National PBM Drug Monograph

Paliperidone Extended-Release Tablets (Invega)

December 2007

VHA Pharmacy Benefits Management Service and the Medical Advisory Panel

*The purpose of VACO PBM drug monographs is to provide a comprehensive
drug review for making formulary decisions. These documents will be
updated when new clinical data warrant additional formulary discussion.
Documents will be placed in the Archive section when the information is
deemed to be no longer current.*

# Executive Summary: 

Paliperidone, an active metabolite of risperidone
(9-hydroxyrisperidone), is the most recent atypical antipsychotic to be
approved and marketed. Paliperidone's formulation, as an
extended-release tablet, employs an osmotic drug-release technology
(OROS) to provide a "gradual ascending" drug delivery which minimizes
fluctuation in peak to trough concentration and permits a 24 hour dosing
interval.

Paliperidone is indicated for the treatment of schizophrenia.
Paliperidone ER is available in 3 mg, 6 mg, and 9 mg tablets. The
initial recommended dose is 6 mg per day taken in the morning. In
clinical trials the trend was for higher doses to provide additional
benefit when needed, but at the risk of dose-related adverse events. The
maximum daily dose is 12 mg. Paliperidone's major route of elimination
is as unchanged drug via the kidney and a dose reduction is recommended
in patients with moderate to severe kidney impairment (including the
elderly). Patients whose creatinine clearance (CrCl) is
[\>]{.underline}50 to \<80 mL/min (mild kidney impairment) should not
receive doses greater than 6 mg per day. Patients whose CrCl is 10 to
\<50 mL/min should not receive doses greater than 3 mg per day.

Three 6-week placebo-controlled trials and one recurrence clinical trial
have been published. Paliperidone demonstrated efficacy superior to
placebo for the treatment of acute exacerbations of schizophrenia and in
delaying recurrence. The initial reports of findings from a comparative
trial with quetiapine determined that paliperidone resulted in a
significantly greater therapeutic response than either quetiapine or
placebo. No significant difference was observed between quetiapine and
placebo which may have been due to an unusually high placebo response.

Paliperidone's adverse effect profile is similar to that of risperidone
and often dose-related; particularly extrapyramidal symptoms and
movement disorders. The most frequently occurring adverse events were
headache, insomnia and tachycardia. Metabolic adverse effects were
uncommon although some were severe enough to warrant discontinuation of
paliperidone.

Paliperidone's potential advantages include a once daily formulation
that allows initiating therapy with a therapeutic dose and minimal
metabolism, thus avoiding drug-drug interactions. Potential
disadvantages or cautions are paliperidone's dependence on the kidney
for its clearance, necessitating dose adjustment based on creatinine
clearance, and that there are no long term data on paliperidone's
efficacy, safety or tolerability currently available.

# Introduction^1^ {#introduction1 .Style-Heading-1-+-Black}

The atypical antipsychotics remain the standard of care in the treatment
of schizophrenia, schizoaffective, and other conditions with psychotic
features. Paliperidone, an active metabolite of risperidone
(9-hydroxyrisperidone), is the most recent atypical antipsychotic to be
approved and marketed. The other atypical antipsychotics are clozapine,
risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Paliperidone's formulation, as an extended-release tablet, employs an
osmotic drug-release technology (OROS) to provide a "gradual ascending"
drug delivery which minimizes fluctuation in peak to trough
concentration and permits a 24 hour dosing interval. One purported
advantage of this drug delivery method permits initiation of
pharmacotherapy with a therapeutic dose limiting the need for dose
titration.

# Pharmacology/Pharmacokinetics^1^ {#pharmacologypharmacokinetics1 .Style-Heading-1-+-Black}

Table 1. Pharmacokinetics of Oral Paliperidone

  ------------------------- ---------------------------------------------
  **Parameter**             **Paliperidone ER**

  Time to Peak              \~24 hours post single dose

  Metabolism                32% recovered as metabolites; dealkylation,
                            hydroxylation, dehydrogenation and
                            benzisoxazole scission. Minimal CYP2D6 and
                            3A4 involvement

  Elimination               59% recovered unchanged in the urine

  Half-life                 23 hours

  Protein Binding           74%

  Bioavailability           28%
  ------------------------- ---------------------------------------------

# FDA Approved Indication(s) and Off-label Uses^1^

Paliperidone is indicated for the treatment of schizophrenia.

Anticipated off-label uses include other labeled indications for
atypical antipsychotics such as bipolar disorder as well as off-label
uses including treatment of delirium, psychotic depression, and
psychiatric and behavioral disorders in patients with dementia. At
present there are no published studies regarding the safety or efficacy
of paliperidone for these conditions.

# Current VA National Formulary Alternatives

All the other atypical antipsychotics (clozapine, risperidone,
olanzapine, quetiapine, ziprasidone and aripiprazole) are on the VANF as
are several conventional antipsychotics.

# Dosage and Administration^1^

*Dosage:*

Paliperidone ER is available in 3 mg, 6 mg, and 9 mg tablets. The
initial recommended dose is 6 mg per day taken in the morning. Some
patients may benefit from a higher dose although dose increases should
only be made following a clinical evaluation and no sooner than 5 day
intervals. In clinical trials the trend was for higher doses to provide
additional benefit when needed, but at the risk of dose-related adverse
events. The maximum daily dose is 12 mg. Lower doses may be needed by
some patients either initially or if intolerant to 6 mg per day
initially.

*Dosage in Special Populations:*

[Hepatic Impairment]{.underline}: A dosage adjustment is not recommended
for patients with mild to moderate hepatic impairment (Child-Pugh class
B); paliperidone has not been studied in patients with more severe
hepatic impairment.

[Renal Impairment]{.underline}: Paliperidone's major route of
elimination is as unchanged drug via the kidney. Hence, a dose reduction
is recommended in patients with moderate to severe kidney impairment.
Patients whose creatinine clearance (CrCl) is [\>]{.underline}50 to \<80
mL/min (mild kidney impairment) should not receive doses greater than 6
mg per day. Patients whose CrCl is 10 to \<50 mL/min should not receive
doses greater than 3 mg per day.

[Elderly]{.underline}: Due to the reduced kidney function frequently
encountered in elderly patients, paliperidone's dose should be adjusted
as recommended under "Renal Impairment."

*Administration:*

Due to the extended-release formulation, paliperidone tablets are to be
swallowed whole and are not to be crushed, split, chewed or altered in
any way.

Paliperidone can be taken without regard to meals, although compared to
fasting conditions, paliperidone's C~max~ and AUC values were increased
by 60% and 54%, respectively, when taken with a high-fat/high-caloric
meal.

Parts of the tablet, insoluble core and shell, may be eliminated intact
in the patient's stool. Patients should be reassured that this is
normal.

*Storage:*

Paliperidone tablets should be stored in temperatures up to 25^o^C
(77^o^F); excursions to 15 -- 30^o^C (59 -- 86^o^F) are permitted. The
tablets should be protected from moisture.

# Efficacy^2-6^

## Primary Efficacy Measure

[Positive and Negative Symptom Scale for Schizophrenia
(PANSS)]{.underline} -- Often used as in entrant criteria as well as a
primary efficacy measure. The PANSS is a 30-item rating scale which that
adapts earlier scales such as the Brief Psychiatric Rating Scale to
assesses the positive and negative symptoms of schizophrenia. Each item
is rated by physician observation and scored from 1 to 7 (the greater
the value, the greater the severity). This scale has been validated.

**Secondary Efficacy Measures**

[The Personal and Social Performance Scale (PSP)]{.underline} -- a
100-point rating scale of function based on the DSM-IV Social and
Occupational Functioning Assessment scale, with 1 to 10 representing
lack of autonomy and 91 to 100 signifying excellent function. The scale
examines social activities, personal and social relationships,
self-care, and disturbing and aggressive behaviors. There are two
analytical interpretations: an absolute change from baseline, and
movement from one 10 point category to another (e.g., from 20-29 to
30-39).

[Clinical Global Impressions -- Severity (CGI-S)]{.underline} -- The
CGI-S is a subscale of the CGI scale the measures severity of illness;
the other two CGI subscales assess global improvement and therapeutic
response. Severity of illness is rated on a 7-point spectrum with 1
signifying "normal" and 7 "among the most severely ill." The CGI-S
measures illness severity over time.

[PANSS Marder factor scores]{.underline} -- refers to the positive,
negative, disorganized thoughts, uncontrolled hostility/excitement, and
anxiety/depression factor scores from the PANSS scale.

[Simpson Angus Scale (SAS)]{.underline} -- This validated 10 item
instrument is used to measure the symptoms of Parkinsonism or
drug-induced parkinsonian side effects. The clinician rates each item
from 0 (normal or absence of the condition) to 4 (the condition is
extreme in severity). The global score is the sum of all scores divided
by the number of items.

[Barnes Akathisia Scale (BAS)]{.underline} -- Used to evaluate akathisia
associated with antipsychotic medications, including an objective and a
subjective component plus a global impression rating for the overall
disorder. The objective and subjective items are rated from 0 (normal,
no evidence) to 3 (constant, severe, intense); the global assessment is
rated from 0 (absent) to 5 (severe). This scale has been validated.

**Efficacy in Schizophrenia**

Three 6-week placebo-controlled trials and one recurrence clinical trial
have been published. Results of a paliperidone-quetiapine comparison
trial are available as a poster only.

All three 6-week placebo-controlled trials evaluated paliperidone's
efficacy and safety in acute exacerbations followed a similar protocol:
multicenter, double-blind, parallel-group, with an active control,
dose-response design. In all three studies a 1:1 randomization was used
with olanzapine 10 mg per day as the active control. No trial was
powered to allow statistical comparisons between paliperidone and
olanzapine. Doses of paliperidone varied across the studies. Inclusion
criteria consisted of men or women [\>]{.underline}18 years of age who
met DSM-IV diagnosis of schizophrenia x 1 year, a PANSS score of 70 --
120, and a willingness to be hospitalized for 14 days. Exclusion
criteria included a diagnosis of substance abuse disorder within 6
months; history of tardive dyskinesia, neuroleptic malignant syndrome;
risk for suicide or violence; pregnancy or breastfeeding; depot
antipsychotic within 120 days; mood stabilizer with 2 weeks; or
antidepressant (unless stable dose x 3 months); history of allergy or
unresponsiveness to antipsychotics. Alternative psychoactive medications
were allowed such as benzodiazepines and anticholinergic medications.
The primary efficacy outcome measure was the change in total PANSS score
from baseline and secondary measures included changes in CGI-S, PSP, and
PANSS Marder factor scores. Safety outcomes included reporting adverse
events using the WHO Adverse Reaction Terminology and assessing reported
movement disorders using the AIMS, BARS, and SAS. All trials defined a
clinical response as patients with a [\>]{.underline}30% reduction in
total PANSS score from baseline to endpoint. Additional individual trial
details are displayed in Table 2.

Table 2. Study Design Parameters for 6-week, Placebo-Controlled Clinical
Trials

+--------------------+---------------+---------------+---------------+
| Study Parameter    | Kane, et al.  | Davidson, et  | Marder, et al |
|                    | 2007          | al. 2007      | 2007          |
+--------------------+---------------+---------------+---------------+
| Number enrolled    | 630           | 618           | 444           |
+--------------------+---------------+---------------+---------------+
| Paliperidone ER    | 6 mg, 9 mg,   | 3 mg , 9 mg,  | 6 mg, 12 mg   |
| dose/day           | 12 mg         | 15 mg         |               |
|                    |               |               | Olanzapine 10 |
| Active control     | Olanzapine 10 | Olanzapine 10 | mg            |
|                    | mg            | mg            |               |
+--------------------+---------------+---------------+---------------+
| Demographics       | 37.1 (10.9)   | 36.8 (10.6)   | 41.6 (NR)     |
|                    |               |               |               |
| > Mean age, years  | 52%           | 68%           | 74%           |
| > (SD)             |               |               |               |
| >                  |               |               |               |
| > Men              |               |               |               |
+--------------------+---------------+---------------+---------------+
| Mean baseline      | 93.9          | 93.0          | 92.3 -- 94.9  |
| total PANSS score  |               |               |               |
+--------------------+---------------+---------------+---------------+
| Frequency of       | PANSS at      |               |               |
| Assessment         | baseline,     |               |               |
|                    | Days 4, 8 and |               |               |
|                    | 15, then      |               |               |
|                    | every 7 days  |               |               |
|                    | and Day 43    |               |               |
|                    |               |               |               |
|                    | PSP at        |               |               |
|                    | baseline and  |               |               |
|                    | endpoint      |               |               |
+--------------------+---------------+---------------+---------------+
| Analysis           | ITT, LOCF     | ITT           | ITT, LOCF     |
+--------------------+---------------+---------------+---------------+

The primary and secondary outcome measure results from the 6-week trials
are shown in Table 3. A greater proportion of patients assigned to
paliperidone or olanzapine completed the trials compared to those
randomized to placebo. Patients assigned to paliperidone had
significantly greater changes in total PANSS scores compared to those
taking placebo. A small dose response was noted with higher doses of
paliperidone (9, 12, and 15 mg) resulting in greater PANSS score
reductions. A significantly greater percentage of paliperidone patients
achieved a clinical response compared to those taking placebo. Among the
secondary outcomes, paliperidone patients had a greater change in PSP
score and a greater percentage achieved a change of one or more PSP
categories. Two trials reported CGI-S results with the percentage of
patients deemed 'marked' or 'severely ill' decreasing slightly in the
placebo arms, while significantly fewer patients in the paliperidone
arms were determined to be so ill.

Table 3. Efficacy Results From 6-week Clinical Trials

+------------------------+---------------------------------------------+
| Kane, et al 2007       | Dose Assignment                             |
+------------------------+---------------------------------------------+
| Randomization, N       | **PLCB PAL ER 6mg PAL ER 9mg PAL ER 12 mg   |
|                        | Olz. 10 mg**                                |
|                        |                                             |
|                        | 127 123 122 130 128                         |
+------------------------+---------------------------------------------+
| Completing             | 46% 65% 71% 78% 70%                         |
+------------------------+---------------------------------------------+
| Outcome                | -4.1 (23.2) -17.9 (22.2)^\*^ -17.2          |
|                        | (20.2)^\*^ -23.3 (20.1)^\*^ -19.9 (19.0)    |
| > [Primary: Change in  |                                             |
| > PANSS                | 30% 56%^\*^ 51% ^\*^ 61%^\*^ 52%            |
| > (SD)]{.underline}    |                                             |
| >                      | 15% 22% 23%^\*^ 32% 26%                     |
| > [\>]{.underline}30%  |                                             |
| > PANSS reduction      | 0.5 (15.5) 9.1 (15.5) ^\*^ 8.1 (14.5) ^\*^  |
| >                      | 11.5 (16.0) ^\*^ 10.3 (15.3)                |
| > [\>]{.underline}50%  |                                             |
| > PANSS reduction      | 32.5%^\*^ 60.5%^\*^ 50.9%^\*^ 59.7%^\*^     |
| >                      | 62.7%                                       |
| > [                    |                                             |
| Secondary]{.underline} | 59.5% 62.6%^\*^ 57.3%^\*^ 64.4%^\*^ 64.1%   |
| >                      |                                             |
| > Change in PSP from   | 50.8% 21.3% 23.0% 16.3% 23.5%               |
| > baseline             |                                             |
| >                      |                                             |
| > Change               |                                             |
| > [\>]{.underline}1    |                                             |
| > PSP category         |                                             |
| >                      |                                             |
| > [CGI-S]{.underline}  |                                             |
| >                      |                                             |
| > Baseline "marked" or |                                             |
| > "severely ill"       |                                             |
| >                      |                                             |
| > Endpoint "marked" or |                                             |
| > "severely ill"       |                                             |
+------------------------+---------------------------------------------+
| Davidson, et al 2007   |                                             |
+------------------------+---------------------------------------------+
| Randomization, N       | **PLCB PAL ER 3mg PAL ER 9mg PAL ER 15 mg   |
|                        | Olz. 10 mg**                                |
|                        |                                             |
|                        | 123 127 125 115 128                         |
+------------------------+---------------------------------------------+
| Completing             | 38% 55% 62% 71% 69%                         |
+------------------------+---------------------------------------------+
| Outcome                | -2.8 (20.9) -15.0 (19.6) ^\*^ -16.3 (21.8)  |
|                        | ^\*^ -19.9 (18.4) ^\*^ -18.1 (20.3)         |
| > [Primary: Change in  |                                             |
| > PANSS                | 18.3% 39.8%^\#^ 45.5%^\#^ 52.7%^\#^ NR      |
| > (SD)]{.underline}    |                                             |
| >                      | -1.5 (15.8) 8.3 (17.1) ^\*^ 7.6 (14.2) ^\*^ |
| > [\>]{.underline}30%  | 12.2 (15.7)^\*^ NR                          |
| > PANSS reduction      |                                             |
| >                      | 30.3% 50.4% 48.3% 63.6% NR                  |
| > [                    |                                             |
| Secondary]{.underline} | 55.8 53.7%^\*^ 52.1%^\*^ 56.6%^\*^ NR       |
| >                      |                                             |
| > Change in PSP from   | 49.2% 31.7% 22.8% 16.9% NR                  |
| > baseline             |                                             |
| >                      |                                             |
| > Change               |                                             |
| > [\>]{.underline}1    |                                             |
| > PSP category         |                                             |
| >                      |                                             |
| > [CGI-S]{.underline}  |                                             |
| >                      |                                             |
| > Baseline "marked" or |                                             |
| > "severely ill"       |                                             |
| >                      |                                             |
| > Endpoint "marked" or |                                             |
| > "severely ill"       |                                             |
+------------------------+---------------------------------------------+
| Marder, et al 2007     |                                             |
+------------------------+---------------------------------------------+
| Randomization, N       | **PLCB PAL ER 6mg PAL ER 12 mg Olz. 10 mg** |
|                        |                                             |
|                        | 110 112 112 110                             |
+------------------------+---------------------------------------------+
| Completing             | 34% 46% 48% 45%                             |
+------------------------+---------------------------------------------+
| Outcome                | -8.0 (21.5) -15.7 (18.9)^\^^ -17.5 (19.8)   |
|                        | ^\*^ -18.4 (19.9)                           |
| > [Primary: Change in  |                                             |
| > PANSS                | 34% 50%^\^^ 51%^\^^ 46%                     |
| > (SD)]{.underline}    |                                             |
| >                      | 31% 41%^\^^ 47%^\^^ 42%                     |
| > [\>]{.underline}30%  |                                             |
| > PANSS reduction      | 2.9 (13.0) 8.8 (13.9) ^\^^ 6.6 (13.1) ^\*^  |
| >                      | 7.6 (13.2)                                  |
| > [\>]{.underline}50%  |                                             |
| > PANSS reduction      | 37.5% 50.6% 46.2% 47.3%                     |
| >                      |                                             |
| > [                    |                                             |
| Secondary]{.underline} |                                             |
| >                      |                                             |
| > Change in PSP from   |                                             |
| > baseline             |                                             |
| >                      |                                             |
| > Change               |                                             |
| > [\>]{.underline}1    |                                             |
| > PSP category         |                                             |
+------------------------+---------------------------------------------+

Comparisons to placebo: \*p\<.001, #p\<.005, \^p\<.05

PLCB=placebo, PAL ER=paliperidone extended-release

## 

## The need for rescue medications (benzodiazepines) varied across the three trials ranging from 45% - 59% to 75% -77% in the active treatment arms and 61% to 78% in the placebo arms. All doses of paliperidone resulted in a significant improvement in all 5 components of the Marder factor scores in the studies by Kane, et al (p\<0.001) and Davidson et al (p\<0.005). In the trial by Marder et al, the paliperidone 6 mg group demonstrated a significant decrease in all Marder factor scores except disordered thoughts and anxiety/depression. A significant decrease was noted in all Marder factor scores in the paliperidone 12 mg group except anxiety/depression. Olanzapine was associated with a significant decrease in all Marder factor scores. The time to onset for improvement with paliperidone as measured by mean total PANSS score was demonstrated by Day 4 or Day 8 in all three studies with the exception of the paliperidone 12 mg group in the study by Marder et al for which an onset was not observed until Day 15. 

[52-Week Open-Label Extension Trials^6,\ 7^]{.underline}

The findings of the pooled analysis of 52-week open-label extension
(OLE) trials of the 3 double-blind, placebo-controlled, 6-week clinical
trial are available in poster form. All subjects completing one of the
6-week trials were eligible; 1083 were enrolled and 47% (n=509)
completed the OLE. The most common reasons for discontinuing
participation was by choice (21%). Other reasons included loss to
follow-up 8%, adverse events 7%, and death \<1%.

The mean modal (SD) dose of paliperidone during the OLE was 10.1(2.74)
mg per day and 9 mg per day was the most common dose. The mean length of
enrollment in the OLE was 231.8 (145.68) days. During the first 12-weeks
of the OLE, total PANSS scores continued to improve and were then
maintained throughout the remainder of the OLE. Although all groups
showed improvement regardless of assignment in the 6-week trial
(placebo, paliperidone, or olanzapine), the greatest improvement was
noted in those converted from placebo to paliperidone for the OLE. These
data appeared as a figure only; no numerical values were provided.
Improvement in the PSP score was also maintained in the OLE with 44% -
59% of subjects experiencing a [\>]{.underline}1 category improvement
over the OLE period; the greatest improvement was in subjects changed
from placebo to paliperidone.

Treatment-related adverse events were reported by 76% of subjects during
the OLE, with 25% of subjects reporting some type of EPS adverse event
(akathisia 11%, dystonia 2%, hypertonia 4%, and tremor 4%). Sinus
tachycardia and tachycardia were reported for 5% and 6% of subjects,
respectively. Other notable adverse events reported include headache,
12%, somnolence, 7%, agitation, 5%, anxiety, 9%, depression, 7%,
insomnia, 14%, psychotic disorder, 9%, and schizophrenia, 7%.
Prolactin-related adverse events were also reported: amenorrhea or
irregular menstruation by 4% and 5% of female subjects, respectively,
and 3% of male subjects reported erectile dysfunction. Prolactin serum
concentrations declined by an average of -24 (74) ng/mL in women and -5
(23) ng/mL in men who'd been assigned to paliperidone in the initial
6-week trial, but increased in subjects switched from olanzapine (79
(77) ng/mL women, 20 (23) ng/mL men) or placebo (93 (87) ng/mL women, 27
(32) ng/mL). The mean change in body weight over the OLE period was 1.1
(5.47) kg and 15% of subjects experienced a 7% or greater increase in
body weight. Weight gain was more likely in patients whose BMI was
\<18.5 at baseline. No clinically relevant changes in lipids were
reported. Small increases (mean) in insulin (2.8 (37) uU/mL) and glucose
(0.2 (1.27) mmol/L) were reported. Less than 1% of subjects (n = 9)
experienced glucose-related adverse events. Eleven subjects (1%) had a
prolonged maximum QTcLD of [\>]{.underline}450msec during the OLE, and
one subject had a maximum QTcLD of [\>]{.underline}480 msec.

[Paliperidone ER and Quetiapine Head-to-Head Trial]{.underline}

Paliperidone was compared to quetiapine and placebo in a 6-week,
head-to-head trial and the findings initial presentation were made in
the October 2007 as a poster presentation. The trials design was similar
to the three other placebo-controlled trials described above with a few
noted differences: 1) patients were hospitalized for 10 days, 2) there
were two double-blind phases -- a 2-week monotherapy phase and a 4-week
additive therapy phase where investigators were allowed to prescribe
additional psychotropic medications, and 3) patients with more severe
exacerbations were recruited by design (a CGI-S scale score
[\>]{.underline}5, i.e., 'markedly ill' was required for admission). The
studies primary outcome was the changes in PANSS total score at Day 14
of monotherapy for paliperidone vs. quetiapine.

Following randomization, patients were assigned to paliperidone (n=158),
quetiapine (n=159), or placebo (n=80) in a 2:2:1 ratio. The dose of
paliperidone was 6 mg per day for Days 1-3, then 9 mg per day thereafter
with an investigator option to increase to 12 mg per day on Day 8. The
quetiapine dose titration was 50 mg per day on Day 1, followed by a
doubling of the dose on Days 2, 3 and 4 to attain a 600 mg per day dose
on Day 5 with the option of increasing to 800 mg per day on Day 8.

Between 63% and 69% of patients enrolled were men with mean ages of the
treatment group of 36-37 years. Baseline PANSS total scores averaged
from 102 to 104 and CGI-S scores averaged 5.2 in all groups denoting the
severity of illness. Between 84% to 88% of patients completed the 14 day
monotherapy phase, while 64% placebo, 67% quetiapine, and 78%
paliperidone completed the entire study. Adverse events, insufficient
response, withdrawal of consent and lost to follow-up were the main
reasons for discontinuation.

During the monotherapy phase the mean doses (SD) of paliperidone and
quetiapine were 10.4 (1.7) and 690.9 (134.3) mg per day, respectively.
At the end of the monotherapy phase, patients treated with paliperidone
had greater improvement as measured by change in total PANSS score
compared to quetiapine (-23.4 (1.8) vs. -17.1 (1.8); p\<.001,
respectively) and placebo (-23.4 (1.8) vs. -15.0 (2.2); p\<0.001,
respectively). Quetiapine was not found to differ from placebo,
p\<0.333). Paliperidone separated from both quetiapine and placebo at
Day 5. Paliperidone resulted in significant improvement in all secondary
measures (PANSS Marder factor scores, CGI-S score, and medication
satisfaction questionnaire) compared to quetiapine and placebo;
quetiapine did not differ from placebo in any of the secondary outcome
measures.

At the end of the 4-week additive therapy phase, 52.9% of paliperidone
patients had received additive psychotropic medications compared to
55.4% taking quetiapine (p=0.733) and 66.7% taking placebo (p=0.051;
p=0.126 vs. quetiapine). Patients assigned to paliperidone continued to
demonstrate significantly greater improvement on the change in PANSS
total score at the end of 6-weeks, -31.2 (1.9), compared to quetiapine,
-26.6 (1.9) \[p=0.023\] and placebo, -23.5 (1.9) \[p=0.002\]. The change
did not differ between quetiapine and placebo, p=0.214.

[Symptom Recurrence Study]{.underline}

Paliperidone's efficacy and safety relative to delaying symptom
recurrence was studied via a multicenter clinical trial using both
open-label and double-blind, placebo-controlled treatment phases.
Following screening, patient's with schizophrenia were hospitalized and
titrated to open-label paliperidone 3 mg to 15 mg per day until they'd
been stable for a minimum of 2-weeks. The next phase consisted of a
6-week outpatient stabilization phase during which open-label
paliperidone was continued in its previous dose. Next, the patients were
a randomized (1:1) in a double-blind fashion to either placebo or their
maintenance dose of paliperidone. Patients remained in this phase until
they experienced a recurrence (using predefined criteria), withdrew
consent, or until the study was completed. At the end of the
double-blind phase, participants were offered enrollment in a 52-week
open-label extension trial. A total of 530 patients enrolled in the
original open-label run-in phase of which 312 were continued in the
stabilization phase, 207 randomized in the double-blind treatment phase
with 179 completing this phase of the trial. Results of the 52-week,
open-label extension trial are not available. Prior to the double-blind,
placebo-controlled phase, the primary reasons for dropping out were as
follows: the subject chose to withdraw, an adverse drug event, no longer
meeting continuation criteria, and lost to follow-up. This study was
terminated early after an independent data monitoring committee's
interim analysis determined that pre-specified efficacy endpoints had
been attained. The findings from the interim and final analyses did not
differ, so only the final analysis will be presented.

During the double-blind, placebo-controlled phase the mean dose of
paliperidone was 10.8 mg per day with dosages divided as follows: 38%, 9
mg/d; 22%, 12 mg/d; and 28%, 15 mg/day. The median duration of exposure
(until recurrence) was 29 days for placebo and 45 days for paliperidone.
Recurrence was the primary reason patients did not complete the
double-blind, placebo-control phase: 52/102 (51%) in the placebo group
and 23/105 (22%) in the paliperidone group. The mean change in total
PANSS scores from baseline to endpoint were 15.1 (19.1) with placebo and
6.0 (13.6) for paliperidone (p[\<]{.underline}0.003). Significant
differences favoring paliperidone were also reported for all secondary
outcome measures: PSP, CGI-S, and Schizophrenia Quality of Life, sleep
quality and daytime drowsiness visual analog scales.

# Adverse Events (Safety Data)^2-5,\ 8^

## Deaths and Other Serious Adverse Events 

Serious adverse events were observed in 1% - 5% of patients in the
placebo comparison trials with psychosis attributed to schizophrenia
being the most common event.

During the recurrence trial one case of possible neuroleptic malignant
syndrome was reported 3-days after the patient had withdrawn from the
study following 19 days of exposure to paliperidone. Three deaths were
reported in this trial: one suicide the day after the patient was
withdrawn from the stabilization phase after period of suicidal ideation
while the patient was hospitalized. A second suicide, considered
secondary to a recurrence, occurred during the double-blind phase in a
patient randomized to placebo. The third death was the homicide of a
patient assigned to placebo and not attributed to a recurrence.

## Common Adverse Events

As shown in Table 4, between 60% and 79% of subjects reported at least
one adverse event across the three placebo comparison trials. Insomnia,
tachycardia and headache were the most frequently reported adverse
events. No prolongation of the QT~c~LD interval (\>450 msec for men or
\>470 ms for women in one trial or \>500 msec in another) was noted with
paliperidone. One patients receiving olanzapine was observed to have a
QT~c~[LD]{.smallcaps} of 456 msec on Day 8.

Table 4. Common Adverse Events Reported in the 6-week Clinical Trials, %

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">ADE</td>
<td colspan="5">Kane, et al. 2007</td>
<td colspan="5">Davidson, et al. 2007</td>
<td colspan="4">Marder, et al. 2007</td>
</tr>
<tr class="even">
<td>PLB</td>
<td><p>PER</p>
<p>6mg</p></td>
<td><p>PER</p>
<p>9mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>3 mg</p></td>
<td><p>PER</p>
<p>9 mg</p></td>
<td><p>PER</p>
<p>15 mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>6 mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
</tr>
<tr class="odd">
<td><p><u>&gt;</u>1 ADE</p>
<p>Insomnia</p>
<p>Somnolence</p>
<p>Headache</p>
<p>Tachycardia</p>
<p>↑ Saliva</p></td>
<td><p>63</p>
<p>17</p>
<p>6</p>
<p>8</p>
<p>10</p>
<p>1</p></td>
<td><p>60</p>
<p>11</p>
<p>4</p>
<p>1</p>
<p>18</p>
<p>1</p></td>
<td><p>63</p>
<p>16</p>
<p>7</p>
<p>7</p>
<p>14</p>
<p>2</p></td>
<td><p>73</p>
<p>12</p>
<p>8</p>
<p>8</p>
<p>22</p>
<p>8</p></td>
<td><p>63</p>
<p>14</p>
<p>14</p>
<p>6</p>
<p>14</p>
<p>0</p></td>
<td><p>60</p>
<p>14</p>
<p>3</p>
<p>10</p>
<p>8</p>
<p>NR</p></td>
<td><p>72</p>
<p>12</p>
<p>6</p>
<p>11</p>
<p>14</p>
<p>NR</p></td>
<td><p>76</p>
<p>15</p>
<p>13</p>
<p>21</p>
<p>10</p>
<p>NR</p></td>
<td><p>77</p>
<p>16</p>
<p>9</p>
<p>18</p>
<p>9</p>
<p>NR</p></td>
<td><p>72</p>
<p>13</p>
<p>17</p>
<p>13</p>
<p>9</p>
<p>NR</p></td>
<td><p>77</p>
<p>12</p>
<p>13</p>
<p>19</p>
<p>3</p>
<p>NR</p></td>
<td><p>73</p>
<p>14</p>
<p>13</p>
<p>25</p>
<p>5</p>
<p>NR</p></td>
<td><p>79</p>
<p>10</p>
<p>13</p>
<p>22</p>
<p>5</p>
<p>NR</p></td>
<td><p>72</p>
<p>8</p>
<p>28</p>
<p>11</p>
<p>4</p>
<p>NR</p></td>
</tr>
</tbody>
</table>

## NR- not reported 

During the recurrence trial, treatment-emergent adverse events were
reported by 73% of patients during the run-in and stabilization phases,
and by 43% treated with placebo and 35% treated with paliperidone during
the double-blind phase. Tremor (16%), headache (14%), hyperkinesia
(12%), and insomnia (10%) were the most frequently reported adverse
events during the open-label phases. Psychosis and aggression were
reported more often in the placebo group (23% and 6%, respectively)
during the double-blind phase than in the paliperidone group (7% and 1%,
respectively). Insomnia occurred in 6% of patients treated with placebo
and 5% treated with paliperidone.

## Other Adverse Events

No significant changes were note in patients' metabolic parameters in
any of the treatment groups throughout the 3 placebo comparison trials.
A total of 12 patients receiving placebo or paliperidone were reported
to experience glycemic events reported as either hyper or hypoglycemia,
diabetes mellitus, or ketosis. The percent of patients who experienced
significant weight gain increased with the dose of paliperidone although
the mean weight gain after 6-weeks tended to be small (Table 5).

Table 5. Change in selected metabolic parameters: baseline to endpoint

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><p>Change in Metabolic</p>
<p>Parameters</p></td>
<td colspan="5">Kane, et al. 2007</td>
<td colspan="5">Davidson, et al. 2007</td>
<td colspan="4">Marder, et al. 2007</td>
</tr>
<tr class="even">
<td>PLB</td>
<td><p>PER</p>
<p>6mg</p></td>
<td><p>PER</p>
<p>9mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>3 mg</p></td>
<td><p>PER</p>
<p>9 mg</p></td>
<td><p>PER</p>
<p>15 mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>6 mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
</tr>
<tr class="odd">
<td><p><strong>Glucose mmol/L</strong></p>
<p>Insulin µU/mL</p>
<p>LDL mmol/L</p>
<p><strong>Cholesterol mmol/L</strong></p>
<p>TG mmol/L</p>
<p>Bodyweight kg</p>
<p>↑ <u>&gt;</u>7%</p></td>
<td><p>0.1</p>
<p>-0.9</p>
<p>0</p>
<p>-0.1</p>
<p>-.03</p>
<p>-0.7</p>
<p>2%</p></td>
<td><p>0</p>
<p>-1.0</p>
<p>0</p>
<p>-0.1</p>
<p>-0.2</p>
<p>0.2</p>
<p>5%</p></td>
<td><p>0.1</p>
<p>2.5</p>
<p>-0.2</p>
<p>-0.2</p>
<p>-0.1</p>
<p>0.6</p>
<p>7%</p></td>
<td><p>0.1</p>
<p>-1.9</p>
<p>-0.1</p>
<p>-0.2</p>
<p>-0.3</p>
<p>0.9</p>
<p>3%</p></td>
<td><p>0</p>
<p>1.5</p>
<p>0.1</p>
<p>0.2</p>
<p>0.1</p>
<p>1.3</p>
<p>1%</p></td>
<td><p>0</p>
<p>0.9</p>
<p>-0.2</p>
<p>-0.2</p>
<p>-0.2</p>
<p>-0.8</p>
<p>6%</p></td>
<td><p>0</p>
<p>-0.2</p>
<p>0</p>
<p>-0.1</p>
<p>-0.2</p>
<p>0.6</p>
<p>7%</p></td>
<td><p>0.1</p>
<p>-1.1</p>
<p>0</p>
<p>-0.1</p>
<p>-0.1</p>
<p>3.14</p>
<p>11%</p></td>
<td><p>0</p>
<p>-1.0</p>
<p>-0.1</p>
<p>0</p>
<p>0</p>
<p>1.9</p>
<p>18%</p></td>
<td><p>0</p>
<p>2.1</p>
<p>0.2</p>
<p>0.3</p>
<p>0.3</p>
<p>2.2</p>
<p>22%</p></td>
<td><p>Not</p>
<p>6%</p></td>
<td><p>Re</p>
<p>7%</p></td>
<td><p>port</p>
<p>18%</p></td>
<td><p>ed</p>
<p>21%</p></td>
</tr>
</tbody>
</table>

There were no significant changes in metabolic laboratory measures
including C-peptide, glucose, insulin, and lipids during the run-in to
stabilization period or during the double-blind phase of the recurrence
trial. Beginning with the run-in phase through the double-blind phase (a
mean of \>24 weeks), a [\>]{.underline}7% increase in body weight was
reported in 12% treated with placebo and 20% treated with paliperidone.
Correspondingly, a [\>]{.underline}7% loss in body weight was noted in
11% and 4% treated with placebo and paliperidone, respectively. Both
groups reported a mean increase in weight: 0.2 kg with placebo and 1.8
kg with paliperidone. Only 2% of patients in either group experienced
what was considered clinically significant weight gain.

[Central and Peripheral Adverse Effects]{.underline}

Extrapyramidal symptoms (EPS) or movement disorders tended to be
experienced by more patients taking higher doses of paliperidone
([\>]{.underline}9 mg per day); for the most part these were considered
mild or moderate in severity (Table 6). However, nine patients
discontinued participation due secondary to movement disorders: 8 taking
paliperidone and 1 placebo.

Table 6. Percentage of Patients Reporting Effect by Clinical Trial

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Effect</td>
<td colspan="5">Kane, et al. 2007</td>
<td colspan="5">Davidson, et al. 2007</td>
<td colspan="4">Marder, et al. 2007</td>
</tr>
<tr class="even">
<td>PLB</td>
<td>6mg</td>
<td>9mg</td>
<td>12mg</td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>3 mg</p></td>
<td><p>PER</p>
<p>9 mg</p></td>
<td><p>PER</p>
<p>15 mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>6 mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
</tr>
<tr class="odd">
<td><p>EPS</p>
<p>Hyperkinesia</p>
<p>Hypertonia</p></td>
<td><p>1</p>
<p>3</p>
<p>0</p></td>
<td><p>3</p>
<p>3</p>
<p>1</p></td>
<td><p>7</p>
<p>6</p>
<p>6</p></td>
<td><p>10</p>
<p>11</p>
<p>4</p></td>
<td><p>2</p>
<p>4</p>
<p>0</p></td>
<td><p>2</p>
<p>4</p>
<p>2</p></td>
<td><p>5</p>
<p>4</p>
<p>3</p></td>
<td><p>10</p>
<p>10</p>
<p>6</p></td>
<td><p>10</p>
<p>10</p>
<p>4</p></td>
<td><p>3</p>
<p>2</p>
<p>3</p></td>
<td><p>4</p>
<p>5</p>
<p>2</p></td>
<td><p>2</p>
<p>4</p>
<p>2</p></td>
<td><p>6</p>
<p>9</p>
<p>6</p></td>
<td><p>2</p>
<p>1</p>
<p>0</p></td>
</tr>
</tbody>
</table>

Change in the global SAS scores tended not to differ between placebo and
paliperidone, although a statistical difference was sometimes noted
between placebo and higher doses of paliperidone; yet the median change
from baseline to study endpoint was 0. Akathisia (as assessed by the
BARS) also tended to occur more frequently with higher doses of
paliperidone occurring in 5%-8% with placebo, 6.5% paliperidone 3 mg,
7%-8% paliperidone 6 mg, 10% paliperidone 9 mg, 13% paliperidone 12 mg,
8% paliperidone 15 mg and 4%-7% with olanzapine. The use of
anticholinergic medications also tended to increase as the dose of
paliperidone increased: 6%-10% placebo, 9%-11% paliperidone 3 mg and 6
mg, 17%-23% paliperidone 9 mg, 22% paliperidone 12 mg and 15%
paliperidone 15 mg. Small, but statistically significant increases in
AIMS scores were observed with the higher doses of paliperidone, but
again the median total AIMS scores at baseline and endpoint were 0 in
all groups studied.

An increase in prolactin concentration and prolactin-related adverse
effects (anorgasmia, impotence, decreased libido and lactation) were
noted in all three trials in both men and women. At least 2 patients
taking paliperidone discontinued the participation secondary to
prolactin-related adverse effects. Prolactin concentrations peaked at
the 6 week mark in two of the three trials and at day 15 in the third
trial with a subsequent decline by the study's conclusion, but remaining
above the upper limit of normal.

During the recurrence trial extrapyramidal symptoms, primarily mild or
moderate severity, occurred in 31% of patients during the run-in and
stabilization phases; most were reported to have resolved within 3-weeks
of continued treatment. During the double-blind phase, EPS-related
adverse events were noted in 7% of paliperidone and 3% of placebo
treated patients. Prolactin concentrations were elevated with
paliperidone, particularly in women, and mean prolactin concentrations
declined after patients were randomized to placebo while remaining
elevated above the reference range in those continuing paliperidone.
Adverse events possibly attributable to elevated prolactin
concentrations such as amenorrhea, nonpuerperal lactation were reported
by 4% and 0% in the paliperidone and placebo groups, respectively.

## 

## Tolerability

Table 7 . Reasons for study withdrawal, %

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Reason</td>
<td colspan="5">Kane, et al. 2007</td>
<td colspan="5">Davidson, et al. 2007</td>
<td colspan="4">Marder, et al. 2007</td>
</tr>
<tr class="even">
<td>PLB</td>
<td>6mg</td>
<td>9mg</td>
<td>12mg</td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>3 mg</p></td>
<td><p>PER</p>
<p>9 mg</p></td>
<td><p>PER</p>
<p>15 mg</p></td>
<td>Olz</td>
<td>PLB</td>
<td><p>PER</p>
<p>6 mg</p></td>
<td><p>PER</p>
<p>12mg</p></td>
<td>Olz</td>
</tr>
<tr class="odd">
<td><p>Any</p>
<p>Lack of efficacy</p>
<p>Subject choice</p>
<p>Adverse event</p>
<p>Lost to follow-up</p>
<p>Other</p></td>
<td><p>54</p>
<p>40</p>
<p>6</p>
<p>7</p>
<p>2</p></td>
<td><p>35</p>
<p>16</p>
<p>7</p>
<p>7</p>
<p>1</p>
<p>5</p></td>
<td><p>30</p>
<p>16</p>
<p>9</p>
<p>3</p>
<p>2</p>
<p>0</p></td>
<td><p>22</p>
<p>10</p>
<p>6</p>
<p>6</p>
<p>0</p>
<p>0</p></td>
<td><p>30</p>
<p>15</p>
<p>4</p>
<p>7</p>
<p>2</p>
<p>3</p></td>
<td><p>62</p>
<p>44</p>
<p>11</p>
<p>4</p>
<p>0</p>
<p>3</p></td>
<td><p>45</p>
<p>24</p>
<p>13</p>
<p>2</p>
<p>0</p>
<p>0</p></td>
<td><p>38</p>
<p>18</p>
<p>14</p>
<p>5</p>
<p>0</p>
<p>0</p></td>
<td><p>29</p>
<p>12</p>
<p>7</p>
<p>3</p>
<p>2</p>
<p>5</p></td>
<td><p>31</p>
<p>13</p>
<p>9</p>
<p>4</p>
<p>2</p>
<p>4</p></td>
<td><p>66</p>
<p>35</p>
<p>15</p>
<p>5</p>
<p>4</p>
<p>8</p></td>
<td><p>54</p>
<p>23</p>
<p>17</p>
<p>7</p>
<p>7</p>
<p>5</p></td>
<td><p>52</p>
<p>14</p>
<p>19</p>
<p>5</p>
<p>9</p>
<p>5</p></td>
<td><p>55</p>
<p>22</p>
<p>15</p>
<p>7</p>
<p>5</p>
<p>5</p></td>
</tr>
</tbody>
</table>

# Precautions/Contraindications^1^

## Precautions

-   Like all atypical antipsychotics, paliperidone carries a warning
    about increased mortality and stroke in elderly patients with
    dementia-related psychosis.

-   Because paliperidone causes a modest increase in QTc interval its
    use should be avoided in patients taking other medications known to
    prolong the QTc interval such as Class IA and III anitarrhythmics,
    other antipsychotics, and certain fluroquinolones. Paliperidone
    should also be avoided in patients with a congenital long QTc
    syndrome or a history of cardiac arrhythmias.

-   Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal
    condition that has been reported following exposure to
    antipsychotics, including paliperidone. Clinicians should be
    familiar with the signs and symptoms of NMS.

-   Antipsychotics are known to be a cause of tardive dyskinesia,
    particularly with prolonged exposure. Although no cases of tardive
    dyskinesia were noted in clinical trials, paliperidone has the
    potential to cause tardive dyskinesia.

-   Parts of the tablet, insoluble core and shell, may be eliminated
    intact in the patient's stool. Patients should be reassured that
    this is normal.

-   A few cases of hyperglycemia and diabetes mellitus were noted in the
    clinical trials with paliperidone.

-   Because of paliperidone's alpha-blocking properties orthostatic
    hypotension and syncope can occur in some patients. A pooled
    analysis of 3 clinical trials determined that syncope was
    experienced by 0.8% (n=850) of patients taking paliperidone compared
    to 0.3% (n=355) taking placebo. Hence, paliperidone should be
    prescribed with caution to patients with known cardiovascular
    disease, cerebrovascular disease, or who may be predisposed to
    hypotension.

-   Antipsychotics are known to lower the seizure threshold. In clinical
    trials seizures were reported in 0.22% of subjects treated with
    paliperidone 3, 6, 9, or 12 mg per day and 0.25% treated with
    placebo.

-   Paliperidone elevates prolactin concentrations and may result in
    related adverse events.

-   Antipsychotic medications have been associated with an increased
    risk for aspiration, aspiration pneumonia and esophageal dysmotility
    and should be used cautiously in patients with dysphagia or who have
    other risk factors for swallowing difficulty.

-   The risk for suicide is inherent in psychotic illness. Paliperidone
    should be prescribed with caution and in small quantities to
    patients with or suspected of having suicidal ideation.

-   Priapism has not been reported with paliperidone, but other
    medications known to antagonize alpha-adrenergic receptors are
    associated with this disorder.

-   Antipsychotics can interfere with the body's ability to regulate its
    temperature.

-   Thrombotic Thrombocytopeina purpura (TTP) has been reported with
    risperidone, although no cases have been reported with paliperidone.

[Use in Pregnancy and Lactation]{.underline}

Paliperidone is FDA Pregnancy Category C. No increase in the incidence
of fetal abnormalities was noted in rats or rabbits exposed to high
doses of paliperidone. No information is available on the use of
paliperidone in pregnant women.

Human and animal studies have shown that paliperidone is excreted in
breast milk. Women receiving paliperidone should not breast-feed
infants.

## Contraindications

Paliperidone is contraindicated in patients with a known
hypersensitivity to paliperidone, risperidone, or to any components in
the paliperidone formulation.

# 

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

LA/SA for generic name: Paliperidone -- risperidone, paroxetine,
haloperidol

LA/SA for trade name: Invega -- Inderal, Inspra, Invagesic

# Drug Interactions^1^

## Drug-Drug Interactions

-   *In vitro* paliperidone did not inhibit Cytochrome P450 isozymes
    known to be responsible for drug metabolism or P-glycoprotein. It is
    not expected that paliperidone will inhibit the clearance of
    medications reliant on these pathways for their clearance.

-   Paliperidone may enhance the properties of alcohol and other drugs
    that affect the central nervous system.

-   Paliperidone may antagonize levodopa and dopamine agonists.

-   Paliperidone's minimal dependence on the CYP2D6 and 3A4 make it
    unlikely that inhibitors or competitive substrates for these enzymes
    will affect paliperidone's clearance.

## Drug-Lab Interactions

No drug-lab interactions are known.

# Acquisition Costs

Table 8. Current VA Prices for Paliperidone

  -------------------- ---------------- ---------------- ----------------
  **Drug**             **Cost/Dose      **Cost/30 days   **Cost/year
                       (\$)**           (\$)**           (\$)**

  Paliperidone 3 mg    7.29             218.70           2660.85

  Paliperidone 6 mg    7.29             218.70           2660.85

  Paliperidone 9 mg    10.92            327.60           3985.80
  -------------------- ---------------- ---------------- ----------------

# Pharmacoeconomic Analysis

No pharmacoeconomic data are available.

# Conclusions

Paliperidone, an active metabolite of risperidone, has demonstrated
efficacy superior to placebo for the treatment of acute exacerbations of
schizophrenia and in delaying recurrence. The initial reports of
findings from a comparative trial with quetiapine determined that
paliperidone resulted in a significantly greater therapeutic response
than either quetiapine or placebo. No significant difference was
observed between quetiapine and placebo which may have been due to an
unusually high placebo response.

Paliperidone's adverse effect profile is similar to that of risperidone
and often dose-related; particularly extrapyramidal symptoms and
movement disorders. Metabolic adverse effects were uncommon although
some were severe enough to warrant discontinuation of paliperidone.

Paliperidone's potential advantages include a once daily formulation
that allows initiating therapy with a therapeutic dose and minimal
metabolism, thus avoiding drug-drug interactions. Potential
disadvantages or cautions are paliperidone's dependence on the kidney
for its clearance, necessitating dose adjustment based on creatinine
clearance, and that there are no long term data on paliperidone's
efficacy, safety or tolerability currently available.

**[Recommendation]{.underline}**

Because individual response and tolerability to antipsychotics varies,
the decision to continue paliperidone or switch to a different
medication is a clinical decision and should be made by the treating
clinician and the patient and/or caregiver. Clinicians within the VA
caring for veterans already started on paliperidone have the option of
continuing paliperidone through the nonformulary request process.

# References:

1.  Anonymous. Paliperidone ER (Invega) package insert.
    [www.invega.com](http://www.invega.com/) accessed September 2007.

2.  Kane J, Canas F, Kramer M, et al. Treatment of schizophrenia with
    paliperidone extended-release tablets: A 6-week placebo-controlled
    trial. Schizophrenia Research 2007;90:147-61.

3.  Davidson M, Emsley R, Kramer M, et al. Efficacy, safety and early
    response of paliperidone extended-release tablets (paliperidone ER):
    Results of a 6-week, randomized, placebo-controlled study.
    Schizophrenia Research 2007;93:117-30.

4.  Marder SR, Kramer M, Ford L, et al. Efficacy and safety of
    paliperidone extended-release tablets: Results of a 6-week,
    randomized, placebo-controlled study. Biological Psychiatry
    doi:10.1016/j.biosych.2007.01.017.

5.  Kramer M, Simpson G, Valentinas M, et al. Paliperidone
    extended-release tablets for prevention of symptom recurrence in
    patients with schizophrenia. J Clin Psychopharmacol 2007;27:6-14.

6.  Eerdekens M, Kramer M, Lane R, et al. Efcacy and tolerability of
    oral paliperidone

> extended-release tablets in the treatment of acute schizophrenia:
> Pooled data from three
>
> 52-week, open-label extension studies \[poster\]. Presented at the
> International Congress
>
> on Schizophrenia Research; Colorado Springs, CO; March 28-April 1,
> 2007.

7.  Kramer M, Eerdekens M, Lane R, et al. Long-term metabolic outcomes
    of oral paliperidone extended-release treatment in patients with
    schizophrenia \[poster\]. Presented at the Society of Biological
    Psychiatry; San Diego, CA; May 17-19, 2007.

8.  Canuso C, Dirks B, Carothers J, et al. A double-blind,
    placebo-controlled trial of paliperidone ER and quetiapine in
    patients with a recent acute exacerbation of schizophrenia. Poster
    presentation at the 20^th^ Annual U.S. Psychiatric & Mental Health
    Congress, October 11-14, 2007, Orlando, FL.

**Approved December 2007. Contact person: Todd Semla, MS, Pharm.D.,
BCPS, FCCP, AGSF**