CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`210563Orig1s000
`210563Orig2s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review
`
`February 7, 2018
`Tanya Wroblewski, M.D.
`Cross-Discipline Team Leader Review
`210563
`
`Pharmacyclics, LLC
`August 31, 2017
`
`February 28, 2018
`
`Imbruvica®
`
`Ibrutinib
`
`Tablets 140mg, 280mg, 420mg and 560mg, for oral use
`No new indications, provides new dosage formulation
`-Mantle cell lymphoma (MCL) (accelerated approval)
`-Marginal zone lymphoma (MZL)who require systemic therapy and have received at lea
`anti-CD20 based therapy (accelerated approval)
`-Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
`-CLL/SLL with 17p deletion
`-Waldenström’s macroglobulinemia (WM)
`-Chronic Graft vs. Host disease (cGVHD) after failure of one or
` more lines of systemic therapy
`No new dosing regimen, provides new dosage formulation.
`
`Accelerated Approval: This NDA provides new tablet formulation,
`existing NDA 205552 for ibrutinib still has accelerated approval for
`some of the indications, thus these PMRs will carry over and as such
`approval of new tablets will be accelerated approval.
`Not applicable
`
`New dosage form: 140mg, 280mg, 420mg, and 560mg tablets for oral
`use. Dosing regimen remains the same.
`
`Date
`From
`Subject
`NDA/BLA # and
`Supplement#
`Applicant
`Date of
`Submission
`PDUFA Goal
`Date
`Proprietary
`Name
`Established or
`Proper Name
`Dosage Form(s)
`
`Applicant
`Proposed
`Indication(s)/Pop
`ulation(s)
`
`Applicant
`Proposed Dosing
`Regimen(s)
`Recommendation
`on Regulatory
`Action
`Recommended
`Indication(s)/Pop
`ulation(s) (if
`applicable)
`Recommended
`Dosing
`Regimen(s) (if
`applicable)
`
`Reference ID: 4217967
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Benefit-Risk Assessment
`1.
`This application provides CMC and clinical pharmacology data to support stability and
`bioequivalence of a new tablet formulations for Ibrutinib; this application is not a new molecular
`entity. There was no new clinical efficacy or safety data included in this NDA and therefore no
`need for benefit-risk assessment. There are no updates to the indication, efficacy or safety
`sections of the USPI.
`
`The Applicant seeks approval of a new tablet formulation at dose strengths of 140mg, 128mg,
`420mg and 560mg. The tablets will have the same indications and dosing as the currently
`marketed ibrutinib capsules. The new tablet formulations are intended to improve pill burden and
`provide for appropriate doses with a single tablet.
`
`Recommend approval of the new tablet formulation at dose strengths of 140mg, 280mg, 420mg
`and 560mg for the approved indications for Ibrutinib. This application will receive accelerated
`approval as two of the existing indications for ibrutinib are accelerated approvals and the PMRS
`will carry over to this application.
`
`2. Background
`Imbruvica® (Ibrutinib, also known as PCI-32765) is a first-in-class, orally administered inhibitor
`of Bruton Tyrosine Kinase (BTK) that was co-developed by Pharmacyclics, LLC and Janssen
`Research & Development, LLC for the treatment of B-cell malignancies.
`
`Ibrutinib is currently approved for the treatment of patients with mantle cell lymphoma (MCL)
`who have received one prior therapy, chronic lymphocytic leukemia/small lymphocytic leukemia
`(CLL/SLL), CLL/SLL with 17p deletion, marginal zone lymphoma (MZL) who require systemic
`therapy and have received at least one prior anti-CD20 based therapy, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host disease (cGVHD).
`
`Ibrutinib is currently available as 70mg and 140mg capsules. The recommended doses are
`mg once daily for MCL and MZL and 420mg once daily for CLL/SLL, WM and cGVHD.
`The recommended dose for patients with mild hepatic impairment is 140mg and for patients with
`moderate hepatic impairment is 70mg.
`
`Patients receiving ibrutinib at the current recommended doses (either 480 or 520mg) are
`currently required to take multiple 140mg capsules daily. This may result in missed doses or
`incomplete doses and places and additional burden on patients. The new tablet formulations will
`provide for appropriate doses with a single tablet and will reduce pill burden and potentially
`missed doses or incomplete doses.
`
`This submission primarily pertains to clinical pharmacology and chemistry manufacturing and
`controls.
`
`Reference ID: 4217967
`
`(b) (4)
`
`

`

`No new clinical efficacy data were submitted with this supplement. The tablet formulations are
`relevant to all the current indications for patients who currently take multiple capsules of
`Imbruvica®. Refer to complete clinical pharmacology review for analysis of drug-drug
`interaction data and bioequivalence data provided with this supplement.
`
`Please refer to the reviews by each specific discipline under NDA 205552 for details pertaining
`to original NDA submission as well as details relevant to each specific indication.
`
`Product Quality
`3.
`There are no outstanding product quality issues with this application. All site inspections were
`complete and there are no outstanding issues. Please refer to the CMC review by Sherita D.
`McLamore, Ph.D. for additional details.
`
`4. Nonclinical Pharmacology/Toxicology
`There are no pharmacology/toxicology issues with this application.
`
`5. Clinical Pharmacology
`
`The Applicant submitted study results of a bioavailability trial, food effect trial and two pivotal
`bioequivalence trials to support the proposed new tablet formulation in 4 different strengths of
`140mg, 280mg, 520mg, 560mg for ibrutinib. The clinical pharmacology review focused on the
`bioequivalence between ibrutinib to be marketed tablets and current available capsules and food
`effect on the new tablets. .
`
`Bioequivalence evaluations demonstrated no clinically significant difference in AUC between
`the tablet and capsule formulations at the 140 and 520mg doses. There was a Cmax decreases of
`10.2% and 27.7% at the 140mg and 520mg doses respectively.
`
`From the review by Liang Li, Ph.D.
`
`“The AUC of the to-be-marketed tablet was BE to that of the reference capsule at 140mg and
`560mg dose strength. Although the Cmax of the to-be-marketed tablet was 10.2% lower at
`140mg and 27.7% lower at 560mg as compared to the reference capsule formulation, such
`difference in Cmax is not expected to translate clinically meaningful impact on the effectiveness
`of ibrutinib. The fold effect was generally comparable between tablet and capsule formulations.
`Overall, no clinically meaningful difference is expected between the reference capsule
`formulation and the to-be-marketed tablet formulation of ibrutinib.”
`
`The Office of Clinical Pharmacology reviewed the information submitted by the Applicant. The
`Office of Clinical Pharmacology tablets formulation at dose strengths of 140mg, 280mg, 420mg
`and 560mg is considered approvable from a clinical pharmacology perspective. Per the clinical
`
`Reference ID: 4217967
`
`

`

`pharmacology review, “the dosing guidelines regarding food timings for ibrutinib tablets should
`follow the same recommendation for ibrutinib capsules in current labeling, i.e., there are no
`restrictions for food consumption when taking ibrutinib tablets or capsules.”
`
`6. Clinical Microbiology
`There are no clinical microbiology issues with this application.
`
`7. Clinical/Statistical- Efficacy
`There was no new efficacy data submitted with this application.
`
`Safety
`8.
`There was no new safety data submitted with this application.
`
`The most common adverse reactions in patients with cGVHD are fatigue, bruising, diarrhea,
`thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia and pneumonia.
`
`The U.S. Prescribing Information (USPI) for Imbruvica® includes Warnings and Precautions for
`hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary
`malignancies, tumor lysis syndrome, and embryo-fetal toxicity.
`
`9. Advisory Committee Meeting
`This application was not referred to the Oncologic Drugs Advisory Committee (ODAC) because
`the application did not raise significant safety or efficacy issues.
`
`10. Pediatrics
`FDA granted Orphan Drug Designation for ibrutinib in 2013 for the treatment of patients with
`relapsed or refractory mantle cell lymphoma. There is one ongoing trial evaluating the safety
`and efficacy of ibrutinib in pediatric and young adult patients with relapsed or refractory mature
`B-cell Non-Hodgkin Lymphoma. Currently there is limited information on the use of ibrutinib
`in pediatric patients.
`
`Reference ID: 4217967
`
`

`

`11. Other Relevant Regulatory Issues
`None
`
`12. Labeling
`
`Label Section
`HIGHLIGHTS
`
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`
`DOSAGE FORMS AND STRENGTHS
`
`DRUG INTERACTIONS
`
`7.1 Effect of CYP3A Inhibitors on
`Ibrutinib
`
`7.2 Effect of CYP3A Inducers on
`Ibrutinib
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`12.2 Pharmacodynamics
`
`Patient Information
`
`Recommended Changes
`● Addition of instructions not to cut, crush, or
`chew tablets
`● Addition of the tablets 140, 280, 420, 560 listed
`to the dosage forms and strengths
`● Addition of instructions not to cut, crush, or
`chew tablets
`
`● Added Tablet: 140 mg, 280 mg, 420 mg, and
`560 mg
`
`● Removed list of examples of CYP3A inhibitors
`and inducers based on current labeling
`recommendations.
`
`● Identifying characteristics of the tablets moved
`to section 3 and 16 per current labeling guidance
`
` Cardiac Electrophysiology subheading heading
`was added with new information regarding
`lack of clinically relevant QT prolongation
`
`● Addition of tablet formulation and instructions
`not to break or chew tablets
`
`13. Postmarketing Recommendations
`Risk Evaluation and Management Strategies (REMS)
`
`Reference ID: 4217967
`
`

`

`There are no recommendations for additional post marketing risk evaluation and mitigation
`strategies for this application.
`
`Postmarketing Requirements (PMRs) and Commitments (PMCs)
`As this NDA provides for a new tablet formulations of ibrutinib, existing PMRs under NDA
`205552 will carry-over to this NDA.
`
`PMR 2060-2 Complete and submit the final results of the ongoing randomized, double-blind,
`placebo controlled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in
`combination with bendamustine and rituximab in patients with newly diagnosed
`mantle cell lymphoma. Enrollment of approximately 520 patients is expected. The
`primary endpoint is progression-free survival as assessed by investigators. Overall
`survival is a key secondary endpoint.
`
`Trial Completion:
`Final Report Submission:
`
`12/2018
`03/2019
`
`Fulfillment of PMR 2060-2 may also fulfill your requirement under this supplement.
`
`We remind you of your postmarketing requirement listed in the January 18, 2017 approval
`letter(NDA 205552):
`
`PMR 3150-1 Submit the complete final report and data from a randomized, Phase 3 trial,
`comparing ibrutinib in combination with bendamustine and rituximab or
`rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone versus
`bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin,
`vincristine, and prednisone in subjects with previously treated follicular
`lymphoma or marginal zone lymphoma. At least 50 enrolled subjects need to have
`a diagnosis of marginal zone lymphoma. The primary endpoint is progression-free
`survival in the overall intent-to-treat population.
`
`Trial Completion:
`Final Report Submission:
`
`05/2019
`08/2019
`
`Fulfillment of PMR 3150-1 may also fulfill your requirement under this supplement.
`
`Reference ID: 4217967
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TANYA M WROBLEWSKI
`02/07/2018
`This CTDL review is a corrected review from initial CTDL review submitted as primary review in
`January 2018.
`
`Reference ID: 4217967
`
`

`

`Cross-Discipline Team Leader Review
`
`January 23, 2018
`Tanya Wroblewski, M.D.
`Cross-Discipline Team Leader Review
`210563
`
`Pharmacyclics, LLC
`September 12, 2017
`
`February 28, 2018
`
`Imbruvica®
`
`Ibrutinib
`
`Tablets 140mg, 280mg, 420mg and 560mg, for oral use
`No new indications, provides new dosage formulation
`-Mantle cell lymphoma (MCL)
`-Marginal zone lymphoma (MZL)who require systemic therapy and have received at lea
`anti-CD20 based therapy
`-Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
`-CLL/SLL with 17p deletion
`-Waldenström’s macroglobulinemia (WM)
`-Chronic Graft vs. Host disease (cGVHD) after failure of one or
` more lines of systemic therapy
`No new dosing regimen, provides new dosage formulation.
`
`Approval
`
`Not applicable
`
`New dosage form: 140mg, 280mg, 420mg, and 560mg tablets for oral
`use. Dosing regimen remains the same.
`
`Date
`From
`Subject
`NDA/BLA # and
`Supplement#
`Applicant
`Date of
`Submission
`PDUFA Goal
`Date
`Proprietary
`Name
`Established or
`Proper Name
`Dosage Form(s)
`
`Applicant
`Proposed
`Indication(s)/Pop
`ulation(s)
`
`Applicant
`Proposed Dosing
`Regimen(s)
`Recommendation
`on Regulatory
`Action
`Recommended
`Indication(s)/Pop
`ulation(s) (if
`applicable)
`Recommended
`Dosing
`Regimen(s) (if
`applicable)
`
`Reference ID: 4210835
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Benefit-Risk Assessment
`1.
`This application provides CMC and clinical pharmacology data to support stability and
`bioequivalence of a new tablet formulations for Ibrutinib; this application is not a new molecular
`entity. There was no new clinical efficacy or safety data included in this NDA and therefore no
`need for benefit-risk assessment. There are no updates to the indication, efficacy or safety
`sections of the USPI.
`
`The Applicant seeks approval of a new tablet formulation at dose strengths of 140mg, 128mg,
`420mg and 560mg. The tablets will have the same indications and dosing as the currently
`marketed ibrutinib capsules. The new tablet formulations are intended to improve pill burden and
`provide for appropriate doses with a single tablet.
`
`Recommend approval of the new tablet formulation at dose strengths of 140mg, 280mg, 420mg
`and 560mg for the approved indications for Ibrutinib.
`
`2. Background
`Imbruvica® (Ibrutinib, also known as PCI-32765) is a first-in-class, orally administered inhibitor
`of Bruton Tyrosine Kinase (BTK) that was co-developed by Pharmacyclics, LLC and Janssen
`Research & Development, LLC for the treatment of B-cell malignancies.
`
`Ibrutinib is currently approved for the treatment of patients with mantle cell lymphoma (MCL)
`who have received one prior therapy, chronic lymphocytic leukemia/small lymphocytic leukemia
`(CLL/SLL), CLL/SLL with 17p deletion, marginal zone lymphoma (MZL) who require systemic
`therapy and have received at least one prior anti-CD20 based therapy, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host disease (cGVHD).
`
`Ibrutinib is currently available as 70mg and 140mg capsules. The recommended doses are
`mg once daily for MCL and MZL and 420mg once daily for CLL/SLL, WM and cGVHD.
`The recommended dose for patients with mild hepatic impairment is 140mg and for patients with
`moderate hepatic impairment is 70mg.
`
`Patients receiving ibrutinib at the current recommended doses (either 480 or 520mg) are
`currently required to take multiple 140mg capsules daily. This may result in missed doses or
`incomplete doses and places and additional burden on patients. The new tablet formulations will
`provide for appropriate doses with a single tablet and will reduce pill burden and potentially
`missed doses or incomplete doses.
`
`This submission primarily pertains to clinical pharmacology and chemistry manufacturing and
`controls.
`
`No new clinical efficacy data were submitted with this supplement. The tablet formulations are
`relevant to all the current indications for patients who currently take multiple capsules of
`
`Reference ID: 4210835
`
`(b) (4)
`
`

`

`Imbruvica®. Refer to complete clinical pharmacology review for analysis of drug-drug
`interaction data and bioequivalence data provided with this supplement.
`
`Product Quality
`3.
`There are no outstanding product quality issues with this application. All site inspections were
`complete and there are no outstanding issues. Please refer to the CMC review by Sherita D.
`McLamore, Ph.D. for additional details.
`
`4. Nonclinical Pharmacology/Toxicology
`There are no pharmacology/toxicology issues with this application.
`
`Reference ID: 4210835
`
`

`

`5. Clinical Pharmacology
`
`The Applicant submitted study results of a bioavailability trial, food effect trial and two pivotal
`bioequivalence trials to support the proposed new tablet formulation in 4 different strengths of
`140mg, 280mg, 520mg, 560mg for ibrutinib. The clinical pharmacology review focused on the
`bioequivalence between ibrutinib to be marketed tablets and current available capsules and food
`effect on the new tablets. .
`
`Bioequivalence evaluations demonstrated no clinically significant difference in AUC between
`the tablet and capsule formulations at the 140 and 520mg doses. There was a Cmax decreases of
`10.2% and 27.7% at the 140mg and 520mg doses respectively.
`
`From the review by Liang Li, Ph.D.
`
`“The AUC of the to-be-marketed tablet was BE to that of the reference capsule at 140mg and
`560mg dose strength. Although the Cmax of the to-be-marketed tablet was 10.2% lower at
`140mg and 27.7% lower at 560mg as compared to the reference capsule formulation, such
`difference in Cmax is not expected to translate clinically meaningful impact on the effectiveness
`of ibrutinib. The fold effect was generally comparable between tablet and capsule formulations.
`Overall, no clinically meaningful difference is expected between the reference capsule
`formulation and the to-be-marketed tablet formulation of ibrutinib.”
`
`The Office of Clinical Pharmacology reviewed the information submitted by the Applicant. The
`Office of Clinical Pharmacology tablets formulation at dose strengths of 140mg, 280mg, 420mg
`and 560mg is considered approvable from a clinical pharmacology perspective. Per the clinical
`pharmacology review, “the dosing guidelines regarding food timings for ibrutinib tablets should
`follow the same recommendation for ibrutinib capsules in current labeling, i.e., there are no
`restrictions for food consumption when taking ibrutinib tablets or capsules.”
`
`6. Clinical Microbiology
`There are no clinical microbiology issues with this application.
`
`7. Clinical/Statistical- Efficacy
`There was no new efficacy data submitted with this application.
`
`Safety
`8.
`There was no new safety data submitted with this application.
`
`The most common adverse reactions in patients with cGVHD are fatigue, bruising, diarrhea,
`thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia and pneumonia.
`
`Reference ID: 4210835
`
`

`

`The U.S. Prescribing Information (USPI) for Imbruvica® includes Warnings and Precautions for
`hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary
`malignancies, tumor lysis syndrome, and embryo-fetal toxicity.
`
`9. Advisory Committee Meeting
`This application was not referred to the Oncologic Drugs Advisory Committee (ODAC) because
`the application did not raise significant safety or efficacy issues.
`
`10. Pediatrics
`FDA granted Orphan Drug Designation for ibrutinib in 2013 for the treatment of patients with
`relapsed or refractory mantle cell lymphoma. There is one ongoing trial evaluating the safety
`and efficacy of ibrutinib in pediatric and young adult patients with relapsed or refractory mature
`B-cell Non-Hodgkin Lymphoma. Currently there is limited information on the use of ibrutinib
`in pediatric patients.
`
`11. Other Relevant Regulatory Issues
`None
`
`12. Labeling
`
`Label Section
`HIGHLIGHTS
`
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`
`DOSAGE FORMS AND STRENGTHS
`
`Recommended Changes
`● Addition of instructions not to cut, crush, or
`chew tablets
`● Addition of the tablets 140, 280, 420, 560 listed
`to the dosage forms and strengths
`● Addition of instructions not to cut, crush, or
`chew tablets
`
`● Added Tablet: 140 mg, 280 mg, 420 mg, and
`560 mg
`
`Reference ID: 4210835
`
`

`

`Label Section
`
`DRUG INTERACTIONS
`
`7.1 Effect of CYP3A Inhibitors on
`Ibrutinib
`
`7.2 Effect of CYP3A Inducers on
`Ibrutinib
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`12.2 Pharmacodynamics
`
`Patient Information
`
`Recommended Changes
`● Removed list of examples of CYP3A inhibitors
`and inducers based on current labeling
`recommendations.
`
`● Identifying characteristics of the tablets moved
`to section 3 and 16 per current labeling guidance
`
` Cardiac Electrophysiology subheading heading
`was added with new information regarding
`lack of clinically relevant QT prolongation
`
`● Addition of tablet formulation and instructions
`not to break or chew tablets
`
`13. Postmarketing Recommendations
`Risk Evaluation and Management Strategies (REMS)
`There are no recommendations for additional post marketing risk evaluation and mitigation
`strategies for this application,
`
`Postmarketing Requirements (PMRs) and Commitments (PMCs)
`There are no recommendations for additional postmarketing requirements for this application. .
`
`Reference ID: 4210835
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TANYA M WROBLEWSKI
`01/23/2018
`
`Reference ID: 4210835
`
`