-daily
`evening. The dose may be adjusted at intervals of 24 hours or greater,
`
`or
`dose in the morning
`in increments of 0.5 mg or
`
`Reference ID: 3495570
`
`VNDA 02700186
`
`Vanda Exhibit 2039 - Page 4
`
`

`
`dose of 3 mg pcr day. Although
`efficacy has bccn
`to a rccommcndcd
`1 mg pcr day, as tolcratcd,
`in studies of adolescent patients with schizophrenia
`at doses between 1 tng to 6 tng
`detnonstrated
`benefit was observed
`doses were
`above 3 mg per day,
`per day, no additional
`and higher
`associated with more adverse events. Doses higher
`than 6 mg per day have not been studied.
`
`Patients experiencing
`twice daily.
`
`persistent
`
`somnolence may benefit
`
`from administering
`
`half the daily dose
`
`Maintenance Thera
`should remain on RISPERDAL',
`how long a patient with schizophrenia
`While it is unknown
`the
`cffcctivcncss of RISPERDAL 2 mg pcr day to 8 mg pcr day at delaying
`rclapsc was
`in adult patients who had been clinically stable for at least 4
`in a controlled trial
`demonstrated
`(14.j)j. Both
`weeks and were then followed for a period of 1 to 2 years jsee Clinical Studies
`be maintained
`and adolescent
`on their
`should
`patients who respond
`adult
`acutely
`generally
`effective dose beyond the acute episode. Patients
`reassessed to determine
`should be periodically
`the need for maintenance
`treatment.
`
`Reinitiation of Treatment
`in Patients Previousl
`there are no data to specifically address
`Although
`that after an interval off RISPERDAL ', the initial
`
`Discontinued
`reinitiation of treatment,
`it is recommended
`titration schedule should be followed.
`
`s chotics
`From Other Anti
`Switchin
`collected data
`There
`to specifically
`are no systematically
`to RISPERDAL,
`or
`from other
`antipsychotics
`patients
`antipsychotics.
`
`address
`
`switching
`
`treating
`
`patients with
`
`schizophrenic
`concomitant
`
`2.2 Bipolar Mania
`Usual Dose
`Adults
`Thc initial dose range is 2 mg to 3 mg pcr day. Thc dose may bc adjusted at intervals of 24 hours
`in incretnents of 1 tng per day. The effective dose range is 1 tng to 6 tng per day, as
`or greater,
`trials. In these trials, short-term (3 week) anti-manic
`studied in the short-term, placebo-controlled
`in a flexible dosage range of 1 mg to 6 mg per day jsee Clinical
`efficacy was demonstrated
`Studies (14.2, 14.3)j.RISPERDAL doses higher
`than 6 mg per day were not studied.
`Pediatrics
`The initial dose is 0.5 mg once daily,
`or
`dose in the morning
`administered
`as a single-daily
`in increments of 0.5 mg or
`evening. The dose may be adjusted at intervals of 24 hours or greater,
`target dose of 1 mg to 2.5 mg per day. Although
`to the recommended
`1 mg per day, as tolerated,
`
`Reference ID: 3495570
`
`VNDA 02700187
`
`Vanda Exhibit 2039 - Page 5
`
`

`
`in studies of pediatric
`efficacy has bccn dcmonstratcd
`at doses
`patients with bipolar mania
`between 0.5 ing and 6 ing per day, no additional benefit was observed above 2.5 ing per day, and
`higher doses were associated with more adverse events. Doses higher
`than 6 mg per day have not
`been studied.
`
`Patients experiencing
`twice daily.
`
`persistent
`
`somnolence may benefit
`
`from administering
`
`half the daily dose
`
`Maintenance Thera
`There is no body of evidence available
`from controlled trials to guide a clinician in the longer-
`of a patient who improves
`during treatment of an acute manic episode with
`term management
`RISPERDAL". While it
`beyond an acute
`is generally
`agreed that pharmacological
`treatment
`response in mania is desirable, both for maintenance of the initial
`response and for prevention of
`the use of
`to support
`new manic
`obtained
`are no
`there
`data
`episodes,
`systematically
`RISPERDAL" in such longer-term treatment
`(i.e., beyond 3 weeks). The physician who elects to
`use RISPERDAL for extended periods
`re-evaluate
`the long-term risks and
`should periodically
`benefits of the drug for the individual patient.
`
`2.3 Irritability Associated with Autistic Disorder —Pediatrics
`Adolescents)
`The dosage of RISPERDAL should be individualized
`according to the response and tolerability
`of the patient. The total daily dose of RISPERDAL'an be administered
`once daily„or half the
`twice daily.
`total daily dose can be administered
`
`(Children and
`
`initiate dosing at 0.25 mg per day. For patients
`For patients with body weight
`less than 20 kg,
`to 20 kg,
`initiate dosing at 0.5 mg per day. After a
`than or equal
`with body weight greater
`minimum of four days,
`dose of 0.5 mg per day
`the dose may be increased to the recommended
`less than 20 kg and 1.0 mg per day for patients
`to 20 kg.
`than or equal
`for patients
`greater
`this dose for a minimum of 14 days.
`clinical
`sufficient
`In patients
`not achieving
`Maintain
`the dose may be increased at intervals of 2 weeks or greater,
`in increments of 0.25 mg
`response,
`less than 20 kg„orincrements of 0.5 mg per day for patients greater
`per day for patients
`than or
`to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available
`equal
`for children who weigh less than 15 kg.
`
`Once sufficient clinical response has been achieved and maintained,
`consider gradually
`lowering
`the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use
`RISPERDAL for extended
`re-evaluate
`the long-term risks
`should periodically
`periods
`and
`benefits of the drug for the individual patient.
`
`Reference ID: 3495570
`
`VNDA 02700188
`
`Vanda Exhibit 2039 - Page 6
`
`

`
`somnolcncc may bcncfit from a once-daily dose administcrcd
`Patients cxpcricncing pcrsistcnt
`half the daily dose twice daily, or a reduction of the dose.
`bedthne or adtninistering
`
`at
`
`2.4 Dosing in Patients with Severe Renal or Hepatic Impairment
`(CLcr ( 30 mL/min)
`(10-15
`For patients with severe renal
`or hepatic
`impairment
`impairment
`starting dose is 0.5 mg twice daily. The dose may be
`points on Child Pugh System),
`the initial
`increased in increments of 0.5 mg or less, administered
`twice daily. For doses above 1.5 mg
`increase in intervals of one week or greater jsee Use iri Specific Populations
`(8.6 and
`twice daily,
`~ 7)j.
`
`2.5 Dose Adjustments
`for Specific Drug Interactions
`When RISPERDAL" is co-administcrcd with
`(c.g., carbamazcpinc),
`thc dose
`cnzymc induccrs
`of RISPERDAL"'hould be increased up to double the patient's usual dose. It tnay be necessary
`the RISPERDAL'ose when
`to decrease
`as carbamazepine
`are
`such
`inducers
`enzyme
`(7.I)j. Similar
`co-
`jsee Drug
`effect may
`Intevactions
`discontinued
`expected with
`be
`of RISPERDAL'ith other enzyme
`(e.g.„phenytoin„rifampin,
`inducers
`administration
`and
`phenobarbital).
`
`Cgh
`
`dose of
`with RISPERDAL',
`or
`co-administered
`fluoxetine
`When
`paroxetine
`is
`the
`RISPERDAL should be reduced. The RISPERDAL'ose should not exceed 8 mg per day in
`adults when co-administered with these drugs. When initiating therapy, RISPERDAL" should be
`It may be necessary to increase the RISPERDAL"'ose when enzyme
`inhibitors
`titrated slowly.
`(7.I)j.
`jsee Drug Interactions
`such as fluoxetine or paroxetine are discontinued
`
`2.6 Administration
`of RISPERDAL Oral Solution
`RISPERDAL" Oral Solution can be administered
`directly from the calibrated pipette, or can be
`mixed with a beverage prior to administration. RISPERDAL"'ral Solution is compatible
`in the
`following beverages: water, coffee, orange juice, and low-fat milk;
`it is NOT compatible with
`either cola or tea.
`
`2.7 Directions for Use of RISPERDAL M-TAB Orally Disintegrating Tablets
`Tablet Accessin
`RISPERDAL '-TAB'rally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
`RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
`blister packs of 4 tablets each.
`
`separate one of the
`ready to administer. For single tablet
`Do not open the blister until
`removal,
`four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
`foil to expose the tablet. DO NOT push the tablet
`through the foil because this could damage the
`tablet.
`
`Reference ID: 3495570
`
`VNDA 02700189
`
`Vanda Exhibit 2039 - Page 7
`
`

`
`RISPERDAL" M-TAB" Orally Disintegrating Tablets 3 mg and 4 mg
`RISPERDAL M-TAB Orally Disintegrating
`3 mg and 4 mg are supplied
`Tablets
`pouch containing a blister with 1 tablet each.
`child-resistant
`
`in a
`
`pouch should bc tom open at thc notch to access thc blister. Do not open thc
`Thc child-resistant
`ready to adtninister. Peel back foil frotn the side to expose the tablet. DO NOT push
`blister until
`through the foil, because this could damage the tablet.
`the tablet
`
`Tablet Administration
`from the blister unit
`remove
`the tablet
`place the entire
`and immediately
`Using dry hands,
`Tablet on the tongue. The RISPERDAL M-
`RISPERDAL M-TAB Orally Disintegrating
`TAB Orally Disintegrating
`Tablet
`as the tablet cannot be
`should be consumed
`immediately,
`stored once retnoved frotn the blister unit. RISPERDAL M- TAB Orally Disintegrating Tablets
`subsequently with or without
`in the mouth within seconds and can be swallowed
`disintegrate
`to split or to chew the tablet.
`liquid. Patients should not attempt
`
`3 DOSAGE FORMS AND STRENGTHS
`and colors: 0.25 mg (dark
`RISPERDAL
`Tablets
`are available
`in the following
`strengths
`yellow), 0.5 mg (rcd-brown),
`1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (grccn). All
`are capsule shaped, and itnprinted with "JANSSEN" on one side and either "Ris 0.25", "Ris 0.5",
`"R1","R2", "R3",or "R4" on the other side according to their respective strengths.
`
`RISPERDAL Oral Solution is available in a I mg/mL strength.
`
`RISPERDAL M-TAB Orally Disintegrating
`Tablets are available
`in the following strengths,
`colors, and shapes: 0.5 mg (light coral, round),
`1 mg (light coral, square), 2 mg (coral, square),
`and 4 mg (coral,
`round). All are biconvex and etched on one side with
`3 mg (coral,
`round),
`"R0.5","Rl", "R2", "R3",or "R4" according to their respective strengths.
`
`4
`CONTRAINDICATIONS
`RISPERDAL's contraindicated
`to RISPERDAL .
`in patients with a known hypersensitivity
`reactions
`been
`reactions,
`have
`and
`including
`anaphylactic
`angio edema,
`Hypersensitivity
`observed in patients
`treated with risperidone.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Increased Mortality in Elderly Patients with Dementia-Related
`Psychosis
`Elderly patients with dementia-related
`treated with antipsychotic
`are at an
`psychosis
`drugs
`trials (modal duration of 10 weeks),
`increased risk of death. Analyses of 17 placebo-controlled
`revealed a risk of death in drug-treated
`largely in patients
`antipsychotic
`taking atypical
`drugs,
`
`Reference ID: 3495570
`
`VNDA 02700190
`
`Vanda Exhibit 2039 - Page 8
`
`

`
`patients of bctwccn 1.6 to 1.7 times thc risk of death in placebo-trcatcd patients. Over thc course
`the rate of death in drug-treated
`of a typical 10-week controlled trial,
`patients was about 4.5%,
`to a rate of about 2.6% in the placebo group. Although
`the causes of death were
`compared
`varied, most of the deaths appeared to be either cardiovascular
`(e.g., heart
`failure,
`sudden death)
`(e.g., pneumonia)
`or infectious
`to atypical
`in nature. Observational
`studies
`that, similar
`suggest
`drugs may increase mortality.
`treatment with conventional
`antipsychotic
`antipsychotic
`drugs,
`to which the findings of increased mortality in observational
`studies may be attributed
`The extent
`drug as opposed to some characteristic(s) of the patients
`is not clear.
`to the antipsychotic
`
`In two of four placebo-controlled
`in cldcrly patients with dcmcntia-rclatcd
`trials
`psychosis,
`of tnortality
`incidence
`observed
`treated with
`was
`furosetnide
`in patients
`higher
`plus
`RISPERDAL'hen compared to patients
`treated with RISPERDAL'lone or with placebo plus
`to explain this
`furosemide. No pathological mechanism has been identified
`and no
`finding,
`consistent pattern for cause of death was observed.
`
`a
`
`RISPERDAL'risperidone)
`Boxed Warnings.
`
`is not approved for the treatment of dementia-related
`
`psychosis
`
`jsee
`
`Including Stroke,
`
`in Elderly Patients
`
`5.2 Cerebrovascular Adverse Reactions,
`Psychosis
`with Dementia-Related
`(e.g., stroke,
`reactions
`Cerebrovascular
`ischemic attack),
`adverse
`fatalities,
`transient
`including
`range 73-97) in trials of risperidone
`were reported in patients
`(mean age 85 years;
`in elderly
`In placebo-controlled
`patients with dementia-related
`there was a significantly
`psychosis.
`trials,
`incidence of cerebrovascular
`treated with risperidone
`adverse events in patients
`compared
`higher
`treated with placebo. RISPERDAL's not approved for the treatment of patients with
`to patients
`(5.1)j
`jsee Boxed 8'arning and 8'arnings and Precautions
`dementia-related
`psychosis.
`
`5.3 Neuroleptic Malignant Syndrome
`including RISPERDAL'an cause a potentially
`fatal
`symptom complex
`Antipsychotic
`drugs
`of NMS include
`(NMS). Clinical manifestations
`referred to as Neuroleptic Malignant Syndrome
`rigidity„altered mental
`(irregular pulse or
`hyperpyrexia„muscle
`status, and autonomic
`instability
`blood pressure,
`and cardiac dysrhythmia). Additional
`signs may include
`tachycardia,
`diaphoresis,
`elevated creatine phosphokinase
`and acute renal failure.
`(CPK), myoglobinuria,
`rhabdomyolysis,
`
`of patients with this
`In arriving
`The diagnostic
`at a
`is complicated.
`evaluation
`syndrome
`to identify cases in which the clinical presentation
`diagnosis„ it is important
`includes both serious
`infection, etc.) and untreated or inadequately
`(e.g., pneumonia,
`medical
`treated
`illness
`systemic
`(EPS). Other
`considerations
`in the differential
`extrapyramidal
`signs and symptoms
`important
`
`Reference ID: 3495570
`
`VNDA 02700191
`
`Vanda Exhibit 2039 - Page 9
`
`

`
`diagnosis
`nervous
`
`central anticholincrgic
`include
`systein pathology.
`
`toxicity, heat stroke, drug fcvcr, and primary
`
`central
`
`of NMS should include: (I) immediate
`of antipsychotic
`The management
`discontinuation
`drugs
`to concurrent
`and other drugs not essential
`(2) intensive
`treatment
`and
`symptomatic
`therapy;
`and (3) treatment of any concomitant
`for which
`medical monitoring;
`serious medical problems
`are available. There is no general agreement
`about specific pharmacological
`specific treatments
`for uncomplicated NMS.
`treatment
`regimens
`
`If a patient
`after
`from NMS,
`treatment
`the potential
`recovery
`requires
`antipsychotic
`drug
`of drug therapy
`should be carefully considered. The patient
`should be carefully
`reintroduction
`since recurrences of NMS have been reported.
`monitored,
`
`5.4 Tardive Dyskinesia
`of potentially
`A syndrome
`dyskinetic movements may develop
`irreversible,
`in
`involuntary,
`drugs. The risk of developing
`treated with antipsychotic
`tardive
`and the
`dyskinesia
`patients
`are believed to increase as the duration of treatment
`it will become irreversible
`likelihood that
`dose of antipsychotic
`increase.
`total
`to the patient
`administered
`cumulative
`and the
`drugs
`brief
`can develop,
`after
`less commonly,
`However,
`although much
`the syndrome
`relatively
`treatment periods at low doses.
`
`for cstablishcd cases of tardivc dyskincsia,
`Thcrc is no known trcatmcnt
`although thc syndrome
`if antipsychotic
`or coinpletely,
`is withdrawn. Antipsychotic
`treatinent
`inay reinit,
`partially
`the signs and symptoms of the
`(or partially
`itself, however, may suppress
`treatment,
`suppress)
`process. The effect that symptomatic
`and thereby may possibly mask the underlying
`syndrome
`has upon the long-term course of the syndrome
`is unknown.
`suppression
`
`prescribe RISPERDAL'n a manner
`likely to minimize
`Given these considerations,
`is most
`that
`the occurrence of tardive
`be
`dyskinesia. Chronic
`treatment
`should
`antipsychotic
`generally
`(I) is known
`rcscrvcd for patients who suffer
`to respond
`to
`from a chronic
`that:
`illness
`drugs, and (2) for whoin alternative,
`equally effective, but potentially
`less harinful
`antipsychotic
`or appropriate.
`In patients who do require
`chronic treatment,
`are not available
`treatments
`the
`smallest dose and the shortest duration of treatment
`clinical
`a satisfactory
`response
`producing
`should be sought. The need for continued treatment
`should be reassessed periodically.
`
`If signs
`and symptoms of tardive dyskinesia
`appear
`consider
`some
`discontinuation.
`However,
`drug
`RISPERDAL'espite the presence of the syndrome.
`
`in a patient
`patients
`
`treated with RISPERDAL,
`treatment
`with
`require
`may
`
`Reference ID: 3495570
`
`10
`
`VNDA 02700192
`
`Vanda Exhibit 2039 - Page 10
`
`

`
`5.5 Metabolic Changes
`drugs have been associated with metabolic
`that may increase
`antipsychotic
`changes
`Atypical
`These metabolic
`risk.
`cardiovascular/cerebro
`include
`changes
`hyperglycemia,
`vascular
`and body weight gain. While all of the drugs
`in the class have been shown to
`dyslipidemia,
`produce some metabolic changes, each drug has its own specific risk profile.
`
`er I cemia and Diabetes Mellitus
`H
`in some cases extreme and associated with ketoacidosis or
`and diabetes mellitus,
`Hyperglycemia
`coma or death, have been reported in patients
`treated with atypical antipsychotics
`hyperosmolar
`including RISPERDAL. Assessment of the relationship
`between atypical antipsychotic
`use and
`by the possibility of an increased
`risk of
`is complicated
`glucose
`abnormalities
`background
`and the increasing incidence of diabetes mellitus
`diabetes mellitus
`in patients with schizophrenia
`between
`Given
`these
`confounders,
`the
`the
`general
`in
`relationship
`population.
`atypical
`understood.
`is not completely
`adverse
`events
`antipsychotic
`use
`and hyperglycemia-related
`of
`risk
`increased
`treatment-emergent
`epidemiological
`studies
`However,
`an
`suggest
`treated with the atypical antipsychotics. Precise
`adverse events in patients
`hyperglycemia-related
`for hyperglycemia-related
`risk estimates
`treated with
`adverse
`events
`in patients
`atypical
`are not available.
`antipsychotics
`
`are
`
`Patients with
`
`of diabetes
`mell itus who
`established
`started
`diagnosis
`on
`atypical
`an
`of
`including RISPERDAL,
`for worsening
`be monitored
`antipsychotics,
`should
`regularly
`(e.g., obesity,
`for diabetes mellitus
`glucose control. Patients with risk factors
`family history
`of diabetes) who are starting
`including RISPERDAL,
`treatment with atypical
`antipsychotics,
`of treatment
`fasting blood glucose testing at
`the beginning
`should undergo
`and periodically
`including RISPERDAL,
`treated with atypical
`treatinent. Any patient
`antipsychotics,
`during
`should be monitored for symptoms of hyperglycemia
`including polydipsia, polyuria, polyphagia,
`and weakness. Patients who develop symptoms of hyperglycemia
`during treatment with atypical
`including RISPERDAL, should undergo fasting blood glucose testing.
`In some
`antipsychotics,
`including RISPERDAL,
`has resolved when the atypical
`cases, hyperglycemia
`antipsychotic,
`of anti-diabetic
`however„some
`continuation
`was discontinued;
`treatment
`patients
`required
`despite discontinuation of RISPERDAL .
`
`Pooled data from three double-blind,
`placebo-controlled
`studies and four double-
`schizophrenia
`studies arc prcscntcd in Table 2.
`blind, placebo-controlled
`bipolar monothcrapy
`
`Reference ID: 3495570
`
`VNDA 02700193
`
`Vanda Exhibit 2039 - Page 11
`
`

`
`3- to 8-Week, Fixed- or Flexible-Dose
`Table 2. Change in Random Glucose from Seven Placebo-Controlled,
`Studies in Adult Subjects with Schizophrenia or Bipolar Mania
`
`Serum Glucose
`
`Serum Glucose
`((140 mg/dL to >200 mg/dL)
`
`RISPERDALs
`
`1-8 mg/day
`Mean change from baseline (mg/dL)
`n=748
`
`0.8
`Proportion of patients with shifts
`
`0 4%
`(3/702)
`
`>8-16 mg/day
`
`n=164
`
`0.6
`
`0%
`(0/158)
`
`Placebo
`
`n=555
`
`-1.4
`
`0 6"i
`(3/525)
`
`studies, RISPERDAL was associated with a mean
`controlled and uncontrolled
`In longer-term,
`change in glucose of +2.8 tng/dL at Week 24 (n=151) and +4.1 tng/dL at Week 48 (n=50).
`
`3- to 6-week study in children and adolescents with
`Data from the placebo-controlled
`(13-17years of age), bipolar mania (10-17 years of age), or autistic disorder
`schizophrenia
`17 years of age) are presented in Table 3.
`
`(5 to
`
`Table 3. Change in Fasting Glucose from Three Placebo-Controlled,
`3- to 6-Week, Fixed-Dose Studies in
`(13-17years of age), Bipolar Mania (10-17years of
`Children and Adolescents with Schizophrenia
`(5 to 17 years of age)
`age), or Autistic Disorder
`
`Serum Glucose
`
`Serum Glucose
`((100 mg/dL to >126 mg/dL)
`
`Placebo
`
`n=76
`
`-1.3
`
`0%
`(0/64)
`
`RISPERDAL~
`0.5-6 mg/day
`
`Mean change from baseline (mg/dL)
`n=135
`
`2.6
`Proportion of patients with shifts
`
`0.8%
`(1/120)
`
`studies, RISPERDAL
`open-label
`extension
`pediatric
`uncontrolled,
`longer-term,
`In
`associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).
`
`was
`
`idemia
`D sli
`Undcsirablc
`antipsychotics.
`
`Reference ID: 3495570
`
`alterations
`
`in
`
`lipids
`
`have
`
`bccn obscrvcd
`
`in patients
`
`trcatcd with
`
`atypical
`
`12
`
`VNDA 02700194
`
`Vanda Exhibit 2039 - Page 12
`
`

`
`Pooled data from 7 placebo-controlled,
`or bipolar
`subjects with schizophrenia
`
`3- to 8- wcck,
`fixed- or flcxiblc-dose
`tnania are presented in Table 4.
`
`studies
`
`in adult
`
`3- to 8-Week, Fixed- or Flexible-Dose
`Table 4. Change in Random Lipids from Seven Placebo-Controlled,
`Studies in Adult Sub'ects with Schizo hrenia or Bi olar Mania
`
`Cholesterol
`Change from baseline
`
`Triglycerides
`Change from baseline
`
`Cholesterol
`((200 mg/dL to >240 mg/dL)
`
`Triglycerides
`((500 mg/dL to >50