`Volume 42, Number 7, pp 637-647
`2007 Wolters Kluwer Health, Inc.
`
`FORMULARY DRUG REVIEWS
`
`Paliperidone
`
`Dennis J. Cada, PharmD, FASHP, FASCP* (Editor), Danial E. Baker, PharmD, FASCP, FASHP,†
`and Terri Levien, PharmD‡
`
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`
`Generic Name:
`PALIPERIDONE
`EXTENDED-RELEASE
`TABLETS
`Proprietary Name: Invega
`(Janssen)
`Approval Rating: 1S
`Therapeutic Class: Atypical
`Antipsychotics
`Similar Drugs: Risperidone
`Sound- or Look-Alike Names:
`Neumega, Invagesic
`
`INDICATIONS
`Paliperidone has received Food
`and Drug Administration (FDA)
`approval for use in the treatment
`of schizophrenia.1 See Table 1 for a
`comparison of the FDA-approved
`
`indications for paliperidone and
`risperidone.
`
`CLINICAL PHARMACOLOGY
`Paliperidone
`(9-hydroxy -
`risperidone) is the major active
`It
`metabolite of risperidone.2,3
`exists as a mixture of two equally
`potent enantiomers, with intercon-
`version observed between the
`enantiomers.4 The pharmacologic
`activity of the two enantiomers is
`qualitatively and quantitatively
`similar in vitro.1
`Paliperidone binds to the cen-
`tral dopamine D2 receptors and
`receptors;
`serotonin
`5-HT2A
`antagonism at these receptors is
`the proposed mechanism of
`action.5,6 The striatal D2 occupancy
`after the administration of a 6 mg
`
`extended-release tablet in healthy
`subjects is 64% at 22 hours and
`53% at 46 hours.6,7 Paliperidone is
`also active as an antagonist at
`alpha1- and alpha2-adrenergic
`receptors and H1 histaminergic
`receptors.1 Paliperidone has no
`affinity for cholinergic muscarinic
`or beta1- or beta2-adrenergic
`receptors.1
`
`PHARMACOKINETICS
`The tablets are formulated
`using the Alza OROS delivery sys-
`tem, utilizing osmotic pressure to
`deliver paliperidone.2 Peak plasma
`concentrations occur at 23.1 to 29
`hours after the oral administration
`of a paliperidone extended-release
`tablet.5 Steady-state concentrations
`occur after 4 to 5 days of dosing in
`most patients.1 The pharmacoki-
`netics are dose-proportional over
`the 3 to 12 mg dosage range.1 The
`oral bioavailability of this formu-
`lation is 28%.4 Administration of
`the 12 mg extended-release tablet
`with a standard high-fat/high-
`caloric meal increased the peak
`concentration 60% and the area
`under the curve (AUC) 54% com-
`pared with administration under
`fasting
`conditions. Although
`administration with meals may
`result
`in
`increased exposure,
`paliperidone was not dosed with
`regard to meals in clinical trials
`and such dosing is not required.1
`Plasma protein binding of paliperi-
`done is 74%.1
`Paliperidone is a substrate and
`
`*Executive Editor, The Formulary; †Director, Drug Information Center and Professor of Pharmacy Practice; College of Pharma-
`cy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495; ‡Clinical Associate Professor of Pharma-
`cotherapy, Drug Information Center, Washington State University Spokane, Wash.
`
`Hospital Pharmacy 637
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`Formulary Drug Reviews
`
`Table 1. Comparison of Indications for Paliperidone and Risperidone1,2
`
`Indication
`
`Paliperidone
`
`Risperidone
`
`Bipolar mania
`Irritability associated
`with autistic disorder
`Schizophrenia
`
`X
`
`X
`X
`
`X
`
`Table 2. Comparison of the Pharmacokinetic Parameters for
`Paliperidone and Risperidone1,2,4,5,9-12
`
`Paliperidone
`
`Risperidone
`
`Time to peak (h)
`Oral bioavailability (%)
`Half-life (h)
`Hepatic metabolism
`Metabolized by CYP2D6
`% excreted unchanged in the urine
`Protein binding (%)
`
`24
`28
`23
`Limited
`-
`59%
`74
`
`1
`70
`3 to 20a
`Extensive
`Yes
`NSb
`90
`
`aDepends on the metabolizer status; extensive metabolizers = 3 hours and poor metabo-
`lizers = 20 hours.
`bNS = not specified; both parent drug and metabolites are renally excreted.
`
`weak inhibitor of P-glycoprotein,
`which makes it predisposed to
`pharmacokinetic drug interactions
`with P-glycoprotein inhibitors.3,8
`However, at therapeutic concentra-
`tions, paliperidone did not inhibit
`P-glycoprotein and, therefore, is
`not expected to inhibit P-glycopro-
`tein-mediated transport of other
`drugs to a clinically important
`extent.1
`Paliperidone undergoes limited
`hepatic metabolism.9 Approxi-
`mately 60% of the dose is excreted
`in the urine as unchanged drug
`(range, 51% to 67%), with anoth-
`er 32% recovered as metabolites.1
`Following administration of an
`immediate-release paliperidone
`formulation, four metabolites were
`identified
`in
`the urine, each
`accounting for up to 6.5% of the
`administered dose. Fecal metabo-
`lites accounted for only 0.4% to
`
`0.9% of the administered dose.9,10
`The elimination half-life is approx-
`imately 23 hours.1,10 Pharmacoki-
`netic analysis revealed no differ-
`ence in exposure or clearance
`between extensive and poor
`metabolizers of CYP-450 2D6 sub-
`strates.1
`A comparison of the pharma-
`cokinetic parameters for paliperi-
`done and risperidone in healthy
`adults can be found in Table 2.
`Plasma concentrations of free
`paliperidone were
`similar
`in
`patients with moderate hepatic
`function impairment (Child-Pugh
`class B) and in healthy subjects,
`although total paliperidone expo-
`sure decreased because of a reduc-
`tion in protein binding. No dosage
`adjustment is necessary in patients
`with mild or moderate hepatic
`function impairment. The effects of
`severe hepatic function impairment
`
`638
`
`Volume 42, July 2007
`
`have not been assessed.1
`The dose of paliperidone
`should be reduced in patients with
`moderate or severe renal function
`impairment.
`Elimination
`of
`paliperidone
`is reduced with
`declining creatinine clearance
`(CrCl). Total paliperidone clear-
`ance was reduced 32% in patients
`with mild renal function impair-
`ment (CrCl 50 to 79 mL/min),
`64% in patients with moderate
`renal function impairment (CrCl
`30 to 49 mL/min), and 71% in
`patients with severe renal function
`impairment
`(CrCl 10
`to 29
`mL/min), corresponding to an
`average increase in AUC of 1.5-,
`2.6-, and 4.8-fold, respectively. The
`mean terminal elimination half-life
`was 24, 40, and 51 hours in
`patients with mild, moderate, and
`severe renal function impairment,
`respectively, compared with 23
`hours in subjects with healthy
`renal function (CrCl 80 mL/min or
`greater).1
`No differences in pharmacoki-
`netics were observed in a pharma-
`cokinetic study enrolling Japanese
`and white subjects.1 No differences
`in pharmacokinetics were observed
`in a pharmacokinetic
`study
`enrolling men and women.1
`
`COMPARATIVE EFFICACY
`Most of the efficacy data for
`paliperidone
`extended-release
`tablets are from three 6-week stud-
`ies enrolling patients with acute
`schizophrenia. The results of long-
`term studies are not available.
`
`Placebo-Controlled Studies
`Paliperidone 6 and 12 mg
`extended-release
`tablets were
`assessed in a 6-week, multicenter,
`double-blind, randomized study
`enrolling 444 patients with schizo-
`phrenia. All patients were experi-
`encing an acute episode of schizo-
`phrenia and agreed to hospitaliza-
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`Mylan v. Janssen (IPR2020-00440) Ex. 1006 p. 002
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`tion for the first 14 days of the
`study. The intent-to-treat popula-
`tion included 432 patients with a
`mean age of 41.6 years, was 55%
`black and 74% male, and had a
`baseline Positive and Negative Syn-
`drome Scale (PANSS) total score of
`93.7. Patients received paliperi-
`done 6 or 12 mg, placebo, or olan-
`zapine 10 mg once daily. The pri-
`mary study end point was change
`in PANSS total score. PANSS total
`score was reduced 15.7 points in
`the paliperidone 6 mg group (P =
`0.006) and 17.5 points in the
`paliperidone 12 mg group (P <
`0.001) compared with a reduction
`of eight points in the placebo
`group. Improvement in Personal
`and Social Performance (PSP)
`scores was observed with paliperi-
`done 6 mg (8.8; P = 0.008) com-
`pared with placebo (2.9).13
`Paliperidone extended-release
`was also assessed in a 6-week, dou-
`ble-blind, placebo-controlled study
`enrolling 114 patients 65 years of
`age and older (mean, 70 years of
`age) with a mean PANSS total
`score of 70 to 120 (mean, 92.6).
`Patients
`received paliperidone
`extended-release 6 mg or placebo.
`The paliperidone dose was
`increased to 9 mg/day after 7 days
`if tolerated, then adjusted in 3 mg
`increments over the range of 3 to
`12 mg. The mean modal paliperi-
`done dose was 8.3 mg/day. The
`mean change in PANSS total score
`was –14.6 in the paliperidone
`group and –9.9 in the placebo
`group (least squares mean differ-
`ence, –5.5; 95% confidence inter-
`val [CI], –9.85 to –1.12). The over-
`all incidence of adverse reactions
`was similar in the paliperidone and
`placebo
`groups,
`although
`extrapyramidal disorders occurred
`more frequently in the paliperi-
`done group. No prolactin- or glu-
`cose-related adverse reactions were
`observed. Weight change at end
`
`point was similar in the two
`groups (–0.05 kg with paliperidone
`vs –0.01 kg in the placebo group).14
`The effects of paliperidone
`extended-release on
`symptom
`recurrence were assessed in anoth-
`er double-blind study enrolling
`530 patients. Patients with acute
`schizophrenia (PANSS total score
`between 70 and 132) were initially
`enrolled in an 8-week, run-in treat-
`ment period and received open-
`label, flexible paliperidone extend-
`ed-release doses (3 to 15 mg once
`daily; starting dose 9 mg/day).
`Patients who achieved sympto-
`matic control during the last 2
`weeks of the run-in phase entered a
`6-week, open-label stabilization
`phase (n = 312) and were contin-
`ued on the same dose of paliperi-
`done. Patients who remained sta-
`ble during the stabilization phase
`entered a double-blind phase (n =
`207) and were randomly assigned
`to paliperidone extended-release
`(at the same dose as in the stabi-
`lization phase) or placebo. The pri-
`mary study end point was the time
`to first recurrence event in the dou-
`ble-blind phase. An interim analy-
`sis was scheduled at the 43rd
`recurrence event, and, at that time,
`the study was terminated at the
`recommendation of the monitoring
`committee based on a prespecified
`threshold for significance versus
`placebo. Among patients entering
`the double-blind phase, recurrence
`events occurred in 52% of place-
`bo-treated patients compared with
`22% of paliperidone-treated
`patients (P < 0.001). The time
`point at which 25% of patients
`experienced a recurrence event was
`23 days with placebo compared
`with 68 days with paliperidone.
`Results for the primary end point
`were not presented in the meeting
`abstract. Mean PANSS total score
`in the double-blind phase was
`increased 15.1 points in the place-
`
`Formulary Drug Reviews
`
`bo group compared with an
`increase of 6 in the paliperidone
`group (P < 0.001).15,16
`
`Placebo-Controlled
`Comparator Group Studies
`The efficacy and safety of
`paliperidone were assessed in a 6-
`week, multicenter, double-blind,
`randomized, placebo-controlled
`study including 628 patients with
`acute
`schizophrenia. Enrolled
`patients were 18 years of age and
`older (mean, 37.1 years of age) and
`experiencing an acute episode of
`schizophrenia, as represented by a
`PANSS total score between 70 and
`120 (mean, 93.9). All patients were
`diagnosed with
`schizophrenia
`according to Diagnostic and Statis-
`tical Manual of Mental Disorders,
`4th Edition (DSM-IV) criteria at
`least 1 year prior to screening and
`agreed to a voluntary hospitaliza-
`tion for a minimum of 14 days.
`The patient population was 52%
`male and 86% white, 42% of
`patients were previously hospital-
`ized for psychosis four or more
`times, 61% received previous ther-
`apy with atypical antipsychotics,
`and 57% received conventional
`antipsychotics. The primary com-
`parison was between paliperidone
`6 mg (123 patients), 9 mg (122
`patients), or 12 mg (129 patients)
`extended-release tablets once daily
`or placebo once daily
`(126
`patients). Another group of
`patients received olanzapine 10 mg
`once daily (128 patients) with
`results compared with placebo as
`an assay sensitivity group to con-
`firm study validity. The study was
`completed by 66% of patients
`(46% of patients in the placebo
`group and 65% to 78% in the
`active-treatment groups). Lack of
`efficacy prompted early discontin-
`uation two and a half to four times
`more frequently in the placebo
`group (40% of discontinuations in
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`the placebo group vs 10% to 16%
`of discontinuations in the active-
`treatment groups). Compared with
`placebo, all doses of paliperidone
`were associated with improvement
`in PANSS total score, all PANSS
`Marder factor scores, and personal
`and social functioning. PANSS
`total score also improved in the
`olanzapine group. PANSS total
`score decreased 17.9 points in the
`6 mg group, 17.2 points in the 9
`mg group, 23.3 points in the 12 mg
`group (all P < 0.001 vs placebo),
`19.9 points in the olanzapine
`group, and 4.1 points in the place-
`bo group. Similar improvements
`compared with placebo (all P <
`0.001) were seen in all PANSS
`Marder factor scores (positive
`symptoms, negative symptoms,
`disorganized
`thoughts, uncon-
`trolled hostility/excitement, and
`anxiety/depression). A 30% or
`greater reduction in PANSS total
`score was achieved in 52% of
`patients treated with olanzapine,
`56% of patients treated with
`paliperidone 6 mg, 51% treated
`with paliperidone 9 mg, and 61%
`treated with paliperidone 12 mg
`compared with 30% of placebo
`recipients (P < 0.001 for all
`paliperidone groups vs placebo). A
`50% or greater reduction was
`achieved in 32% of patients treat-
`ed with paliperidone 12 mg com-
`pared with 15% treated with
`placebo (P = 0.001). The incidence
`of movement disorder-related
`adverse reactions and rating scale
`measurements were similar to
`placebo in the paliperidone 6 mg
`group, but more common in the 9
`and 12 mg groups. There were no
`reports of glucose-related adverse
`reactions, clinically important lipid
`changes, or changes in body weight
`of more than 1 kg in the paliperi-
`done-treated patients, although the
`study duration was only 6 weeks.2
`Paliperidone extended-release
`
`640
`
`Volume 42, July 2007
`
`was also assessed in a 6-week, dou-
`ble-blind, placebo-controlled study
`enrolling 618 patients with an
`episode of acute schizophrenia.
`Patients
`received paliperidone
`extended-release 3, 9, or 15 mg,
`placebo, or olanzapine 10 mg once
`daily. The primary efficacy end
`point was the change from baseline
`to end point in PANSS total score.
`The enrolled population was 49%
`white and 68% male, with a mean
`age of 36.8 years and a mean
`PANSS total score of 93. At end
`point, PANSS total score was
`reduced 18.1 in the olanzapine
`group, 2.8 in the placebo group, 15
`in the 3 mg group, 16.3 in the 9 mg
`group, and 19.9 in the 15 mg
`group (P < 0.001 for paliperidone
`vs placebo).
`Improvement
`in
`PANSS total score was observed
`within 4 days of initiation of
`paliperidone therapy. PSP scores
`were also
`improved at each
`paliperidone dose compared with
`placebo (8.3 at 3 mg, 7.6 at 9 mg,
`12.2 at 12 mg, and 1.5 with place-
`bo (P < 0.001).17
`
`Pooled Analysis
`A pooled analysis of these
`three 6-week studies was also con-
`ducted with results from 1,306
`patients included in the intent-to-
`treat analysis. Mean patient age
`was 38.3 years; 62% were white
`and 62% were male. Baseline
`PANSS total score was 93.5. Mean
`PANSS total score at end point was
`improved at each paliperidone
`dose (–15 with 3 mg, –16.9 with 6
`mg, –16.8 with 9 mg, –20.6 with
`12 mg, –19.9 with 15 mg com-
`pared with –4.8 with placebo; P <
`0.001). All PANSS Marder factor
`scores were also improved for
`paliperidone compared with place-
`bo (P ≤ 0.001). Response was
`achieved in 39.8% of patients
`treated with paliperidone 3 mg,
`53.2% treated with paliperidone 6
`
`mg, 48.2% treated with paliperi-
`done 9 mg, 56.7% treated with
`paliperidone 12 mg, and 52.7%
`treated with paliperidone 15 mg,
`compared with 27.4% treated with
`placebo; P < 0.001). Mean changes
`in body weight with placebo and
`paliperidone 3, 6, 12, and 15 mg,
`respectively, were –0.4, 0.6, 0.6, 1,
`1.1, and 1.9 kg.18
`A post hoc pooled analysis
`from these three 6-week paliperi-
`done studies also assessed the effi-
`cacy of paliperidone
`in 270
`patients with predominant nega-
`tive symptoms. At end point,
`improvements in PANSS negative
`factor scores were greater in the
`paliperidone groups (–6.3 in the 3
`mg group, –5.5 in the 9 mg group,
`and –5.6 in the 12 mg group com-
`pared with –2.8 in the placebo
`group [P < 0.02]). PANSS total,
`Clinical Global Impression-Severi-
`ty (CGI-S), and PSP scores were
`also improved in all three paliperi-
`done dose groups compared with
`placebo.19 In an additional post hoc
`pooled assessment of the effects of
`paliperidone on negative symp-
`toms, improvement in negative
`symptoms was determined to be
`directly related to paliperidone
`effects on negative symptoms as
`well as secondary to indirect
`paliperidone effects on both posi-
`tive and depressive symptomatol-
`ogy.20
`In another post hoc pooled
`analysis from the three 6-week
`paliperidone studies,
`including
`1,306
`patients,
`paliperidone
`extended-release 3, 6, 9, 12, and 15
`mg doses were associated with
`greater improvements in quality of
`sleep than placebo, as assessed by a
`visual analog scale (VAS). VAS
`scores were improved 9 points in
`the paliperidone 3 mg group, 11.1
`points with 6 mg, 11.4 points with
`9 mg, 9.7 points with 12 mg, and
`11.3 points with 15 mg, compared
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`with a change of 0.6 on placebo (P
`< 0.05). Daytime drowsiness, also
`assessed by mean change in VAS,
`was not observed at any paliperi-
`done dose compared with place-
`bo.21
`In another post hoc pooled
`assessment,
`including
`1,192
`patients from these three 6-week
`studies, improvement in PANSS
`total score compared with placebo
`was observed for all paliperidone
`doses by treatment day 4 (–2.9 for
`placebo vs –5.8, –5.6, –5.1, and
`–5.8 for paliperidone 3, 6, 9, and
`12 mg, respectively; P < 0.05). Sus-
`tained improvement was observed
`over the duration of the studies.
`Improvement in all PANSS Marder
`factor scores was also observed by
`day 4 in at least one paliperidone
`group. Improvement in CGI-S
`score for all doses compared with
`placebo was observed on day 8,
`with sustained improvement also
`observed over the duration of the
`studies.22,23
`Another post hoc pooled
`assessment from these three 6-
`week studies examined paliperi-
`done compared with placebo in
`384 patients diagnosed with schiz-
`ophrenia within 5 years of study
`entry. The mean time since diagno-
`sis was 2.8 years. Mean baseline
`PANSS total scores ranged from
`90.7 to 93.4. At end point, mean
`PANSS total scores improved from
`baseline at each paliperidone dose
`compared with placebo (–15.5,
`–16.4, –18.7, –17.7, –7.4 for
`paliperidone 3, 6, 9, and 12 mg,
`and placebo, respectively; P <
`0.02). Similar improvement was
`also observed for CGI-S scores and
`PSP scores.24
`
`CONTRAINDICATIONS
`Paliperidone is contraindicated
`in patients with a history of hyper-
`sensitivity to paliperidone, risperi-
`done, or any of the product ingre-
`
`dients (eg, carnauba wax, cellulose
`acetate, hydroxyethyl cellulose,
`propylene glycol, polyethylene gly-
`col, polyethylene oxides, povidone,
`sodium chloride, stearic acid, buty-
`lated hydroxytoluene, hypromel-
`lose,
`titanium dioxide,
`iron
`oxides).1
`
`WARNINGS AND PRECAUTIONS
`The warnings and precautions
`associated with paliperidone are
`similar to those of risperidone.1,12
`Paliperidone labeling contains
`the class warnings regarding tar-
`dive dyskinesia, neuroleptic malig-
`nant syndrome, hyperglycemia,
`and diabetes mellitus, and the class
`black box warning regarding
`increased mortality
`in elderly
`patients with dementia-related psy-
`chosis.1 Labeled precautions are
`also similar to those of risperidone
`and include orthostatic hypoten-
`sion and syncope, seizures, dyspha-
`gia, hyperprolactinemia, potential
`for cognitive and motor impair-
`ment, priapism, body temperature
`regulation disruption, suicide risk,
`and renal function impairment.1,12
`Because of the risk of orthostatic
`hypotension with paliperidone, the
`agent should be used with caution
`in patients with known cardiovas-
`cular disease.1
`Paliperidone causes a modest
`increase in corrected QT interval.
`The use of paliperidone should be
`avoided in combination with other
`drugs that are known to prolong
`QTc, including class 1A (eg, quini-
`dine, procainamide) or class 3 (eg,
`amiodarone, sotalol) antiarrhyth-
`mic medications, antipsychotic
`medications (eg, chlorpromazine,
`thioridazine), antibiotics (eg, gati-
`floxacin, moxifloxacin), or any
`other class of medications known
`to prolong the QTc
`interval.
`Paliperidone should also be avoid-
`ed in patients with congenital long
`QT syndrome and in patients with
`
`Formulary Drug Reviews
`
`a history of cardiac arrhythmias. In
`a study of the effects of paliperi-
`done on QTc interval, paliperi-
`done 8 mg
`immediate-release
`showed a mean placebo-subtracted
`increase from baseline of 12.3 msec
`(90% CI, 8.9, 15.6) on day 8 at 1.5
`hours postdose. The mean steady-
`state peak plasma concentration
`with this 8 mg dose (113 ng/mL)
`was more than twice the exposure
`for the 12 mg extended-release for-
`mulation (45 ng/mL). With a 4 mg
`immediate-release
`tablet
`(peak
`concentration, 35 ng/mL), the
`placebo-subtracted QTc was 6.8
`msec (90% CI, 3.6, 10.1) on day 2
`at 1.5 hours postdose. No subjects
`in this study had a change exceed-
`ing 60 msec or a QTc exceeding
`500 msec at any time during the
`study. While in the efficacy studies
`with the extended-release formula-
`tion, only one subject treated with
`the 12 mg dose had a QTc change
`exceeding 60 msec and no subjects
`had a QTc exceeding 500 msec at
`any time in any of the three place-
`bo-controlled studies.1
`The paliperidone extended-
`release tablet is nondeformable
`and does not change shape in the
`gastrointestinal (GI) tract, there-
`fore it should not be administered
`to patients with pre-existing severe
`GI narrowing (eg, esophageal
`motility disorders, small bowel
`inflammatory disease, “short gut”
`syndrome due to adhesions or
`decreased transit time, past history
`of peritonitis, cystic fibrosis, chron-
`ic intestinal pseudo-obstruction, or
`Meckel diverticulum) to minimize
`the risk of a bowel obstruction.1
`Oral bioavailability from the
`tablet
`formulations may be
`reduced with conditions
`that
`decrease GI transit time (eg, diar-
`rhea), while bioavailability may be
`increased with conditions that
`increase GI transit time (eg, GI
`neuropathy and diabetic gastro-
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`Table 3. Adverse Reactions with Paliperidone vs Placebo in
`6-Week, Placebo-Controlled Studies1
`
`Adverse Reaction Placebo
`(n = 355)
`
`Paliperidone
`12 mg
`6 mg
`9 mg
`3 mg
`(n = 127)(n = 235) (n = 246) (n = 242)
`
`Tachycardia
`Nausea
`QTc prolongation
`Akathisia
`Dizziness
`Dystonia
`Extrapyramidal
`disorder
`Headache
`Somnolence
`Anxiety
`
`7%
`5%
`3%
`4%
`4%
`1%
`
`14% 12%
`6%
`4%
`3%
`4%
`4%
`3%
`6%
`5%
`1%
`1%
`
`12%
`4%
`3%
`8%
`4%
`5%
`
`14%
`4%
`5%
`10%
`5%
`4%
`
`2%
`12%
`7%
`8%
`
`5% 2% 7% 7%
`11% 12% 14% 14%
`6% 9% 10% 11%
`9% 7% 6%
`5%
`
`paresis). Changes in oral bioavail-
`ability are more likely when the
`changes in transit time occur in the
`upper GI tract.1
`The paliperidone extended-
`release tablets utilize the OROS
`osmotic drug-release technology to
`release paliperidone at a controlled
`rate. The tablets should only be
`administered to patients who are
`able to swallow the tablet whole;
`the product cannot be cut or
`crushed. In addition, the biologi-
`cally inert components of the tablet
`remain intact during GI transmit
`and are eliminated in the stool as a
`tablet shell.1
`The safety and efficacy of
`paliperidone have not been estab-
`lished in patients younger than 18
`years of age.1
`Paliperidone is in Pregnancy
`Category C. An increase in fetal
`abnormalities was not observed
`with paliperidone in animal mod-
`els. With risperidone, which is
`extensively converted to paliperi-
`done in rats and humans, an
`increase
`in pup deaths was
`observed in rat reproduction stud-
`
`ies at doses lower that the maxi-
`mum human risperidone dose on
`an mg/m2 basis. Paliperidone
`should be used during pregnancy
`only if the potential benefit justifies
`the potential risk to the fetus.1 In
`animal studies with paliperidone
`and human studies with risperi-
`done, paliperidone was excreted in
`milk. Women receiving paliperi-
`done
`should not breast-feed
`infants.1
`
`ADVERSE REACTIONS
`Adverse reactions observed in
`paliperidone-treated patients have
`included insomnia, somnolence,
`headache, dry mouth, extrapyra-
`midal disorders, hyperkinesia,
`hypertonia, tachycardia, postural
`hypotension, dizziness, electrocar-
`diogram abnormalities, and elevat-
`ed prolactin levels.2,13,25 Table 3
`summarizes adverse
`reactions
`occurring in 5% or more of
`patients in 6-week, placebo-con-
`trolled studies.1 The incidence of
`somnolence, orthostatic hypoten-
`sion,
`salivary hypersecretion,
`akathisia, dystonia, extrapyrami-
`
`642
`
`Volume 42, July 2007
`
`dal disorder, hypertonia, and
`Parkinsonism
`increased with
`increasing dose.1 Effects on glu-
`cose, insulin, total cholesterol, and
`triglycerides were not observed in
`clinical trials.1,14,26
`symptoms
`Extrapyramidal
`occurred with similar frequency in
`patients treated with paliperidone
`extended-release 3 and 6 mg, olan-
`zapine 10 mg, and placebo, but at
`a higher frequency in patients
`treated with paliperidone extend-
`ed-release 9, 12, and 15 mg.2,13,17,22
`Weight gain of more than 7%
`of body weight during the course
`of a 6-week study occurred in 2%
`of placebo-treated patients, 5% of
`patients treated with paliperidone
`6 mg, 7% treated with paliperi-
`done 9 mg, 3% treated with
`paliperidone 12 mg, and 13%
`treated with olanzapine 10 mg.
`Overall, body weight at 6 weeks
`was reduced 0.7 kg in the place-
`bo group, and increased 0.2, 0.6,
`0.9, and 1.3 kg in the paliperi-
`done 6, 9, and 12 mg, and olan-
`In
`zapine groups, respectively.2
`another 6-week study, body
`weight was increased 0.4 kg with
`placebo, 1 kg with paliperidone 6
`mg, 2 kg with paliperidone 12
`mg, and 2.7 kg with olanzapine.13
`Overall, in a pooled analysis
`from the three 6-week studies of
`paliperidone in acute schizophre-
`nia (n = 1,318), body weight was
`increased at end point by 1 kg in
`the combined paliperidone group
`compared with a reduction of 0.4
`kg in the placebo group. Weight
`gain was dose-related (0.6 kg
`with 3 mg, 0.6 kg with 6 mg, 1 kg
`with 9 mg, 1.1 kg with 12 mg,
`and 1.9 kg with 15 mg). Weight
`gain of 7% or more occurred in
`5% of patients in the placebo
`group, 7% in the 3 mg group,
`6% in the 6 mg group, 9% in the
`9 mg group, and 9% in the 12 mg
`group.1,26
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`Table 4. Comparison of the Product Formulations for
`Paliperidone and Risperidone1,2,12
`
`Paliperidone
`
`Risperidone
`
`Oral solution
`Tablet, extended-release
`Tablet, orally disintegrating
`Tablet, prompt-release
`
`X
`
`X
`
`X
`X
`
`DRUG INTERACTIONS
`Interactions due to changes in
`CYP-450 metabolism are not
`anticipated because of its minimal
`hepatic metabolism.10 Paliperidone
`does not substantially inhibit the
`metabolism of drugs metabolized
`by CYP-450 isozymes, including
`CYP1A2, CYP2A6, CYP2C8/9/10,
`CYP2D6, CYP2E1, CYP3A4, and
`CYP3A5. Paliperidone is also not
`expected to have enzyme-inducing
`properties.1 At therapeutic concen-
`trations, paliperidone also did not
`inhibit P-glycoprotein and, there-
`fore, is not expected to inhibit P-
`glycoprotein-mediated transport of
`other drugs to clinically important
`extent.1
`Administration of a single dose
`of paliperidone extended-release
`6 mg after trimethoprim 200 mg
`administered twice daily for 5 days
`resulted in small, clinically insignif-
`icant increases in the paliperidone
`fraction unbound
`(29.7% vs
`25.7%), renal clearance (59.2 vs
`52.4 mL/min), total exposure (356
`vs 391 ng/mL(cid:129)h), and terminal
`half-life (21.8 vs 26.8 hours).
`Effects on the paliperidone phar-
`macokinetics with chronic dosing
`were not assessed.11
`Paliperidone should be used
`with caution in combination with
`other centrally acting drugs or
`alcohol. Paliperidone may antago-
`nize the effect of levodopa and
`other dopamine agonists.1 An addi-
`tive effect may be observed with
`other agents that cause orthostatic
`
`hypotension.1
`
`RECOMMENDED MONITORING
`Patients should be monitored
`for therapeutic response. At this
`time, routine laboratory monitor-
`ing has not been recommended;
`however, because weight gain can
`occur, periodic monitoring of
`blood glucose levels should be con-
`sidered.
`
`DOSING
`The recommended dose of
`paliperidone is 6 mg once daily,
`administered in the morning with
`or without food. Initial dose titra-
`tion is not required. Although
`doses greater than 6 mg have not
`been proven to have additional
`benefit, a general trend towards
`greater effect has been observed
`with greater doses. An increased
`incidence of some adverse reac-
`tions has also been observed with
`increasing doses. The approved
`dose range is 3 to 12 mg/day,
`depending on need and tolerability.
`Dose increases above 6 mg/day
`should occur at intervals of more
`than 5 days. Doses should be
`increased in 3 mg increments.1
`For patients with mild to mod-
`erate hepatic function impairment,
`no dosage adjustment is recom-
`mended.1 Dosage adjustments are
`necessary in patients with renal
`function impairment. For patients
`with mild renal function impair-
`ment (CrCl 50 to 79 mL/min), the
`maximum recommended dose is 6
`
`Formulary Drug Reviews
`
`mg once daily. For patients with
`moderate to severe renal function
`impairment
`(CrCl 10
`to 49
`mL/min), the maximum recom-
`mended dose is 3 mg once daily.1
`No dosage adjustment is necessary
`in elderly patients on the basis of
`age alone; however, dose adjust-
`ment may be required because of
`age-related reductions in CrCl.1
`
`PRODUCT AVAILABILITY
`AND STORAGE
`Paliperidone extended-release
`tablets were granted FDA approval
`in December 2006.27 See Table 4
`for a comparison of the product
`formulations approved for pali -
`peridone and risperidone.
`Paliperidone is available in 3,
`6, and 9 mg extended-release tablet
`strengths, supplied in bottles of 30
`and 350, and unit dose packs of
`Paliperidone
`extended-
`100.1
`release tablets should be stored at
`controlled
`room
`temperature
`(25°C [77°F]; excursions are per-
`mitted to 15° to 30°C [59° to
`86°F]) and protected from mois-
`ture.1
`
`CONCLUSION
`Paliperidone offers an alterna-
`tive to risperidone, with less poten-
`tial for drug interactions. Other
`advantages over risperidone are
`not readily apparent. Head-to-
`head studies with risperidone have
`not been conducted. Risperidone is
`approved for use in broader indi-
`cations and is available in multiple
`dosage forms.
`
`REFERENCES
`1.
`Invega [package insert]. Titusville,
`NJ; Janssen, LP: 2006.
`2. Kane J, Canas F, Kramer M, et al.
`Treatment of
`schizophrenia with
`paliperidone extended-release tablets: a
`6-week placebo-controlled trial. Schizo-
`phr Res. 2007;90:147-161.
`3. Zhu HJ, Wang JS, Markowitz JS,
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`Donovan JL, Gibson BB, Devane CL.
`Risperidone and paliperidone inhibit P-
`glycoprotein activity in vitro [abstract].
`Int J Neuropsychopharmacol. 2006;
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`4. Cleton A, Rossenu S, Vermeulen A, et
`al. A pharmacokinetic model to docu-
`ment
`the
`interconversion between
`paliperidone’s enantiomers [abstract].
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`5. Karlsson P, Dencker E, Nyberg S, et
`al. Pharmacokinetics and dopamine D2
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`cy of paliperidone in healthy subjects
`[abstract]. Eur Neuropsychopharmacol.
`2005;15(suppl 3):S386.
`6. Karlsson P, Dencker E, Nyberg S, et
`al. Pharmacokinetics and dopamine D2
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