IRISPERDALo
`
`(Risperidone) Tablets/Oral Solution
`
`DESCRIPTION
`
`RISPERDAL" (risperldone) is an antipsychotic agent belonging to a new chemical class, the
`benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6—fluorovl ,2-benzisoxazol-3 vyl)-
`l-piperidinyl]ethyl}~6,7,8,9—tetrahydro-2-methyl-4H-pyrido[ l ,2-a]pyrimidin—4-one. Itsmolecular
`formula is C23H27FN402 and its molecular weight is 410.49. The structural formula is:
`
`Risperidone is a white to slightly beige
`powder. It is practically insoluble in water,
`freely soluble in methylene chloride, and
`soluble in methanol and 0.1 N HCl.
`
`
`
`RISPERDAL” tablets are available in M
`m (dark yellow). 0.: mg (Minoan). 1
`mg (white, scored), 2 mg (orange), 3 mg
`. (yellow), and 4 mg (green) strengths.
`Inactive ingredients are colloidal silicon dioxide, hydroxypropyl methylcellulosc, lactose,
`magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and
`starch (com). Tablets of Q2; O_.5, 2, 3, and 4 mg also cantain talc and titanium dioxide. The
`9,2: mg mum thin yellow m oxide, me Q; mg tablets contain red iron oxide; the 2 mg
`tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
`Yellow No. 10;
`the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
`
`RISPERDAL"15 also available as a lmg/mL oral solution The inactive ingredients for this
`solution are: tartaric acid, benzoic acid, sodium hydmxide and purified water-WW
`
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`The mechanism of action of RISPERDAL0 (risperldone), as with other antipsychotic drugs, is
`unknown. However, it has been proposed that this drug's antipsychotic activity is mediated
`through accombination of dopamine type 2 (D2) and Serotonin type 2 (SHyT) antagonism.
`Antagonism at receptors other than D2 and SH]; may exPlain some of the other effects of
`RlSPERDAL“.
`
`RISPERDAL° is a selective monoarninergic antagonist with high affinity (Ki of 0. l 2 to 7.3 nM)
`for the serotonin type 2 (SHTQ), dopamine type 2 (D ). a and a: adrenergic, and H
`histaminergic receptors. RISPERDAL“ antagouizes other receptors, but with lower potency.
`RISPERDAL" has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin iii-ITIC,
`SHIN, and 51-11",A receptors, weak affinity (Ki of 620 to 800 nM) for the dOpamine D and
`haloperidol-sensitive sigma site, and no affinity (when tested at concentratioris >10" M) for
`cholinergic muscarinic Or [31 and [52 adrenergic receptors.
`
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`Exhibit 2023
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`Slayback v. Sumitomo
`|PR2020-01053
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`Slayback v. Sumitomo
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`Pharmacokinetics
`
`Risperidone is well absorbed, as illustrated by a mass balance study involving a single 1 mg oral
`dose of "C-risperidone as a solution in three healthy male volunteers. Total recovery of
`radioactivity at one week was 85%, including 70% in the urine and 15% in the feces.
`
`Risperidone is extensively metabolized in the liver by cytochrome P..,°IID6 to a major active
`metabolite, 9-hydroxyrisperidone, which is the predominant simulating specie, and appears
`approximately equi-effective with risperidone with respect to receptor binding activity and some
`effects in animals.
`(A second minor pathway is N-dealkylation). Consequently, the clinical
`effect of the drug likely results from the combined concantrations of riSperidone plus 9-
`hydroxyrisperidone.
`Plasma cancentrations of risperidone, 9-hydroxyrisperidone, and
`risperidone plus 9-hydroxyri5peridone are dose preportional over the dosing range of 1 to 16 mg
`daily (0.5 to 8 mg BID). The relative Oral bioavailability of risperidone from a tablet was 94%
`(CV=10%) when compared to a solution. Food does not affect either the rate er extent of
`absorption of risperidone. Thus, risperidone can be given with or without meals. The absolute
`oral bioavailability of risperidone was 70% (CV=25%).
`
`The enzyme catalyzing hydroxylation of risperidone to 9-hydroxyrisperidone is cytochrome
`P601106, also called debrisoquin hydroxylase, the enzyme resporisible for metabolism of man}r
`neuroleptics, antidepressants, antiarrhythmics, and other drugs. Cytochrome P450 MD, is subject
`to genetic polymorphism (about 6-8% of caucasians, and a very low percent ofAsians have little
`or no activity and are ”poor metabolizers") and to inhibition by a variety of substrates and some
`non-substrates, notably quinidine. Extensive metabolizers convert risperidone rapidly into 9-
`hydroxyrisperidone, while poor metabolizers convert
`it much more slowly. Extensive
`metabolizers, therefore, have lower risperidone and higher 9-hydroxyri5peridone concentrations
`than poor metabolizers. Following oral administration of solution or tablet, mean peak plasma
`concentrations occurred at about 1 hour. Peak 9-hydroxyrisperidone Occurred at about 3 hours
`in extensive metabolizers, and 17 hours in poor metabolizers. The apparent half~life of
`risperidone was three hours (CV=30%) in extensiVe metabolizers and 20 hours (CV=40%) in
`poor metabolizers. The apparent half-life of 9-hydr0xyrisperidone was about 21 hours
`(CV=20%) in extensive metabolizers and 30 hours (CV=25%) 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 pom metabolizers. Steady state concentrations
`of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers).
`
`Because risperidone and 9-hydroxyrisperidone are approximately cqui-cifective, the sum of their
`concentratious is pertinent.
`The pharmacokinetics of the sum of risperidone and 9-
`hydroxyrisperidone, after single and multiple doses, were similar in extensive and poor
`metabolizers, with an overall mean elimination half—life of about 20 hours.
`In analyses
`comparing adverse reaction rates in extensive and poor metabolizers in centrolled and open
`studies, no important differences were seen.
`
`RiSperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of
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`cytochrome PWIID‘5 could interfere with conversion of risperidone to 9-hydroxyrisperidone.
`This in fact occurs with quinidine, giving essentially all recipients a risperidone phannacokinetic
`profile typical of poor metabolizers. The favorable 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. It would also be possible for risperidone to interfere with metabolism
`of other dmgs metabolized by cytochrome PmIIDs. Relatively weak binding of risperidone to
`the enzyme suggests this is unlikely (See PRECAUTIONS and DRUG INTERACTIONS).
`
`The plasma protein binding of risperidone was about 90% over the in vitro concentration range
`of 0.5 to 200 ng/mL and increased with increasing concentrations of «acid glycoprotein. The
`plasma binding of 9-hydroxyrisperidone was 77%. Neither the parent nor the metabolite
`diSpIaced each other from the plasma binding sites. High therapeutic concentrations of
`sulfmnefliazine (100 ug/mL), warfarin (10 pg/mL) and carbamazepine (10 ng/mL) caused only
`a slight increase in the free fi'acticn of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50
`ng/mL, changes of unknovm clinical significance.
`
`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).
`
`Hepatic Impairment: While the phannacokinetics of risperidone in subjects with liver disease
`were comparable to those in young healthy subjects, the mean free fraction of risperidone in
`plasrna was increased by about 35% because of the diminished concentration of both albumin
`and aracid glyc0protein. RISPERDAL“ doses should be reduced in patients with liver disease
`(See PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`renal clearance of both risperidone and 9-
`In healthy elderly subjects
`Elderly:
`hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to
`young healthy subjects. Dosing should be modified accordingly in the elderly patients (See
`DOSAGEAND ADMINISTRATION).
`
`Race and Gender Emm: No specific pharrnacokinetic study was conducted to investigate race
`and gender effects, but a population phannacokinetic analysis did not identify important
`differences in the disposition of risperidone due to gender (whether corrected for body weight
`or not) or race.
`
`Clinical Trials
`
`Thegefficacy of RISPERDAL" in the management of the manifestatioas of psychotic disorders
`was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who
`met DSM-III-R criteria for schizophrenia.
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`Several instruments were used for assessing psychiatric signs and symptoms in these studies,
`among them the Brief Psychiatric Rating Scale (BPRS), a multi-itern inventory of general
`psychopathology traditionally used to evaluate the effects of drug treatment in psychosis. The
`BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and
`unusual thought content) is considered a particularly useful subset for assessing actively
`psychotic schizophrenic patients. A secorrd traditional assessment,
`the Clinical Global
`Impression (CGI), reflects the impression of a skilled observer. fully familiar with the
`manifestations of schizophrenia, about the overall clinical state of the patient.
`In additiou, two
`more recently developed, but less well evaluated scales. were employed; these included the
`Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
`Symptoms (SANS).
`
`The results of the trials follow:
`
`(I) In a 6—week, placebo-controlled trial (n=160) involving titration of RISPERDAL" in doses
`up to 10 mg/day (BID schedule), RISPERDAL" was generally superior to placebo on the BPRS
`total score, 011 the BPRS psychosis cluster, and marginally superior to placebo on the SANS.
`
`(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL‘ (2,
`6, 1.0, and 16 mg/day, on a BID schedule), £1114 RISPERDAL‘D groups were generally superior
`to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity Score; the 3 highest
`RISPERDAL" dose groups were generally superior to placebo on the PANSS negative subseale.
`The most consistently positive responses on all measures were seen for the 6 mg dose group, and
`there was no suggestion of increased benefit from larger doses.
`
`(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL0 (1,
`4, 8, 12. and 16 rug/day, on a BID schedule), the four highest RISPERDALD dose groups were
`generally superior to the 1 mg RISPERDAL" dose group on BPRS total score, BPRS psychosis
`cluster, and CGI severity score. None ofthe dose groups were superior to the 1 mg group on the
`PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose
`group.
`
`(4) In a 4‘-week; placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
`RISPERDAL'> (4 and 8 mg/day on a QD schedule), both RISPERDRL dose groups were
`generally superior to placebo on several PANSS measures, including a response measure (> 20%
`reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived
`from PANS S). The results were generally stronger for the 8 mg than for the 4 mg dose group.
`
`INDICATIONS AND USAGE
`
`RISPERDAL" (risperidone) is indicated for the management of the manifestations of psychotic
`disorders.
`
`The antipsychotic efficacy of RISPERDAL’ was established in shortvterm (6 to 8—weeks)
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`controlled trials of schizophrenic inpatients (See CLINICAL PHARMACOLOGY).
`
`The effectiveness of RISPERDALw in long—term use, that is, more than 6 to 8 weeks, has not
`been systematically evaluated in controlled trials. Therefore, the physician who elects to use
`RISPERDAL" for extended periods should periodically reevaluate the long-term usefulness of
`the drug for the individual patient (See DOSAGE AND ADMINISTRATION).
`
`CONTRAINDICATIONS
`
`RISPERDAL' (risperidone) is contraindicated in patients with a known hypersensitivity to the
`product.
`
`WARNINGS
`
`Neuroleptic Malignant Syndrome (NMS)
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
`(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
`NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic
`instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia).
`Additional
`signs may
`include
`elevated
`creatinine
`phosphokinase, myoglobinuria
`(rhabdomyolysis), and acute renal failure.
`
`In arriving at a
`The diagnostic evaluation of patients with this syndrome is complicated.
`diagnosis, it is important to identify cases where the clinical presentation includes both serious
`medical illness (e.g., pneumonia, systemic infectiou, etc.) and untreated or inadequately treated
`extrapyramidal signs and symptoms (BPS). Other important considerations in the differential
`diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
`nervous system pathology.
`
`The management of NMS Should include: 1) immediate discontinuation of antipsychotic drugs
`and other drugs not essential to concurrent therapy: 2) intensive symptomatic treatment and
`medical monitonng; and 3) treatment of any concomitant serious medical problems for which
`specific treatments are available. There is no general agreement about specific pharmacological
`treatment regimens for uncomplicated NMS.
`
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
`reintroduction of drug therapy should be carefully considered. The patient should be carefully
`monitored, since recurrences of NMS have been reported.
`
`Tardive Dyskinesia
`A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
`patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to
`be highest among the elderly, eSpecially elderly women, it is impossible to rely upon prevalence
`estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
`develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
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`tardive dyskinesia is unknown.
`
`The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
`believed to increaSe as the duration of treatment and the total cumulative dose of antipsychotic
`drugs administered to the patient increase. However, the syndrome can develop, although much
`less cornmonly, afier relatively brief treatment periods at low doses.
`
`There is no known treatment for established cases of tardive dyskinesia, although the syndrome
`may remit, partially or completely, if antipsyehotic treatment is withdrawn. Antipsychotic
`treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
`syndrorne and thereby may possibly mask the underlying process. The effect that symptomatic
`suppression has upon the long-tenn emirSe of the syndrome is unknown.
`
`Given these considerations, RISPERDAL" (riSperidone) should be prescribed in a manner that
`is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
`should generally be reserved for patients who suffer from a chronic illness that (l) is known to
`respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially
`less harmful treatments are not available or appropriate.
`In patients who do require chronic
`treatment, the smallest dose and the shortest duration of treatment producing a satisfactory
`clinical response should be sought. The need for continued treatment should be reassessed
`periodically.
`
`If signs and symptoms of tardive dyskinesia appear in a patient‘on RISPERDAL‘, drug
`discorrtinuation should be considered. However, seme patients may require treatment with
`RISPERDAL“ deSpite the presence of the syndrome.
`
`Potential for Proarrhythmic Effects: Risperidone and/or 9-hydroxyrisperidone appears to
`lengthen the QT interval in some patients, although there is no average increase in treated
`patients, even at 12-16 rug/day, well above the recommended dose. Other drugs that prolong the
`QT interval have been associated with the occurrence of torsades de pointes, a life-threatening
`arrhytlunia. Bradycardia, electrolyte imbalance, concomitant usa with other drugs that prolong
`QT, or the presence of congenital prolongation in QT can increase the risk for occurrence of this
`arrhythmia.
`‘
`
`PRECAUTIONS
`General
`
`Orthostatic Hypertension: RISPERDAL“ (risperidone) may induce orthostatic hypotension
`associated with dizziness, tachycardia, and in some patients, syncope, especially during the
`initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties.
`Syncope was reported in 0.2% (6/2607) of RISPERDAL” treated patients in phase 2-3 studies.
`The risk of orthostatic hypotension and syncOpe may be minimized by limiting the initial dose
`to 2 mg total (either QD or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and
`patients with renal or hepatic impairment (See DOSAGE AND ADMINISTRATION).
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`Wfiwhtati mmmmmmmmm @1395
`gunman A dose reduction should be considered if hypotcnsiOn occurs. RISPERDAL0 should
`be used with particular caution in patients with known cardiovascular disease (history of
`myocardial infarction or ischernia, heart failure, or conduction abnormalities), cerebrovascular
`disease, and conditiOns which would predispose patients to hypotension e.g._. dehydration and
`hypovolernia. Clinically significant hypotension has been observed with concomitant use of
`RISPERDAL" and antihypertensive medication.
`
`Seizures: During premarketing testing, seizures occurred in 0.3% (9/2607) of RISPERDALQ
`treated patients, two in association with hyponatremia. RISPERDAL‘9 should be used cautiously
`in patients with a history of seizures.
`
`
`
`Hyperprolacrinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone
`elevates prolactin levels and the elevation persists during chronic administration. Tissue culture
`experiments indicate that approximately one-third of human breast cancers are prolactin
`dependent in vitro, a factor of potential importance if the prescription of these drugs is
`contemplated in a patient with previously detected breast cancer. Although disturbances such
`as galactorrhea, arnenorrhea, gynecomastia, and impotence have been reported with prolactin—
`elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for
`most patients. As is common with compounds which increase prolactin release, an increase in
`pituitary gland, mammary gland, and pancreatic islet cell hyperplasia and/or neoplasia was
`observed in the rispcridone carcinogenicity studies conducted in mice and rats (See
`CARCINOGENESIS) However, neither clinical studies nor epidemiologic studies coriducted
`to date have shown an association between chronic administration of this class of drugs and
`turnorigenesis in humans; the available evidence is considered too limited to be conclusive at this
`time.
`
`Potentialfir Cognitive and Motor Impairment: Somnolence was a commonly reported adverse
`event associated with RISPERDAL” treatment, especially when ascertained by direct
`questioning of patients. This adverse event is dose related, and in a study utilizing a checklist
`to detect adverse events, 41% of the high dose patients (RISPERDAL' 16 mg/day) reported
`somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for
`detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL" 16 mg/day
`patients and 1% of placebo patients reported somnolence as an adverse event.
`Since
`RISPERDAL" has the potential to impair judgment, thinking, or motor skills, patients shOuld
`beicautioned about Operating hazardous machinery, including automobiles, until they are
`reasonably certain that RISPERDAL‘” therapy does not affect them adversely.
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`Priapism: Rare cases of priapism have been reported. While the relationship of the events to
`RISPERDAL‘” use has not been established, other drugs with alpha-adrenergic blocking effects
`have been reported to induce priapisrn, and it is possible that RISPERDAL‘” may share this
`capacity. Severe priapism may require surgical intervention.
`
`Thrombotic Thmmbacytopenic Purpura (TTP): A single case of TTP was reported in a 28
`year-old female patient receiving RISPERDAL" in a large, open premarketing experience
`(approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually
`recovered after receiving plasmapheresis. The relationship to RISPERDAL" therapy is
`unknown.
`
`Antiemetic efl‘ect: Risperidone has an antiernetic effect in animals; this effect may also occur
`in humans, 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 of body temperature regulation has been attributed
`to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association
`with RISPERDALO use. Caution is advised when prescribing for patients who will be exposed
`to temperature extremes.
`
`Suicide: The possibility of a suicide attempt is inherent in schizophrenia, and close supervision
`of high risk patients should accompany drug therapy. PreScriptions for RISPERDAL" should
`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 or conditions that could affect metabolism or
`hemodynamic responses.
`
`RISPERDALO 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. The electrocardiograms
`of approximately 380 patients who received RISPERDAL° and 120 patients who received
`placebo in two double-blind, placebo-controlled trials were evaluated and the data revealed one
`finding of potential concern, i.e., 8 patients taking RISPERDALO whose baseline QTc interval
`was less than 450 msec were observed to have QTc intervals greater than 450 msec during
`treatment; no such prolongations were seen in the smaller placebo group. There were 3 such
`episodes in the approximately 125 patients who received halopen'dol. Because of the risks of
`cithostatic hypotensiOn and QT prolongation, caution should be obServed in cardiac patients (See
`WARNINGS and PRECAUTIONS).
`
`Increased plasma concentrations of risperidorie and 9-hydroxyrisperidonc occur in patients with
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`severe renal impairment (creatinine clearance <30 mL/min/i .73 ml), and an increase in the free
`fraction of the risperidtine is seen in patients with severe hepatic impairment. A lower starting
`dose should be used in such patients (See DOSAGE AND ADMINISTRATION).
`
`Information for Patients
`
`Physicians are advised to discuss the following issues with patients for whom they prescribe
`RISPERDAL”:
`
`Orthostatic Hypotension: Patients should be advised of the risk of orthostatic hypotensiott,
`especially during the period of initial dose titration.
`
`Interference With Cognitive and Motor Pedomance: Since RISPERDAL” 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
`RISPERDAL'” therapy does not affect them adversely.
`
`Pregnancy: Patients should be advised to notify their physician if they become pregnant or
`intend to became pregnant during therapy.
`
`Patients should. be advised not to breast feed an infant if they are taking
`Nursing:
`RISPERDAL".
`
`Concomitant Medication: Patients should be advised to inform their physicians if they are
`taking, or plan to take, any prescription or over-the-coanter drugs, since there is a potential for
`interactions.
`
`Alcohol: Patients should be advised to avoid alcohol while taking RISPERDAL'.
`
`Laboratory Tests
`No specific laboratory tests are recommended,
`
`Drug Interactions
`The interactionsof RISPERDAL“ and other drugs have not been systematically evaluated.
`Given the primary CNS effects of risperidone, caution shOuld be used when RISPERDAL® is
`taken in combination with other centrally acting drugs and alcohol.
`
`Because of its potential for inducing hypotension, RISPERDAL‘” may enhanCe the hypotensive
`effects of other therapeutic agents with this potential.
`
`RISPERDAL" may antagonize the effects of levodopa and dopamine agoriists.
`
`Chronic administration of carbamazepine with risperidone may increase the clearance of
`risPen'done.
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`Chronic administration of clozapine With rispetidone may decrease the clearance of risperidone.
`
`Fluoxetine may increase the plasma concentration ofthe anti-psychotic fiaction (risperidone plus
`9-hydroxyrisperidone) by raising the concentration of risperidone, although not the active
`metabolite, 9—hydroxyrisperidone.
`
`Drugs that Inhibit Cytochrome PMIID, and Other Pm Isozymes: Risperidone is metabolized
`to 9-hydroxyrisperidone by cytochrome P501105, an enzyme that
`is polymorphic in the
`population and that can be inhibited by a variety of psychotropic and other drugs (See
`CLINICAL PHARMACOLOGY). Drug interactions that reduce the metabolism of rispcridone
`to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the
`concentrations of 9vhydroxy'risperidone. Analysis of clinical studies involving a modest number
`of poor metabolizers (n370) does not suggest that poor and extensive metabolizers have different
`rates of adverse effects. No comparison of effectiveness in the two groups has been made.
`
`In vitro studies showed that drugs metabolized by other Pm isozymes, including 1A1, 1A2, IIC9,
`MP, and IIIA4, are only weak inhibitors of risperidone metabolism.
`
`In vitro studies indicate that risperidone is a
`Drugs Metabolized by cytochrome P,,,IID,.-
`relatively weak inhibitor of cytochrome P‘soIIDé. Therefore, RISPERDAL" is not expected to
`substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway.
`However, clinical data to confirm this expectation are not available.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis: Carcinogenicity studies were cenducted in Swiss albino mice and Wistar rats.
`Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/lcg 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 human dose (16 mg/day) on a trig/kg basis or 0.2, 0.75 and 3 times the maximum
`human dose (mice) er 0.4, 1.5, and 6 times the maximum human dose (rats) on a mg/m2 basis.
`A maximum tolerated dose was not achieved in the 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
`21' mph2 (mg/kg)‘basis at which these tumors occurred.
`
`MULTIPLE OF MAXIMUM
`HUMAN DOSE
`
`
`in mg/rn2 (mg/kg)
`
`
`
`HIGHEST
`LOWEST
`
`
`
`
`EFFECT
`NO EFFECT
`LEVEL
`LEVEL
`
`
`
`TUMOR TYPE
`
`SPECIES
`
`'
`
`07594)
`
`am
`
`10
`
`10
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`Endocrine pancreas
`adenomas
`
`Mammary gland
`adenocarcinomas
`
`Mammary gland
`neoplasms,
`
`Total
`
`rat
`
`1.5 (9.4)
`
`0.4 (2.4)
`
`0.2 (2.4)
`
`0.4 (2. 4)
`
`none
`
`none
`
`6 (37.5)
`
`1.5 (9.4)
`
`1.5 (9.4)
`
`0.4 (2.4)
`
`Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
`prolactin levels were not measured during the risperidone carcinogenicity studies; however,
`measurements during subchronic toxicity studies showed that risperidone elevated serum
`prolactin levels 5 to 6 fold in miCe and rats at the same doses used in the carcinogenicity studies.
`An increase in mammary, pituitary, and end0crine pancreas neoplasms has been found in
`rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin
`mediated. The relevance for human risk of the findings of prolaotin-mediated endocrine tumors
`in rodents is unknown (See Hyperprolactinernia under PRECAUTIONS, GENERAL).
`
`Mutagenesrlr: No evidence of mutagenic potential for risperidone was found in the Ames
`reverse mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo
`micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chrornosomal
`aberration test in human lymphocytes or Chinese hamster cells.
`
`Impairment of Fertility: RiSperidone (0.16 to 5 mg/kg) was shown to impair mating, but not
`fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational
`study) at doses 0.1 to 3 times the maximum recommended human dose on a mg/rn2 basis. The
`effect appeared to be in females since impaired mating behavior was not noted in the Segment
`I study in which males only were treated.
`In a subchronic study in Beagle dogs in which
`risperidoné was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were
`decreased at doses 0.6 to 10 times the human dose on a rug/m2 basis. Dose-related decreases
`were also noted in serum testosterone at the same doses. Serum testosterone and sperm
`parameters partially recovered but remained decreased after treatment was discontinued. No no-
`effeet doses were noted in either rat or dog:
`7
`Pregnancy
`Pregnancy Category C: The teratogenic potential of risperidone was studied in three Segment
`II studies in Sprague—Dawley and Wistar rats and in one Segment II study in New Zealand
`rabbits. The incidence of malformations was not increased compared to control in offspring of
`rats or rabbits given 0.4 to 6 times the human dose 011 a rng/‘rn2 basis.
`In three reproductive
`studies in rats (two Segment III and a multigenerational study), there was an increase in pup
`
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`deaths during the first 4 days of lactation at doses 0.1 to 3 times the human dose on 3 mg/m’
`basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or
`to effects 0n the dams. There was no rib-effect dose fer increased rat pup mortality.
`In one
`Segment III study, there was an increaSe in stillborn rat pups at a dose 1.5 times higher than the
`human dose on a mg/rn2 basis.
`
`Placental transfer of riSpen'done occurs in rat pups. There are no adequate and well-controlled
`studies in pregnant women. However, there was one report of a case of agenesis of the corpus
`callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL“
`therapy is unknovm.
`
`RISPERDAL" should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Labor and Delivery
`The effect of RISPERDAL” on labor and delivery in humans is unknown.
`
`Nursing Mothers
`In animal studies,
`It is not known whether or not risperidone is excreted in human milk.
`risperidone and 9-hydroxyrisperidone were excreted in breast milk. Therefore, women receiving
`RISPERDAL0 should not breast feed.
`
`Pediatric Use
`
`Safety and effectiveness in children have not been established.
`
`Geriatric Use
`Clinical studies ofRISPERDAL“ did not include sufficient numbers ofpatients aged 65 and over
`
`to determine whether they respond differently from younger patients Either
`I...
`.1
`.
`genera-1,3lowerstarting doseis recommended for-anelderly patient, reflecting a decreased
`pharmacokinetic clearancein the elderly, as well as a greater frequency. ofdecreased hepatic,
`renal or cardiac function andof. g-_ ‘p
`. ”WW“,
`.
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`ADVERSE REACTIONS
`Associated with Discontinuation of Treatment
`Approximately 9% percent (244/2607) of RISPERDAL0 (lisperidone)—treated patients in phase
`2-3 studies discoutinued treatment due to an adverse event, compared with about 7% on placebo
`and 10% on active control drugs. The more common events (2 03%) associated with
`discontinuation and considered to be possibly or probably drug-related included:
`
`45de
`Extr