CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22-264
`22-264
`
`
`
`APPLICA TION NUMBER:
`
`CLINICAL PHARMACOLOGY AND
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`
`
`

`

`
`
`NDAs
`Submission Dates
`Brand Name
`
`Generic Name
`Reviewer
`
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`22264
`03 February 2009
`INVEGA SUSTENNA TM
`(25mg, 50, 75, 100, 150 mg paliperidone)
`Paliperidone Palmitate
`Hao Zhu, Ph.D.
`Kofi Kumi, Ph.D.
`Yaning Wang, Ph.D.
`Raman Baweja, Ph.D.
`DCP1 (HFD-860)
`DPP (HFD-130)
`Johnson & Johnson R&D, L.L.C.
`
`
`
`
`Pharmacometrics Team Leader
`Clinical Pharmacology Team Leader
`OCP Division
`OND Division
`Sponsor
`Submission Type
`
`
`
`
`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMMARY.....................................................................................................2
`1.1 Recommendations.........................................................................................
`
`1.2 Phase 4 Commitments..................................................................................
`
`2 QUESTION BASED REVIEW..............................................................................................
`3 LABELING RECOMMENDATIONS..................................................................................
`4 APPENDICES..........................................................................................................................7
`4.1 Pharmacometrics Review ............................................................................
`
` 4.2 Analytical Review ……………………………………………………..…………...64
`
`
`
`5566 7
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`
`
`(b) (4)
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`

`

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`
` 1
`
` EXECUTIVE SUMMARY
`
`Paliperdione has been marked as an extended release (ER) formulation with a once-daily
`administration schedule for the treatment of schizophrenia. Paliperidone palmitate
` was originally submitted by Johnson & Johnson Pharmacetucial Research and
`Development (J&JPRD) on 25 October 2007. On 25 August 2008, the division issued a complete
`response letter. Following the complete response letter, the discussion meetings between the
`sponsor and the FDA were held on 9 September 2008 and 21 November 2008. J&JPRD filed the
`resubmission on 03 February 2009 to address the comments and questions raised by the division
`in the complete response letter.
`
`In the resubmission package, the sponsor included a recently completed clinical study report
`(R092670-PSY-3007) to support the initial and maintenance dose of 150 mg eq. An interim
`analysis of safety data from Study R092670-PSY-1008, a long-term (up to 53 weeks), open-label,
`safety study, was also provided to support the use of a higher initiation and maintenance dose.
`
`The sponsor proposed dosing regimen was summarized in Table 1. The sponsor’s proposal was
`based on the findings from the recently finished clinical trials and the population PK simulation
`studies.
`
`
`
`
`Table 1 Summary of the Sponsor Proposed Dosing Regimen
`
`Patient Population
`
`Initial Dosing
`
`Dosing Window Maintenance Dosing Dosing Window
`
`
`
`Our findings, based on the independent simulation studies, were summarized below.
`
`
`• The sponsor proposed target maintenance dose is 75 mg eq. q 4 weeks and can be
`adjusted between 25 to 150 mg eq q 4 weeks. The recommended maintenance dosing
`regimen is acceptable.
`o Paliperidone once daily ER formulation has been approved for the treatment of
`schizophrenia. The recommended dosing is 6 mg q 24 hour and can be adjusted
`between 3 mg to 12 mg q 24 hour.
`
`DA 22264
`INVEGA SUSTENNATM (Paliperidone Palmitate)
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

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`o The simulation showed that 75 mg eq q 4 week using long acting injection yields
`similar exposure as 6 mg q 24 hour for the ER formulation.
`o The simulation also indicated that 25 and 150 mg eq q 4 weeks using long acting
`injection yields similar exposure as 2 mg q 24 hour and 12 mg q 24 hour for the
`ER formulation. In the current submission, 25 mg eq q 4 weeks has shown to be
`effective in treating patients with schizophrenia.
`
`
`• The sponsor also proposed an initial dose of 150 mg eq on the first day, followed by 100
`mg eq by the end of the first week. The proposed initial dosing regimen is acceptable.
`o The desirable exposure is defined as median exposure between the steady state
`peak and trough concentration following 6 mg q.d. oral ER formulation.
`o Starting the treatment with 150 mg eq dose provides the benefit that the desirable
`exposure can be achieved within 1 week. Following the proposed initial dosing
`regimen, the peak exposure is below the highest clinical tested exposure that
`appears to be safe and well tolerated.
`
`• The sponsor proposed that the second initial dose can be administered within 2 days prior
`to or after the scheduled time. In addition, the maintenance dose can be given within 1
`week prior to or after the scheduled time. The simulation results demonstrated that
`paliperidone exposure is within the desirable exposure. Therefore the proposed dosing
`window is acceptable.
`
`• The sponsor proposed an initial dose of 100 mg eq and 75 mg eq on day1 and one week
`later in combination with a maintenance dose of 50 mg eq for patients with mild renal
`impairment. The simulation results indicated that paliperidone exposure is mainly within
`the desirable exposure range. The peak exposure is below the highest clinical tested
`exposure that appears to be safe and well tolerated. Therefore, the proposed dosing
`regimen in patients with mild renal impairment is acceptable. It is to note that
`paliperidone palimtate is not recommended in patients with moderate or severe renal
`impairment.
`
`•
`
`•
`
`DA 22264
`INVEGA SUSTENNATM (Paliperidone Palmitate)
`
`3
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`(b) (4)
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`(b) (4)
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`

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`• We have the following proposals for patients who intend to switch from other long acting
`injection to paliperidone palimtate long acting injection.
`
`o One proposal is to use paliperidone ER formulation between the two long acting
`injections. This would allow the physician to titrate paliperidone dose to
`compensate the elimination of the previous antipsychotic drug based on the
`clinical response and also provide a flexible regimen to adjust the dose timely for
`adverse events. After the patient is stabilized on paliperidone ER formulation and
`most of the previous antipsychotic drug is eliminated, the paliperidone palmitate
`injection can be started with the standard initiation dosing.
`
` For patients that cannot follow the proposed switching strategy, the alternative
`proposal is to switch the patients to the maintenance dosing of paliperidone
`palmitate long acting injection without the loading dose. However, the appropriate
`maintenance dose will be determined by the physician’s clinical judgment and
`cannot be established by using pharmacokinetic simulation alone.
`
` o
`
`
`
`• The sponsor proposed a re-initiation dosing regimen (Table 1). We found that the re-
`initiation dosing regimens for patients who miss doses for 4 - 6 weeks and > 6 months are
`acceptable with the assumption that paliperidone tolerability and the underlying disease
`progression are not affected due to the missing doses.
`
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`• We recommend the re-initiation dose (doses on day 1 and day 8) for a patient who
`discontinues paliperidone palmitate treatment for 6 weeks – 6 months be the same dose as
`the previous maintenance dose with a maximum of 100 mg eq.
`
`
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`DA 22264
`INVEGA SUSTENNATM (Paliperidone Palmitate)
`
`4
`
`(b) (4)
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`(b) (4)
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`In addition, we reviewed the sponsor submitted analysis assay validation report. We found that
`the analytical method used to determine paliperidone concentrations in the plasma is acceptable.
`
`
`4.1 Recommendations
`
`The Office of Clinical Pharmacology has found this sNDA to be acceptable provided that
`satisfactory agreement is reached between the sponsor and the division regarding the language in
`the package insert (PI) and patient prescription information (PPI). Recommendations for
`consideration for the final labeling are included in the Labeling Section (Section 3) of the review.
`
`4.2 Phase 4 Commitments
`None.
`
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`
`___________________________________________
`Hao Zhu, Ph.D.
`Pharmacometrics and Clinical Pharmacology Reviewer
`Office of Clinical Pharmacology
`
`___________________________________________
`Kofi Kumi, Ph.D.
`Clinical Pharmacology Reviewer
`Office of Clinical Pharmacology
`
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`Concurrence: ___________________________________________
`Yaning Wang, Ph.D.
`Pharmacometrics Team Leader
`Office of Clinical Pharmacology
`
`___________________________________________
`Raman Baweja, Ph.D.
`Clinical Pharmacology Team Leader
`Office of Clinical Pharmacology
`
`
`
`DA 22264
`INVEGA SUSTENNATM (Paliperidone Palmitate)
`
`5
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`

`

` QUESTION BASED REVIEW
`
`
`
` 2
`
`
`Please refer to the pharmacomtrics review Section 1.1 in the appendix 4.1.
`
`
`
` 3
`
` LABELING RECOMMENDATIONS
`
`Please refer to the pharmacomtrics review Section 1.3 in the appendix 4.1.
`
`DA 22264
`INVEGA SUSTENNATM (Paliperidone Palmitate)
`
`6
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`

`

`7
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` 4
`
` APPENDICES
`4.1 Pharmacometrics Review
`
`
`
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`
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`

`

`OFFICE OF CLINICAL PHARMACOLOGY:
`PHARMACOMETRIC REVIEW
`
`
`1 SUMMARY OF FINDINGS
`
`1.1 Key Review Questions
`The purpose of this review is to address the following key questions.
`
`1.1.1 Is the sponsor proposed initial and maintenance dosing regimen justified?
`
`In the current submission, the sponsor proposed a different initial and maintenance
`dosing regimen from its original submission (Table 1). The proposed dosing regimen was
`not completely investigated in the clinical trials (Table 2). Our simulation indicated that
`the proposed dosing regimen is acceptable.
`
`Evaluation of the maintenance dosing regimen
`The sponsor indicated that the target maintenance dose is 75 mg eq. q 4 weeks and can be
`adjusted between 25 to 150 mg eq q 4 weeks. Paliperidone ER oral formulation has been
`approved for the treatment of schizophrenia. The recommended maintenance dosing for
`the ER oral formulation is 6 mg q 24 hours. The simulation showed that 75 mg eq q 4
`week using long-acting injection yields similar exposure as 6 mg q 24 hours for the ER
`injection. Likewise, the exposure following 150 mg and 25 mg eq. q 4 weeks from the
`long acting injection is similar to the approved 12 mg q 24 hours and 2 mg q 24 hours
`dosing for the ER oral formulation (Figure 1). Therefore, the sponsor proposed
`maintenance dose appears to be reasonable.
`
`Evaluation of the initial dosing regimen
`The sponsor also proposed an initial dose of 150 mg eq on the first day, followed by 100
`mg eq by the end of the first week of the treatment. We evaluated the sponsor proposed
`initial dosing in two different scenarios.
`
`In the first scenario, patients who have been receiving a different antipsychotic treatment
`(non-long acting injection) other than paliperidone need to switch to paliperidone long
`acting injection. The initial paliperidone concentration is zero before the long acting
`injection is administered. Using 150 mg as the initial dose, the desirable exposure (i.e.
`median exposure between the steady state peak and trough concentration following 6 mg
`q.24 hours of oral ER formulation) can be achieved within the first week of the treatment.
`Whereas using 100 mg and 75 mg as the starting dose, the describable exposure cannot
`be achieved until 1.5 – 2 weeks later.
`
`
`NDA22264 Paliperidone Palmitate
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`- 8 -
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`In the second scenario, a patient receiving paliperidone ER formulation is switched to
`paliperidone long-acting injection. The paliperidone initial concentration is assumed to be
`equivalent to the median steady state trough concentration by the time paliperidone long
`acting injection is given. As shown in Figure 2 B, the exposure in the first week of the
`treatment using the initial dose of 75 mg and 100 mg decreases from the desirable
`concentration range and cannot return until 1.5-2 weeks later. Paliperidone exposure
`returns to the desirable range in less than 1 week following the initial dose of 150 mg.
`
`In addition, using the proposed initial dosing, the peak exposures under the two simulated
`scenarios were below the highest exposure tested in the Study R092670-PSY-3007 (i.e.
`150 mg administered on the first day and by the end of the first week), which was
`administered to about 160 subjects and appears to be safe and well tolerated [Please refer
`to the medical officer: Dr. Jing Zhang’s review].
`
`In summary, starting the treatment with 150 mg eq dose provides the benefit to reach the
`desirable exposure within 1 week. Following the proposed initial dosing regimen, the
`peak exposure is below the clinical tested exposure that appears to be safe and well
`tolerated. Therefore, the sponsor proposed initial dosing regimen is reasonable.
`
`
` Table 1 Summary of the Proposed Initial and Maintenance Dosing Regimen
`
`
`
`
`
`Maintenance Dosing:
`Document
`Initial Dosing:
`Date
`Injection Site: Detoid
`Injection Site: Detoid Muscle
`or Gluteal Muscle
`Type
`
`Dose1
`Time1
`Dose2
`Time 2
`Dose
`Time
`
`
`(mg eq)
`(Day)
`(mg eq)
`(Day)
`(mg eq)
`
`Original
`Monthly 25-Oct-07
`25 - 100
`Submission
`Monthly
`9-Sep-08 CR Letter
`25 - 100
`75 ( 25 - 150) Monthly
`3-Feb-09 Resubmission
`
`100
`75 - 100
`100
`
`8
`8
`8
`
`1
`100
`75-100 1
`150
`1
`
`Table 2 Initial and Maintenance Doses being Investigated in the Clinical Trials
`
`
`Dose Evaluated
`
`Time
`Maintenance
`(Day)
`(mg eq)
`25, 100, 150 8, 36, 64
`
`Initial
`(mg eq)
`150
`
`Time
`(Day)
`1
`
`R092670-PSY-3007
`
`
`
`
`
`
`
`Clinical Trial
`
`
`
`
`Document
`
`
`
` Date
`
`
`Resubmission
`Original
`Submission
`Original
`Submission
`
`3-Feb-09
`
`25-Oct-07
`
`25-Oct-07
`
`
`
`- 9 -
`
`None
`
`None
`
`None 50, 100, 150 1, 8, 36, 64 R092670-PSY-3003
`
`None 25, 50, 100
`
`1, 8, 36, 64 R092670-PSY-3004
`
`NDA22264 Paliperidone Palmitate
`
`
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`

`

`
`
`Figure 1 the Simulated Median Exposure following 25 mg (A), 75 mg (B), 150 mg
`(C) of Long-Acting Injection (Q 4 Weeks) versus the Observed Median Exposure
`Following 2 mg, 6 mg, and 12 mg (Q24 hour) ER Formulation
`
`Median Steady State Cmax - Cmin:
` (2 mg QD)
`
`Median Exposure (25 mg q 4 weeks)
`
`19
`
`20
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`21
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`23
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`24
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`25
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`22
`Time [Week]
`
`(A)
`
`Median Cmax (6 mg QD ER at steady state)
`
`Median Cmin (6 mg QD ER at steady state)
`
`Dosing Interval at Steady State
` (75 mg im. Q 4week)
`
`19
`
`20
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`21
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`23
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`24
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`25
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`22
`Time [Week]
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`(B)
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`10
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`8
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`6
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`4
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`2
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`0
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`30
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`25
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`Concentration [ng/mL]
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`10
`Concentration [ng/mL]
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`15
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`20
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`5
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`0
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`NDA22264 Paliperidone Palmitate
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`Median Cmax (12 mg QD ER at steady state)
`
`Median Cmin (12 mg QD ER at steady state)
`
`60
`
`50
`
`20
`Concentration [ng/mL]
`
`40
`
`30
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`Dosing Interval at Steady State
` (150 mg im. Q 4week)
`
`10
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`0
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`19
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`20
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`21
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`22
`Time [Week]
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`23
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`24
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`25
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`(C)
`Note: red line= Model predicted steady state median exposure following 25, 75, 150 mg i m. injection
`every 4 weeks.
`Source:
`1. Median Cmax and Cmin at steady state following 6 mg and 12 mg dose once every 24 hours
`(Obtained from Attachment 2.23 in CSR R092670-SCH-01, P-1051 and P-1048).
`2. Median Cmax and Cmin at steady state following 2 mg once daily dosing was derived from the 6
`mg and 12 mg q 24 hr data based on the linear PK feature of paliperidone.
`Figure 2 Evaluation of Initial Dosing Regimen
`
`Dosing Interval at Steady State
` (Q 4week)
`
`Median Cmax (6 mg QD ER at steady state)
`
`Median Cmin (6 mg QD ER at steady state)
`
`50
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`40
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`30
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`20
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`10
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`0
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`Concentration [ng/mL]
`
`0
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`2
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`NDA22264 Paliperidone Palmitate
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`Time [Week]
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`- 11 -
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`(A)
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`50
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`40
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`30
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`20
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`10
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`0
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`Concentration [ng/mL]
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`0
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`1
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`2
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`3
`Time [Week]
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`4
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`5
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`(B)
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`Note:
`A = A patient switches from a different antipsychotic formulation (non-long acting injection) other than
`paliperidone ER oral formulation to paliperidone long acting injection.
`
`
`
`1.1.2 Is the sponsor proposed dosing window justified?
`In clinical practice, patients might not be able to receive the paliperidone palmitate
`injection exactly following the scheduled time. Therefore, the sponsor proposed a dosing
`window to guide the medical caregiver (Table 3). Our simulations indicated that the
`sponsor proposed dosing window is acceptable.
`
`The first simulation was to identify the dosing window for the second initial dose. The
`simulation compared the paliperidone pharmacokinetic profiles when it is given within 2
`days prior to and after the scheduled dosing time. The simulation assumes paileridone
`initial concentration is zero, because the pharmacokinetic profile of the second dose is the
`primary focus. Even when the initial paliperidone concentration is not zero, the residual
`
`NDA22264 Paliperidone Palmitate
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`- 12 -
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`(b) (4)
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`(b) (4)
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`

`

`of paliperdione concentration from the prior treatment (such as paliperidone ER and IR
`formulations) can be neglected by the time when the second initial dosing window is
`reached. Simulation results demonstrated that paliperidone exposure levels are similar if
`the second initial dose is given within 2 days prior to or after the scheduled time (Figure
`3 A). It is beyond the scope of our simulation to evaluate a patient who is receiving
`another long acting antipsychic injection before switching to paliperidone palmitate
`injection.
`
`The second simulation was conducted to evaluate the proposed dosing window for the
`maintenance dose. As shown in Figure 3 B, the paliperidone concentrations are within the
`desired concentration range even when paliperidone is administered 1 week prior to or
`after the scheduled time.
`
`
`Table 3 the Sponsor Proposed Dosing Window
`
`Dosing
`Second Initial Dose
`Maintenance Dose
`
`Scheduled Dosing Time
`End of the first week
`Every 4 weeks
`
`Dosing window
`± 2 days
`± 7 days
`
`Figure 3 Evaluation of Dosing Window
`
`
`
`
`50
`
`40
`
`30
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`20
`
`10
`
`0
`
`Concentration [ng/mL]
`
`0
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`2
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`4
`Time [Week]
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`6
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`NDA22264 Paliperidone Palmitate
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`- 13 -
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`30
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`25
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`10
`Concentration [ng/mL]
`
`15
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`20
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`5
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`0
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`19
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`20
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`21
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`22
`Time [Week]
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`(B)
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`23
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`24
`
`25
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`
`
`A) Dashed blue line = 150 mg on Day1 and Day 8
`Dashed brown line = 150 mg on Day 1 and 100 mg on Day 6
`Solid red line = 150 mg on Day 1 and 100 mg on Day 8
`Dashed green line = 150 mg on Day 1 and 100 mg on Day 10
`Dashed black line = 75 mg on Day 1 and Day 8
`B) Dashed light blue line = maintenance dose 75 mg 1 week prior to the scheduled time
`Solid red line = maintenance dose 75 mg on the scheduled time
`Dashed dark blue line = maintenance dose 75 mg 1 week after the scheduled time
`
`
`Note:
`
`
`
`1.1.3 Is the sponsor proposed re-initiation dosing regimen justified?
`The sponsor proposed a re-initiation dosing regimen for patients who miss paliperidone
`palmitate injection (Table 4). Our simulations indicated that the sponsor’s proposal for
`patients who miss doses for 4-6 weeks and > 6 months are acceptable with the
`assumption that paliperidone tolerability and the underlying disease progression are not
`affected due to the missing doses.
`
` We recommend
`that the re-initiation dose for a patient who discontinues paliperidone palmitate treatment
`for 6 weeks – 6 months be the same as the previous maintenance dose with a maximum
`of 100 mg.
`NDA22264 Paliperidone Palmitate
`
`
`
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`- 14 -
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`(b) (4)
`
`

`

`Table 4 The Proposed and Recommended Re-Initiation Dosing Regimen
`
`
`
`
`
`Re-initiation Dosing Regimen
`
`Missing Time
`1 month - 6 week
`
`Dose
`The Same Regular Dose
`
`Dosing Time
`q 4 week
`
`
`
`
`
`6 week - 6 month
`
`
`6 month
`
`
`
`*: The Same Regular Dose
`(Up to 100 mg)
`
`
`
`Day 1, Day 8, followed by q 4
`week
`
`
`
`
`
`Restart the initial dosing regimen
`
`*: FDA reviewer’s recommended dose.
`
`If a patient misses paliperidone dose for more than 6 months, the pharmacokinetic profile
`of paliperidone is shown in Figure 4 A. The results demonstrated that if 6 months have
`elapsed since the last injection, the concentration is almost zero. Therefore, the patient
`should restart the initial dose in order to ensure that the desirable concentration range can
`be reached within 1 week (Figure 4A). If a patient misses a dose for about 1 month to 6
`weeks, the pharmacokinetic profile can be found in Figure 4 B. Paliperidone
`concentration returns to the desirable range rapidly following the administration of
`paliperidone with regular monthly interval (Figure 4 B).
`
`Furthermore, pharmacokinetic simulations were conducted to evaluate the appropriate
`dosing regimen for a patient who misses doses between 6 weeks to 6 months. The
`sponsor proposed
`
`
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The 23% increase in exposure does not lead to safety concern if the patient is stabilized at
`a dose less than or equal to 100 mg eq, because the overall exposure is still below the
`highest clinical tested exposure. However, the following example demonstrates how this
`proposal can lead to potential safety concern. Following the current proposal,
`
`
`
`NDA22264 Paliperidone Palmitate
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`- 15 -
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`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

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`We recommend the re-initiation dose for a patient who misses dose for 6 weeks – 6
`months should not exceed 100 mg. Following our recommendation, the simulated
`pharmacokinetic profiles were shown in Figure 4E and 4F. Paliperidone concentration
`will not exceed the highest median exposure observed in the trial. In the mean time,
`paliperidone exposure returns to the desirable concentration in less than 2-3 dosing cycles.
`
`
`Figure 4 Evaluation of Alternative Dosing Regimen for Missing Dose
`
`30
`
`25
`
`10
`Concentration [ng/mL]
`
`15
`
`20
`
`5
`
`0
`
`20
`
`25
`
`30
`
`35
`Time [Week]
`
`(A)
`
`40
`
`45
`
`
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`NDA22264 Paliperidone Palmitate
`
`
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`- 16 -
`
`(b) (4)
`
`

`

`
`
`
`
`30
`
`25
`
`10
`Concentration [ng/mL]
`
`15
`
`20
`
`20
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`25
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`30
`
`35
`Time [Week]
`
`(B)
`
`40
`
`45
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`5
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`0
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`30
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`25
`
`10
`Concentration [ng/mL]
`
`15
`
`20
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`5
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`0
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`20
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`30
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`50
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`40
`Time [Week]
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`(C)
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`30
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`25
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`10
`Concentration [ng/mL]
`
`15
`
`20
`
`5
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`0
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`20
`
`25
`
`30
`Time [Week]
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`35
`
`40
`
`
`
`(D)
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`50
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`40
`Concentration [ng/mL]
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`30
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`20
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`20
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`30
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`40
`Time [Week]
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`50
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`
`
`10
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`0
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`(E)
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`50
`
`40
`Concentration [ng/mL]
`
`30
`
`20
`
`10
`
`0
`
`20
`
`25
`
`30
`Time [Week]
`
`35
`
`40
`
`
`
`(F)
`
`Note:
`A = A patient who misses doses for greater than 6 months
`B = A patient who misses dose for less than 6 weeks receives the sponsor proposed re-
`initiation dosing.
`C = A patient who misses dose for less than 6 months (6 month minus 1 day) receives the
`sponsor proposed re-initiation dosing.
`D = A patient who misses dose for greater than 6 weeks (6 weeks plus 1 day) receives the
`sponsor proposed re-initiation dosing.
`D = A patient who misses dose for less than 6 months (6 moth minus 1 day) receives the
`FDA recommended re-initiation dosing.
`E = A patient who misses dose for greater then 6 weeks (6 week plus 1 day) receives the
`FDA recommended re-initiation dosing.
`
`Solid red line = Median PK Profile.
`Blue Shaded Area =Median Cmax and Cmin at steady state following 6 mg once daily dosing.
`(Obtained from Attachment 2.23 in CSR R092670-SCH-01, P-1051)
`Brown Shaded Area = Median Cmax and Cmin at steady state following 12 mg once daily dosing.
`(Obtained from Attachment 2.23 in CSR R092670-SCH-01, P-1051)
`
`
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`1.1.4 Is the sponsor proposed paliperidone palmitate dosing regimen for patients
`who intend to
` justified?
`
`
`No. The sponsor did not provide adequate rationale to support their
`regimen.
`
`The sponsor proposed a paliperidone palmitate dosing regimen for patients who intend to
`
`
`
`
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`1.1.5 Is the sponsor proposed paliperidone palmitate dosing regimen for patients
`with mild renal impairment justified?
`
`Yes. The sponsor proposed dosing regimen for patients with mild renal impairment is
`acceptable.
`
`The sponsor indicated that the initial dosing for patients with mild renal impairment is
`100 mg and 75 mg on Day 1 and one week later, respectively. The recommended
`maintenance dosing is 50 mg q 4 weeks. Paliperidone palmitate is not recommended for
`patients with moderate and severe renal impairment.
`
`The sponsor’s dosing adjustment is necessary for patients with mild renal impairment
`because paliperidone is mainly excreted through kidney, with 59% of the dose being
`excreted unchanged into urine. The sponsor’s population PK analysis confirmed that
`creatinine clearance is a significant covariate for paliperidone clearance. Therefore, for a
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`patient with compromised renal function, paliperidone exposure will be increased if the
`dose is not adjusted accordingly.
`
`The sponsor proposed maintenance dosing is 50 mg q 4 weeks for patients with mild
`renal impairment (50 mL/min ≤ creatinine clearance < 80 mL/min). Our simulation was
`conducted in patients with creatinine clearance of 50 mL/min. Following the sponsor
`proposed maintenance dosing regimen, paliperidone concentration profile is shown in
`Figure 5. The steady state concentration is within the desirable concentration range.
`
`The sponsor proposed initial dosing is 100 mg and 75 mg on Day 1 and Day 8. The
`simulated pharmacokinetic profiles of paliperidone are shown in Figure 6. Even though
`the peak concentration following the sponsor proposed initial dosing is above the
`desirable exposure range, the overall exposure is still below the highest clinical tested
`exposure level (150 mg on both Day 1 and Day 8).
`
`Figure 5 Pharmacokinetic Profile of Palieridone at Steady State Following 50 mg q
`Paliperidone Palmitate Long Acting Injection q 4 Weeks in Patients with Mild
`Renal Impairment (CRCL = 50 mL/min)
`
`30
`
`20
`
`10
`
`0
`
`Concentration [ng/mL]
`
`19
`
`20
`
`21
`
`22
`Time [Week]
`
`23
`
`24
`
`25
`
`
`
`Note: Solid red line = Median PK Profile.
`Shaded Area =Median Cmax and Cmin at steady state following 6 mg once daily dosing was
`obtained from Attachment 2.23 in CSR R092670-SCH-01, P-1051
`
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`Figure 6 Pharmacokinetic Profile of Paliperidone Palmitate Long Acting Injection
`Following 100 mg / 75 mg on Day1/8
`
`0
`
`2
`
`4
`Time [Week]
`
`6
`
`30
`
`20
`
`10
`
`0
`
`Concentration [ng/mL]
`
`Note: Shaded area = Desirable Concentration range
` Solid line = Pharmacokinetic profile for palimperidone in patients with mild renal impairment
`following the adjusted initial dosing.
` Blue dashed line = highest exposure tested in the clinical trial (150 mg on both Day 1 and 1 week
`later).
`
`
`
`1.1.6
`
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`Switching from an oral formulation to paliperidone palmitate long acting injection is of
`less concern because the apparent half-life for an oral formulation is usually short (i.e., <
`24 hour). Paliperidone concentration reaches peak within 2 weeks following the initiation
`dosing (150 mg on Day 1 and 100 mg on Day 8). During the same time, most of the
`previous antipsychotic drug is eliminated from the body. In the following example, we
`assume that a patient receiving palieridone ER formulation is intended to switch to the
`long acting injection. We demonstrated that paliperidone concentration returns to regular
`therapeutic exposure within one week and the peak concentration is below the highest
`exposure tested in the trial, following the standard initiation dosing (Figure 1 A). In
`addition, our simulation indicated that similar steady state paliperidone exposure
`following various doses of paliperidone ER formulation can be achieved by using
`palieridone long acting injection (Table 5).
`
`
`Table 5 Similar paliperidone exposure at steady state using different doses of
`INVEGA ® and INVEGA ® SUSTNNA TM
`INVEGA ® SUSTENNA TM
`INVEGA ®
` Extended Release Tablet
`Injection
`Once Daily
`Once every 4 Weeks
`12
`234
`6
`117
`3
`39-78
`
`Formulation
`Dosing Frequency
`Dose
`(mg)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`One proposal is to use palieridone ER formulation between the two long acting injections.
`This would allow the physician to titrate paliperidone dose to compensate the elimination
`of the previous antipsychotic drug based on the clinical response and also provide a
`flexible regimen to adjust the dose timely for adverse events. After the patient is
`stabilized on paliperidone ER formulation and most of the previous antipsychotic drug is
`
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`eliminated, the paliperidone palmitate injection can be started with the standard initiation
`dosing.
`
`For patients that cannot follow the proposed switching strategy, the alternative proposal
`is to switch the patients to the maintenance dosing of paliperidone palmitate long acting
`injection without the loading dose. However, the appropriate maintenance dose will be
`determined by the physician’s clinical judgment and cannot be established by using
`pharmacokinetic simulation alone.
`
`
`1.1 Recommendations
`The sponsor proposed initial and maintenance dosing regimen, alternative dosing window,
`and dosing regimen for patients with mild renal impairment are acceptable from clinical
`pharmacology point of view.
`
`However, we found:
`•
`
`
`
`.
`
`•
`
`
`
`
`We recommend that the re-initiation dose for a patient who misses paliperidone long
`acting injection for 6 weeks to 6 months should not exceed 100 mg.
`
`
`
`
`1.1 Label Statements
`Labeling statements to be removed are shown in red strikethrough font and suggested
`labeling to be included is shown in underline blue font.
`
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing2
`
`
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`NDA22264 Paliperidone Palmitate
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`3 pp withheld in full immediately after this page as (b)(4) Draft Labeling
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`

`

`2 PERTINENT REGULATORY BACKGROUND
`Paliperdione has been marked as an extended release (ER) formulation with a once-daily
`administration schedule for the treatment of schizophrenia. Paliperidone palmitate
` was originally submitted by Johnson & Johnson Pharmacetucial Research
`and Development (J&JPRD) on 25 October 2007. On 25 August 2008, the division
`issued a complete response letter. Following the complete response letter, meetings for
`the discussion of the resubmission were held on 9 September 2008 and 21 November
`2008. J&JPRD filed a resubmission on 03 February 2009 to address the comments raised
`by the division in the complete response letter.
`In the resubmission package, the sponsor included a recently completed R092670-PSY-
`3007 clinical study report to support the initial and maintenance dose of
`. An
`interim analysis of safety data from Study R092670-PSY-1008, a long-term (up to 53
`weeks), open-label, safety study, was also provided to support the use of a higher
`initiation and maintenance dose.
`
`3 RESULTS OF SPONSOR’S ANALYSIS
`
`1.1 Summary of the Clinical Study Report: (R09267-PSY-3007)
`Study R092670-PSY-3007 was a multicenter, randomized, double-blind, placebo-
`controlled, parallel-group, dose-response study designed to evaluate the efficacy and
`safety of 3 fixed maintenance doses of paliperidone palmitate (25, 100, and 150 mg eq.)
`compared with placebo. Study medication was administered as 4 doses: an initial i.m.
`injection of placebo or paliperidone palmitate 150 mg eq. followed by 3 fixed i.m. doses
`of placebo or paliperidone palmitate (25, 100, or 150 mg eq.) on Days 8, 36, and 64. The
`initial dose of study medication was given in the deltoid muscle. Subsequent injections
`were given either in the deltoid or gluteal muscle at the discretion of the investigator.
`Randomized subjects were to remain in the study for 28 days after the last injection on
`Day 64 with the end of study visit scheduled for Day 92 during the double-blind period.
`The study included a screening period of up to 7 days and a 13-week double-blind
`treatment period (Figure 7). The screening period included a washout of disallowed
`psychotropic medications. The entire study, including the screening period, lasted
`approximately 14 weeks. The screening period included oral tolerability testing for
`subjects without documented previous exposure to risperidone or paliperidone. Subjects
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`(b) (4)
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`with documente