JANSSEN
`PHARMACEUTICA
`PRODUCTS, L.P.
`
`RISPERDAL
`(RISP ERIDONE)
`TABLETS/ORAL SOLUTION
`RISPERDAL M-TAB™
`(RISP ERIDONE)
`ORALLY DISINTEGRATING TABLETS
`
`DESCRIPTION
`RISPERDAL'risperidone)
`class of
`to the chetnical
`is a psychotropic
`agent belonging
`3-[2-[4-(6-fluoro-
`benzisoxazole
`The
`chemical
`derivatives.
`is
`designation
`1,2-benzisoxazo1-3-yl)-
`l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-
`pyrido[1„2-a]pyrimidin-4-one.
`is C29H27FN402 and its molecular
`Its molecular
`formula
`is 410.49.The structural
`formula is:
`weight
`
`N
`
`CHg
`
`CH2—CH2—
`
`0
`
`is a white to slightly beige powder. It is practically insoluble
`Risperidone
`and 0.1 N HC1.
`chloride, and soluble in methanol
`soluble in methylene
`
`in water,
`
`freely
`
`RISPERDAL 'ablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown),
`1 mg
`(white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths.
`Inactive ingredients
`are
`colloidal silicon dioxide, hypromellose,
`lactose, magnesium stearate, microcrystalline
`cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). Tablets of 0.25, 0.5,
`2, 3, and 4 mg also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow
`iron oxide; the 0.5 tng tablets contain red iron oxide; the 2 tng tablets contain FD&C
`Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain DAC Yellow No. 10; the
`4 mg tablets contain FDIC Blue No. 2 Aluminum Lake.
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`RISPERDAL is also available as a 1 mg/mL oral solution. The inactive ingredients
`this solution are tartaric acid, benzoic acid, sodium hydroxide,
`and purified water.
`
`for
`
`RISPERDAL M-TAB™Orally Disintegrating Tablets are available in 0.5 mg, 1.0 mg,
`and 2.0 mg strengths
`and are light coral in color.
`
`RISPERDAL M-TAB™Orally Disintegrating Tablets contain the following inactive
`ingredients: Amberlite"'esin,
`carbomer,
`gelatin, mannitol, glycine, simethicone,
`sodium
`oil.
`red ferric oxide, and peppermint
`hydroxide,
`aspartame,
`
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`Thc mechanism of action of RISPERDAL (rispcridonc), as with other drugs used to treat
`it has been proposed that the drug's therapeutic
`is unknown. However,
`schizophrenia,
`is mediated through a combination of dopamine Type 2 (D2) and
`activity in schizophrenia
`serotonin Type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and
`5HT2 may explain some of the other effects of RISPERDAL.
`
`antagonist with high affinity (Ki of 0.12 to
`RISPERDAL is a selective monoaminergic
`7.3 nM) for thc scrotonin Type 2 (5HT2), dopamine Type 2 (D2), xi and u2 adrcncrgic, and
`receptors. RISPERDAL acts as an antagonist
`at other receptors, but with
`Hi histaminergic
`lower potency. RISPERDAL has low to moderate affinity (Ki of 47 to 253 nM) for the
`serotonin 5HT|c, 5HT», and 5HTiA receptors, weak affinity (Ki of 620 to 800 nM) for the
`dopamine Dl and haloperidol-sensitive
`sigma site, and no affinity (when tested at
`receptors.
`concentrations
`
`)10') for cholinergic muscarinic or pi and p2 adrenergic
`
`Pharmacokinetics
`Absorption
`is well absorbed. The absolute oral bioavailability of risperidone
`is 70%
`Risperidone
`(CV=25%). The relative oral bioavailability of risperidone
`is 94%
`from a tablet
`(CV=10%) when compared to a solution.
`studies showed that RISPERDAL M-TAB™Orally Disintegrating
`Pharmacokinetic
`to RISPERDAL Tablets.
`Tablets are bioequivalent
`
`Plasina concentrations of risperidone,
`its inajor inetabolite, 9-hydroxyrisperidone,
`and
`over the dosing range of 1 to
`are dose proportional
`risperidone plus 9-hydroxyrisperidone
`16 mg daily (0.5 to 8 mg BID). Following oral administration of solution or tablet, mean
`peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
`and 17 hours in
`occurred at about 3 hours in extensive metabolizers,
`9-hydroxyrisperidone
`poor metabolizers. Steady-state concentrations of risperidone
`are reached in 1 day in
`and would bc cxpcctcd to reach steady state in about 5 days in poor
`cxtcnsivc mctabolizcrs
`metabolizers. Steady-state concentrations of 9-hydroxyrisperidone
`are reached in 5-6 days
`(measured in extensive metabolizers).
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`Food Effect
`Food does not affect either the rate or extent of absorption of risperidone.
`can be given with or without
`ineals.
`risperidone
`
`Thus,
`
`Distribution
`is rapidly distributed. The volume of distribution
`is 1-2 L/kg. In plasma,
`Risperidone
`is bound to albumin and ui-acid glycoprotein. The plasma protein binding of
`risperidone
`is 90%, and that of its major metabolite, 9-hydroxyrisperidone,
`is 77%.
`risperidone
`displaces each other froin plasina binding
`risperidone nor 9-hydroxyrisperidone
`Neither
`concentrations of sulfamethazine
`(100 pg/mL), warfarin (10 pg/mL),
`sites. High therapeutic
`increase in the free fraction of
`(10 Ng/mL) caused only a slight
`and carbamazepine
`at 50 ng/mL, changes of unknown
`at 10 ng/mL and 9-hydroxyrisperidone
`risperidone
`clinical significance.
`
`Metabolism
`is extensively metabolized in the liver. The main metabolic pathway is
`Risperidone
`through hydroxylation of risperidone
`by the enzyme, CYP 2D6. A
`to 9-hydroxyrisperidone
`minor metabolic pathway is through N-deallg lation. The main metabolite,
`has similar pharmacological
`activity as risperidone. Consequently,
`9-hydroxyrisperidone,
`the clinical effect of the drug (i.e., the active moiety)
`results from the combined
`concentrations of risperidone plus 9-hydroxyrisperidone.
`
`CYP 2D6, also called dcbrisoquin hydroxylasc,
`is thc cnzymc rcsponsiblc for metabolism
`of many neuroleptics,
`and other drugs. CYP 2D6 is
`antidepressants,
`antiarrhythmics,
`to genetic polymorphism (about 6%-8% of Caucasians,
`and a very low percentage
`subject
`of Asians, have little or no activity and are "poor metabolizers")
`and to inhibition by a
`variety of substrates
`notably quinidine. Extensive CYP 2D6
`and some non-substrates,
`whereas poor CYP
`convert
`metabolizers
`rapidly into 9-hydroxyrisperidone,
`risperidone
`2D6 metabolizers
`convert
`it much more slowly. Although extensive metabolizers
`have
`concentrations
`lower risperidone
`than poor inetabolizers,
`and higher 9-hydroxyrisperidone
`of the active moiety, after single and multiple doses, are similar
`the pharmacokinetics
`in
`extensive and poor metabolizers.
`
`to two kinds of drug-drug
`could be subject
`(see Drug Interactions
`interactions
`Risperidone
`under PRECAUTIONS). First, inhibitors of CYP 2D6 interfere with conversion of
`This occurs with quinidine, giving essentially all
`to 9-hydroxyrisperidone.
`risperidone
`profile typical of poor metabolizers. The
`recipients a risperidone pharmacokinetic
`therapeutic benefits and adverse effects of risperidone
`receiving quinidine have
`in patients
`(n-=70) of poor metabolizers
`not been evaluated, but observations
`in a modest number
`important differences between poor and extensive
`do not suggest
`given risperidone
`of known enzyine inducers
`(e.g., phenytoin,
`inetabolizers. Second, co-adininistration
`and phenobarbital) with risperidone may cause a decrease in the combined
`rifampin,
`plasma concentrations of risperidone
`It would also be possible
`and 9-hydroxyrisperidone.
`to interfere with metabolism of other drugs metabolized by CYP 2D6.
`for risperidone
`Relatively weak binding of risperidone
`to the enzyme suggests
`this is unlikely.
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`patients, 11 subjects received risperidone
`In a drug interaction study in schizophrenic
`administration of carbamazepine
`titrated to 6 mg/day
`for 3 weeks, followed by concurrent
`the plasina concentrations of
`for an additional 3 weeks. During co-adininistration,
`active metabolite, 9-hydroxyrisperidone,
`were
`and its pharmacologically
`risperidone
`decreased by about 50%. Plasma concentrations of carbamazepine
`did not appear to be
`of other known enzyme inducers
`(e.g.„phenytoin„rifampin„and
`affected. Co-administration
`phenobarbital) with risperidone may cause similar decreases in the combined plasma
`concentrations of risperidone
`which could lead to decreased
`and 9-hydroxyrisperidone,
`efficacy of risperidone
`treatment.
`
`Fluoxetine (20 mg QD) has been shown to increase the plasma concentration of risperidone
`2.5-2.8 fold, while the plasma concentration of 9-hydroxyrisperidone
`was not affected.
`
`Rcpcatcd oral doses of rispcridonc
`(3 mg BID) did not affect thc cxposurc (AUC) or peak
`plasma concentrations (C„„gof lithium (n=13).
`Repeated oral doses of risperidone
`(4 mg QD) did not affect the pre-dose or average
`and exposure (AUC) of valproate (1000 mg/day
`in three divided
`plasma concentrations
`doses) compared to placebo (n=21). However„ there was a 20% increase in valproate
`administration of risperidone.
`(Cmax) after concomitant
`peak plasma concentration
`
`There were no significant
`interactions between risperidone
`(1 mg QD) and erythromycin
`(500 mg QID) (see Drug Interactions under PRECAUTIONS).
`
`Excretion
`are eliminated via the urine and, to a much lesser extent,
`and its metabolites
`Risperidone
`via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of
`'-risperidone
`total recovery of
`as solution to three healthy male volunteers,
`administered
`at 1 wcck was 84%, including 70% in thc urine and 14% in thc fcccs.
`radioactivity
`
`The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers
`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
`of the active moiety, after single and multiple doses„
`metabolizers. The pharmacokinetics
`in extensive and poor metabolizers, with an overall mean elimination half-life
`were similar
`of about. 20 hours.
`
`and
`
`Special Populations
`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. RISPERDAL
`doses should be reduced in patients with renal disease (see PRECAUTIONS and
`DOSAGE AND ADMINISTRATION).
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`Hepatic Impairment
`of risperidone
`in subjects with liver disease were comparable
`While the pharmacokinetics
`the mean free fraction of risperidone
`to those in young healthy subjects,
`in plasma was
`incrcascd by about 35% bccausc of thc diminished
`concentration of both albumin and
`u 1-acid glycoprotein. RISPERDAL doses should be reduced in patients with liver
`disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`Elderly
`In healthy elderly subjects renal clearance of both risperidone
`and 9-hydroxyrisperidone
`half-lives were prolonged compared to young healthy
`was decreased, and elimination
`(see DOSAGE
`subjects. Dosing should be modified accordingly in the elderly patients
`AND ADMINISTRATION).
`
`Race and Gender Effects
`race and gender effects,
`study was conducted to investigate
`No specific pharmacokinetic
`but a population pharmacokinetic
`analysis did not identify important differences
`in the
`disposition of risperidone
`(whether corrected for body weight or not) or
`due to gender
`race.
`
`Clinical Trials
`
`Schizophrenia
`Short-Term Efficacy
`The efficacy of RISPERDAL'n the treatment of schizophrenia was established in four
`short-term (4 to 8-week) controlled trials of psychotic inpatients who met DSM-III-R
`criteria for schizophrenia.
`
`instruments were used for assessing psychiatric
`Several
`in these
`signs and symptoms
`studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of
`used to evaluate the effects of drug treatment
`general psychopathology
`in
`traditionally
`schizophrenia. The BPRS psychosis cluster (conceptual disorganization,
`hallucinatory
`is considered a particularly
`thought content)
`behavior,
`useful
`suspiciousness,
`and unusual
`patients. A second traditional
`subset for assessing actively psychotic schizophrenic
`thc Clinical Global Impression (CGI), rcflccts thc impression of a skilled
`asscssmcnt,
`fully familiar with the manifestations of schizophrenia,
`the overall clinical
`about
`observer,
`state of the patient.
`In addition,
`two more recently developed, but less well evaluated
`these included the Positive and Negative Syndrome Scale
`scales, were employed;
`(PANSS) and the Scale for Assessing Negative Symptoms
`(SANS).
`
`The results of the trials follow:
`trial (n=160) involving titration of RISPERDAL 'n
`(1) In a 6-week, placebo-controlled
`doses up to 10 mg/day (BID schedule), RISPERDAL'as generally superior
`to placebo
`on the BPRS total score, on the BPRS psychosis cluster, and marginally
`to
`superior
`placebo on the SANS.
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`trial (n=513) involving 4 fixed doses of
`(2) In an 8-week, placebo-controlled
`RISPERDAL '2, 6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL 'roups
`to placebo on the BPRS total score, BPRS psychosis cluster, and
`were generally superior
`CGI severity score; the 3 highest RISPERDAL 'ose groups were generally superior
`to
`placebo on the PANSS negative subscale. The most consistently positive responses on all
`measures were seen for the 6 mg dose group„and there was no suggestion of increased
`from larger doses.
`benefit
`
`(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of
`RISPERDAL" (1, 4, 8, 12, and 16 mg/day, on a BID schedule),
`the four highest
`to the 1 mg RISPERDAL"'ose group
`RISPERDAL" dose groups were generally superior
`on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose
`to the 1 mg group on the PANSS negative subscale. The most
`groups were superior
`consistently positive responses werc scen for thc 4 mg dose group.
`
`dose comparison trial (n=246) involving 2 fixed
`In a 4-week, placebo-controlled
`(4)
`doses of RISPERDAL (4 and 8 mg/day on a QD schedule), both RISPERDAL dose
`to placebo on several PANSS measures,
`groups were generally superior
`including a
`response measure (>20% reduction in PANSS total score), PANSS total score, and the
`BPRS psychosis cluster (derived from PANSS). The results were generally stronger
`for
`the 8 mg than for the 4 mg dose group.
`
`Long- Term Efficacy
`ineeting DSM-IV criteria for
`In a longer-terin trial, 365 adult outpatients predoininantly
`and who had been clinically stable for at least 4 weeks on an antipsychotic
`schizophrenia
`to RISPERDAL (2-8 mg/day) or to an active comparator,
`medication were randomized
`for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL
`'xperienced a
`longer time to relapse over this time period compared to those receiving the
`significantly
`active comparator.
`
`Bipolar Mania
`The efficacy of Risperdal
`in the treatment of acute manic or mixed
`Monothera
`episodes was established in 2 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.
`
`used for assessing manic symptoms
`The primary rating instrument
`in these trials was the
`Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated
`scale traditionally
`used to
`assess the degree of manic symptomatology
`behavior,
`(irritability,
`disruptive/aggressive
`increased activity, sexual
`sleep, elevated mood, speech,
`interest,
`language/thought
`in a range froin 0 (no inanic features)
`to
`and insight)
`thought content, appearance,
`disorder,
`60 (maximum score). The primary outcome in these trials was change from baseline in the
`Y-MRS 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 Risperdal
`1-6 mg/day, once daily, starting at
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`(mean modal dose was 4.1 mg/day), Risperdal was superior
`3 mg/day
`the reduction of Y-MRS total score.
`
`to placebo in
`
`~
`
`trial (n=286), which involved a dose range of 1-
`In another 3-week placebo-controlled
`(mean modal dose was 5.6 mg/day),
`6 mg/day, once daily, starting at 3 mg/day
`to placebo in the reduction of Y-MRS total score.
`Risperdal was superior
`
`The efficacy of risperidone with concomitant
`lithium or valproate
`Combination Thera
`in the treatment of acute manic or mixed episodes was established in one controlled trial
`in
`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
`controlled manic or mixed symptoms were
`or valproate therapy with inadequately
`to receive Risperdal„placebo„or an active comparator,
`in combination
`randomized
`in a dose range of 1-6 mg/day, once daily,
`with their original
`therapy. Risperdal,
`(mean modal dose of 3.8 mg/day),
`starting at 2 mg/day
`combined with lithium or
`range of 0.6 mEq/L to 1.4 mEq/L or 50 pg/mL to
`valproate (in a therapeutic
`to lithium or valproatc alone in thc reduction of
`125 pg/mL,
`respectively) was superior
`Y-MRS total score.
`
`In a second 3-week placebo-controlled
`combination trial, 142 in- or outpatients on
`controlled manic or
`lithium, valproate, or carbamazepine
`therapy with inadequately
`to receive Risperdal or placebo,
`inixed syinptoins were randoinized
`in coinbination
`in a dose range of 1-6 mg/day, once daily,
`with their original
`therapy. Risperdal,
`(mean modal dose of 3.7 mg/day),
`starting at 2 mg/day
`combined with lithium,
`ranges of 0.6 mEq/L to 1.4 mEq/L for
`valproate, or carbamazepine
`(in therapeutic
`lithium, 50 pg/mL to 125 pg/mL for valproate, or 4-12 pg/mL for carbamazepine,
`to lithium, valproate, or carbamazepine
`respectively) was not superior
`alone in the
`reduction of Y-MRS total score. A possible explanation for the failure of this trial was
`induction of risperidone
`clearance by carbamazepine,
`and 9-hydroxy risperidone
`levels of risperidone
`leading to subtherapeutic
`and 9-hydroxy risperidone.
`
`INDICATIONS AND USAGE
`
`Schizophrenia
`RISPERDAL (risperidone)
`
`is indicated for the treatment of schizophrenia.
`
`The efficacy of RISPERDAL'n schizophrenia was established in short-term (6 to
`8 weeks) controlled trials of schizophrenic
`(see CLINICAL
`inpatients
`ACOLOGY).
`P
`
`The efficacy of RISPERDAL'n delaying relapse was demonstrated
`in schizophrenic
`with RISPERDAL 'r an active comparator
`patients who had been clinically stable for at least 4 weeks before initiation of treatment
`and who were then observed for relapse
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`during a period of 1 to 2 years (see Clinical Trials, under CLINICAL
`the physician who elects to use RISPERDAL for
`ACOLOGY). Nevertheless,
`PH
`the long-terin usefulness of the drug for
`extended periods should periodically re-evaluate
`(see DOSAGE AND ADMINISTRATION).
`the individual
`patient
`Bipolar Mania
`RISPERDAL 's indicated for the short-terin treatinent of acute inanic or
`Monothera
`mixed episodes associated with Bipolar I Disorder.
`The efficacy of RISPERDAL 'as established in two placebo-controlled
`trials (3-week)
`with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an
`acute manic or mixed episode with or without psychotic features
`(see CLINICAL
`ACOLOGY).
`P
`
`The combination of RISPERDAL with lithium or valproate is
`Combination Thera
`indicated for the short-term treatment of acute manic or mixed episodes associated with
`Bipolar I Disorder.
`
`The efficacy of RISPERDAL in combination with lithium or valproate was established in
`(3-week) trial with patients meeting DSM-IV criteria for Bipolar I
`one placebo-controlled
`Disorder who currently displayed an acute manic or mixed episode with or without
`(see CLINICAL P
`COLOGY).
`psychotic features
`
`The effectiveness of RISPERDAL'or longer-term use, that is, for more than 3 weeks of
`treatment of an acute episode, and for prophylactic
`use in mania, has not been
`trials. Therefore, physicians who elect to
`evaluated in controlled clinical
`systematically
`use RISPERDAL for extended periods should periodically re-evaluate
`the long-term risks
`and benefits of the drug for the individual patient
`(see DOSAGE AND
`ADMINISTRATION).
`
`CONTRAINDICATIONS
`RISPERDAL 'risperidone)
`the product.
`
`is contraindicated
`
`in patients with a known hypersensitivity
`
`to
`
`WARNINGS
`Neuroleptic Malignant Syndrome
`(NMS)
`A potentially
`fatal symptom complex sometimes
`referred to as Neuroleptic Malignant
`(NMS) has been reported in association with antipsychotic
`drugs. Clinical
`Syndrome
`manifestations of NMS arc hypcrpyrcxia, muscle rigidity, altcrcd mental
`status, and
`evidence of autonomic
`instability (irregular pulse or blood pressure,
`tachycardia,
`and cardiac dysrhythmia). Additional
`signs may include elevated creatinine
`diaphoresis,
`and acute renal failure.
`phosphokinase, myoglobinuria
`(rhabdomyolysis),
`
`The diagnostic evaluation of patients with this syndrome
`In arriving at a
`is complicated.
`to identify cases in which the clinical presentation
`includes both
`it is important
`diagnosis,
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`systemic infection, etc.) and untreated or
`illness (e.g., pneumonia,
`serious medical
`(EPS). Other important
`treated extrapyramidal
`signs and symptoms
`inadequately
`considerations
`include central anticholinergic
`toxicity, heat
`in the differential diagnosis
`stroke, drug fever, and primary central nervous
`system pathology.
`
`The management of NMS should include: (I) immediate discontinuation of antipsychotic
`to concurrent
`drugs and other drugs not essential
`(2) intensive
`symptomatic
`therapy;
`and (3) treatment of any concomitant.
`and medical monitoring;
`serious medical
`treatment
`for which specific treatments
`are available. There is no general agreement
`about
`problems
`for uncomplicated NMS.
`specific pharmacological
`treatment
`regimens
`
`If a patient
`after recovery from NMS, the potential
`drug treatment
`requires antipsychotic
`reintroduction of drug therapy should be carefully considered. The patient should be
`since rccurrcnccs of NMS have bccn rcportcd.
`carefully monitored,
`
`Tardive Dyskinesia
`A syndrome of potentially
`irreversible„ involuntary,
`dyskinetic movements may develop in
`drugs. Although the prevalence of the syndrome
`treated with antipsychotic
`patients
`appears
`to be highest among the elderly, especially elderly women,
`it is impossible
`to rely upon
`to predict, at the inception of antipsychotic
`treatment, which patients
`estimates
`prevalence
`are likely to develop the syndrome. Whether antipsychotic
`drug products differ in their
`to cause tardive dyskinesia
`is unknown.
`potential
`
`The risk of developing tardive dyskinesia
`it will become
`and the likelihood that
`irrcvcrsiblc arc bclicvcd to incrcasc as thc duration of trcatmcnt
`and thc total cumulative
`dose of antipsychotic
`increase. However,
`to the patient
`drugs administered
`the syndrome
`after relatively brief treatment periods at low
`can develop, although much less conunonly,
`doses.
`
`for established cases of tardive dyskinesia,
`There is no known treatment
`although the
`if antipsychotic
`syndrome may remit, partially or completely,
`is withdrawn.
`treatment
`(or partially suppress)
`itself, however,
`the signs and
`Antipsychotic
`treatinent,
`inay suppress
`symptoms of the syndrome
`and thereby may possibly mask the underlying process. The
`has upon the long-term course of the syndrome
`effect that symptomatic
`is
`suppression
`uilkilowil.
`
`C~iven these considerations, RISPERDAL (risperidone)
`should be prescribed in a manner
`the occurrence of tardive dyskinesia. Chronic antipsychotic
`is most
`likely to minimize
`that
`should generally be reserved for patients who suffer from a chronic illness that
`treatment
`(I) is known to respond to antipsychotic
`drugs, and (2) for whom alternative,
`equally
`are not available or appropriate.
`In
`effective, but potentially less harmful
`treatments
`the smallest dose and the shortest duration of
`patients who do require chronic treatment,
`treatment producing a satisfactory clinical response should be sought. The need for
`should be reassessed periodically.
`continued treatment
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`
`treated on RISPERDAL ',
`If signs and symptoms of tardive dyskinesia
`in a patient
`appear
`should be considered. However,
`some patients may require treatment
`drug discontinuation
`with RISPERDAL 'espite the presence of the syndrotne.
`
`Including Stroke,
`
`in Elderly Patients With
`
`Cerebrovascular Adverse Events,
`Dementia
`adverse events (e.g., stroke,
`ischemic attack),
`Cerebrovascular
`transient
`including
`(mean age 85 years; range 73-97) in trials of
`fatalities, were reported in patients
`In placebo-controlled
`in elderly patients with dementia-related
`psychosis.
`risperidone
`incidence of cerebrovascular
`adverse events in
`there was a significantly
`trials,
`higher
`compared to patients
`treated with placebo.
`treated with risperidone
`patients
`not approved for thc trcatmcnt of patients with dcmcntia-rclatcd
`psychosis.
`
`RISPERDAL's
`
`and Diabetes Mellitus
`Hyperglycemia
`Hyperglycemia„ in some cases extreme and associated with ketoacidosis or hyperosmolar
`coma or death, has been reported in patients
`treated with atypical antipsychotics
`including
`RISPERDAL"'. Assessment of the relationship
`between atypical antipsychotic
`use and
`is complicated by the possibility of an increased background risk of
`glucose abnormalities
`and the increasing incidence of diabetes
`diabetes mellitus
`in patients with schizophrenia
`between
`in the general population. Given these confounders,
`mellitus
`the relationship
`adverse events is not completely
`use and hyperglycemia-related
`atypical antipsychotic
`studies suggest an increased risk of treatment-
`understood. However, epidemiological
`trcatcd with thc atypical
`advcrsc cvcnts in patients
`cmcrgcnt hypcrglyccmia-rclatcd
`antipsychotics. Precise risk estimates
`for hyperglycemia-related
`adverse events in patients
`are not available.
`treated with atypical antipsychotics
`
`Patients with an established diagnosis of diabetes mellitus who are started on atypical
`should be monitored regularly for worsening of glucose control. Patients
`antipsychotics
`family history of diabetes) who are
`(e.g., obesity,
`with risk factors for diabetes mellitus
`should undergo fasting blood glucose testing
`starting treattnent with atypical antipsychotics
`at the beginning of treatment
`treated with
`and periodically during treatment. Any patient
`should be monitored for symptoms of hyperglycemia
`atypical antipsychotics
`including
`and weakness. Patients who develop symptoms of
`polydipsia, polyuria, polyphagia,
`should undergo fasting blood
`during treatment with atypical antipsychotics
`hyperglycemia
`In some cases, hyperglycemia
`has resolved when the atypical antipsychotic
`glucose testing.
`required continuation of anti-diabetic
`some patients
`however,
`treatment
`was discontinued;
`despite discontinuation of the suspect drug.
`
`PRECAUTIONS
`General
`Orthostatic Hypotension
`RISPERDAL (risperidone) may induce orthostatic hypotension
`associated with dizziness,
`syncope, especially during the initial dose-titration
`and in some patients,
`tachycardia,
`antagonistic properties. Syncope was
`period, probably reflecting its alpha-adrenergic
`reported in 0.2% (6/2607) of RISPERDAL '-treated patients
`in Phase 2-3 studies. The risk
`of orthostatic hypotension
`and syncope may be minimized by limiting the initial dose to
`
`10
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`
`2 mg total (either QD or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and
`(see DOSAGE AND ADMINISTRATION).
`patients with renal or hepatic impairment
`Monitoring of orthostatic vital signs should be considered in patients
`for whoin this is of
`concern. A dose reduction should be considered if hypotension
`occurs. RISPERDAL
`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
`has been observed
`and hypovolemia. Clinically significant. hypotension
`with concomitant use of RISPERDAL'nd antihypertensive medication.
`
`'hould
`
`Seizures
`testing, seizures occurred in 0.3 10 (9/2607) of RISPERDAL -treated
`During premarketing
`two in association with hyponatremia. RISPERDAL should be used cautiously in
`patients,
`patients with a history of seizures.
`
`Dysphagia
`and aspiration have been associated with antipsychotic
`drug use.
`Esophageal dysmotility
`is a common cause of morbidity and mortality in patients with
`Aspiration pneumonia
`dementia. RISPERDAL'nd other antipsychotic
`advanced Alzheimer's
`drugs should be
`used cautiously in patients at risk for aspiration pneumonia.
`
`Hyperprolactinemia
`As with other drugs that antagonize dopamine D2 receptors,
`elevates prolactin
`risperidone
`levels and the elevation persists during chronic administration. Tissue culture experiments
`one-third of human breast cancers are prolactin dependent
`indicate that approximately
`in
`if the prescription of these drugs is contemplated
`vitvo, a factor of potential
`in a
`importance
`patient with previously detected breast cancer. Although disturbances
`such as galactorrhea,
`and impotence have been reported with prolactin-elevating
`gynecomastia,
`amenorrhea,
`the clinical significance of elevated serum prolactin levels is unknown
`for
`compounds,
`most patients. As is common with compounds which increase prolactin release, an increase
`gland, and pancreatic islet cell hyperplasia
`and/or neoplasia
`in pituitary gland, mammary
`studies conducted in mice and rats (see
`was observed in the risperidone
`carcinogenicity
`CARCINOGENESIS). However, ncithcr clinical studies nor cpidcmiologic
`studies
`of this class
`conducted to date have shown an association between chronic administration
`of drugs and tumorigenesis
`the available evidence is considered too limited to
`in humans;
`be conclusive at this time.
`
`for Cognitive and Motor Impairment
`Potential
`Somnolence was a commonly reported adverse event associated with RISPERDAL
`especially when ascertained by direct questioning of patients. This adverse
`treatment,
`to detect adverse events, 41 /0 of
`and in a study utilizing a checklist
`is dose-related,
`event
`(RISPERDAL" 16 mg/day)
`comp ared to 16 10
`reported somnolence
`the high dose patients
`of placebo patients. Direct questioning
`is inore sensitive for detecting adverse events than
`reporting, by which 8 10 of RISPERDAL'6 mg/day patients and 1 /0 of
`spontaneous
`as an adverse event. Since RISPERDAL has the
`reported somnolence
`placebo patients
`to impair judgment„ thinking, or motor skills„patients should be cautioned about
`potential
`
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`
`

`
`operating hazardous machinery,
`including automobiles,
`until
`that RISPERDAL 'herapy does not affect them adversely.
`
`they are reasonably certain
`
`Priapism
`Rare cases of priapism have been reported. While the relationship of the events to
`RISPERDAL 'se has not been established, other drugs with alpha-adrenergic
`blocking
`and it is possible that RISPERDAL may
`effects have been reported to induce priapism,
`share this capacity. Severe priapism may require surgical
`intervention.
`
`Thrombotic Thrombocytopenic
`(TTP)
`Purpura
`A single case of TTP was reported in a 28 year-old female patient
`receiving
`RISPERDAL" in a large, open prcmarkcting
`1300 patients).
`cxpcricncc (approximately
`recovered after receiving
`She experienced jaundice,
`fever, and bruising, but eventually
`to RISPERDAL 'herapy is unknown.
`plasmapheresis. The relationship
`
`Antiemetic Effect
`this effect may also occur in humans,
`Risperidone has an antiemetic effect in animals;
`and
`may mask signs and symptoms of overdosage with certain drugs or of conditions
`such as
`intestinal obstruction, Reye's syndrome,
`and brain tumor.
`
`Body Temperature Regulation
`Disruption ofbody temperature
`agents. Both
`has been attributed to antipsychotic
`regulation
`have been reported in association with oral RISPERDAL"
`and hypothermia
`hyperthermia
`use. Caution is advised when prescribing for patients who will be exposed to temperature
`extremes.
`
`Suicide
`and close supervision of
`The possibility of a suicide attempt
`is inherent
`in schizophrenia,
`for RISPERDAL 'hould
`should accompany drug therapy. Prescriptions
`high-risk patients
`be written for the smallest quantity of tablets, consistent with good patient management,
`in
`order to reduce the risk of overdose.
`
`Use in Patients With Concomitant
`Illness
`Clinical experience with RISPERDAL in patients with certain concomitant
`systemic
`illnesses is limited. Caution is advisable in using RISPERDAL" in patients with diseases
`that could affect metabolism or hemodynamic
`or conditions
`responses.
`
`RISPERDAL has not been evaluated or used to any appreciable
`extent
`in patients with a
`recent history of myocardial
`infarction or unstable heart disease. Patients with these
`diagnoses were excluded from clinical studies during the product's premarket
`testing.
`
`Increased plasma concentrations of risperidone
`occur in patients
`and 9-