CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022549Orig1s000
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`MEDICAL REVIEW(S)
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`CLINICAL REVIEW
`Cycle 3 Addendum
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`Application Type NDA
`Submission Number 22549 SD-47
`Submission Code CR
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`Letter Date June 20, 2012
`Stamp Date June 21, 2012
`PDUFA Goal Date December 21, 2012
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`Reviewer Name Francis E. Becker, M.D.
`Review Completion Date November 27, 2012
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`Established Name Loxapine
`Trade Name Staccato Loxapine for
`Inhalation (ADASUVE)
`Therapeutic Class Antipsychotic
`Applicant Alexza Pharmaceuticals
` Related IND 73248
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`Priority Designation Standard
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`Reference ID: 3222256
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` Table of Contents
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`1. Introduction………………………………………………………………………..….3
`2. Regulatory History…………………………………………………………………....3
`3. Manufacturing Deficiencies……………………………………………………….….5
`4.
`6
`4.1 CMC Review (DPP): David Claffey, Ph.D………………………………………….7
`5. Safety Update……………………………………………………………………….....7
`6. Updated labeling………………...…………………………………………………….8
`6.1 FDA Revised Labeling……………………………………………………………….8
`6.2 Sponsor’s Proposed Labeling…………………………………………...…………13
`7. Updated Risk Evaluation and Mitigation Strategy (REMS)……………………...22
`7.1 Updated Boxed Warning to Reflect Current Prescribing Information…………23
`7.2 Updated Contraindications to Reflect Current Prescribing Information………24
`7.3 Updated Warnings and Precautions, Bronchospasm, to Reflect Current
`Prescribing Information……………………………..…………………………………24
`7.4 Updated Dosage and Administration to Reflect Current Prescribing
`Information……………………………………………………………………………..25
`8. Proposed Post-Marketing Study…………………………………………………….25
`8.1 Proposed Study...................................................................................................…...26
`8.1.1 Primary Objectives……………………………………………………………….26
`8.1.2 Secondary Objective……………………………...………………………………26
`8.1.3 Subjects…………………………………...……………………………………….26
`8.1.4 Study Design………………………...…………………………………………….26
`8.1.5 Key Inclusion Criteria……………………………………………………………27
`8.1.6 Key Exclusion Criteria…………………...………………………………………27
`8.1.7 Minimization of Bias……………………………………………………………...28
`8.1.8 Outcome Measures and Assessments………………………………………...….28
`9. Reviews from other Disciplines……………………………………………………...30
`9.1 Division of Epidemiology…………………………………………………………...30
`9.2 Division of Medication Error Prevention and Analysis (DMEPA)…………...…31
`9.3 Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)…………31
`9.4Office of Compliance……………………………………………………………….32
`10. Discussion…………………………………………………………...………………33
`11. Recommendations for Postmarketing Study……………………………………..34
`12. Conclusions and Final Recommendations……………..…………………………35
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`Reference ID: 3222256
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`1. Introduction
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`ADASUVE (loxapine) inhalation powder (Staccato Loxapine) is a single-use, hand-held,
`drug-device combination product that provides rapid systemic delivery by inhalation of a
`thermally generated aerosol of loxapine. Staccato Loxapine represents a new dosage form
`for loxapine, an antipsychotic with dopamine D2 blocking activity that has been available
`in the United States (US) since 1975. Staccato Loxapine (5-mg and 10-mg dose levels)
`has been developed by the sponsor for the treatment of agitation in patients with
`Schizophrenia or Bipolar Disorder. Since agitation in these psychiatric populations is an
`acute and intermittent condition, it is expected that patients will be treated with Staccato
`Loxapine on an infrequent basis.
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`Staccato Loxapine is based on the proprietary Staccato delivery system developed by the
`sponsor. Oral inhalation through the Staccato Loxapine for Inhalation product initiates
`the controlled rapid heating of a thin film of excipient-free loxapine to form a thermally
`generated, highly pure drug vapor. The vapor condenses into aerosol particles with a
`particle size distribution appropriate for efficient delivery to the deep lung. The resulting
`rapid absorption of the drug provides peak plasma levels in the systemic circulation
`within minutes after administration.
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`This review is a Cycle 3 Clinical Review based on review of the sponsor’s Class 2
`Complete Response resubmission dated June 21, 2012. Therefore, this review will focus
`on issues addressed in the Cycle 2 CR letter, the sponsor’s response to those issues in
`Cycle 3, and any updated or revised information provided by the sponsor in this
`submission which has not been adequately addressed in the previous cycles. For a
`complete clinical review, the reader is referred to this reviewer’s Cycle 1 Clinical
`Review (September 17, 2010), Cycle 2 Pre-AC Meeting Clinical Review (November 8,
`2011), and Post-AC Meeting Clinical Review, Cycle 2 Addendum (April 9, 2012).
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`2. Regulatory History
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`The key aspects of the regulatory history of the application are outlined below:
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` August 31, 2005: Alexza submitted an IND application (73-248) for Staccato
`Loxapine in the treatment of acute agitation associated with schizophrenia or
`bipolar I disorder.
` December 11, 2009: The sponsor submitted the original NDA (22549) for the
`treatment of acute agitation associated with schizophrenia or bipolar I disorder.
` October 8, 2010: The Division took a Complete Response action, identifying
`pulmonary toxicity (bronchospasm) as the primary issue.
` December 17, 2010: The Division and Alexza held an End of Review Meeting to
`discuss the complete response action and potential means of resolving issues. The
`Division stated that it would be reasonable to propose a REMS program to
`mitigate the risk of pulmonary toxicity.
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` April 29, 2011: Type C Meeting was held with the sponsor to discuss the possible
`components of a REMS, including Elements to Assure Safe Use (ETASU).
` August 4, 2011: Alexza submitted a Class 2 Complete Response resubmission.
`The submission included a REMS with the following components: Elements to
`Assure Safe Use, revised product labeling, a Medication Guide, a Communication
`Plan, a Healthcare Facility Certification, an Implementation System, and a
`timetable for submission of Assessments.
` October 14, 2011: REMS Oversight Committee (ROC) meeting: DRISK and DPP
`presented the review team’s minimum requirements for the ADASUVE REMS
`program. The committee agreed that ETASU would be required. They also
`recommended obtaining input from outside stakeholders (from the Drug Safety
`Board, for example) during the development of the REMS.
` November 16, 2011: Drug Safety Oversight Board (DSB) Meeting – DRISK
`presented the proposed minimum requirements for the ADASUVE REMS. The
`board commented on the impact the REMS program might have on their
`healthcare facilities. The discussion did not result in revisions to the Agency’s
`proposed REMS.
` December 12, 2011: Psychopharmacologic Drugs Advisory Committed (PDAC)
`Meeting. The committee was supplemented with members of the Pulmonary –
`Allergy Drugs Advisory Committee and the Drug Safety and Risk Management
`Advisory Committee. The committee discussed the potential risks and benefits of
`treatment of ADASUVE, and they considered the REMS programs proposed by
`FDA and the sponsor. The Advisory Committee members voted 9 to 8 (with one
`abstention) to approve ADASUVE with the FDA-recommended REMS and with
`limiting administration to one dose within a 24-hour period.
` January 10, 2012: Alexza submitted REMS Amendment #2 to take into
`consideration and align with the Agency’s REMS presented at the PDAC
`meeting.
` January 19, 2012: The Division decided to extend the review by 3 months, in
`order to review the REMS (a major amendment to the submission).
` Throughout the review cycle, FDA provided comments to the sponsor about the
`requirements for the REMS with ETASU. During a teleconference with Alexza
`on March 1, 2012, the Division clarified that “Immediate, on-site access to
`advanced airway management capabilities” meant that these capabilities must be
`available within the healthcare facility in which the product would be
`administered, as opposed to being available by calling emergency response
`services.
` April 5, 2012: REMS Oversight Committee (ROC) meeting – DPP and DRISK
`updated the committee on the DSB and PDAC meetings. The ROC members
`agreed that ADASUVE could be approved with the finalized REMS. In addition,
`the ROC recommended that the labeling emphasize the pulmonary risk and
`discourage inappropriate claims not supported by adequate data
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` April 5, 2012: Alexza submitted a complete proposed protocol for the
`observational post-marketing study.
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`0 May 2, 2012: The Division took a Complete Response action, citing
`manufacturing deficiencies noted during a facilities inspection as the primary
`issue. The Division’s currently preferred version of labeling was included in the
`CR action letter, based on negotiations with the sponsor during this review cycle.
`June 7, 2012: CDRH General Advice Letter issued to the sponsor, specifying the
`manufacturing deficiencies noted during the facilities inspection.
`June 14, 2012: Alexza notified the Division, CDRH Office of Compliance, and
`the District Office of
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`June 21, 2012: Alexza submitted a Class 2 Complete Response resubmission. The
`submission includes complete responses to manufacturing deficiencies, revised
`draft labeling for ADASUVE, revised proposed REMS document, and required
`safety update.
`ma)
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`July 12, 2012: Alexza submitted other revised REMS materials (Order Set
`Protocol, Safe Use Checklist, Education Program, etc)
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`3. Manufacturing Deficiencies
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`During the first review cycle, a preapproval inspection was performed by the FDA at the
`drug product manufacturing site, Alexza Pharmaceuticals, Mountain View, California,
`which resulted in a “Withhold” recommendation from CDER Office of Compliance.
`During the second cycle, the sponsor resolved the main issues uncovered during the
`inspection concerning the inappropriate stability storage conditions,
`an“)
`and lack of link of stability studies to the final commercial version by
`initiating new stability studies
`M“) with the final commercial version
`of the device. Other outstanding issues were resolved during the second cycle by
`including or modifying in-process tests for weight of drug on tray-side, addition of
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`controls
`, changes
`controlled by the thermogram test, and initiation of appropriate heat package stability
`studies.
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`However, other issues were not adequately addressed during the second cycle and thus
`required resolution during the third cycle. In the CDRH General Advice Letter of June 7,
`2012, the following manufacturing deficiencies were conveyed to the sponsor:
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`1. Failure to adequately ensure that when the results of a process cannot be fully
`verified by subsequent inspection and test that the process shall be validated with
`a high degree of assurance and approved according to established procedure, as
`required by 21 CFR 820.75(a). A number of production/manufacturing processes
`had not been validated under proposed commercial batch conditions (Product
`Performance Qualification [PPQ]) in order to provide assurance that the process
`will consistently produce product that meets acceptance criteria throughout the
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`duration of the manufacturing cycle. In addition, the sponsor had provided the
`protocol and reports for the completed and approved 10-mg dose PPQ report.
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`2. Failure to establish and maintain adequate procedures for implementing corrective
`and preventive action (CAPA) to include identifying the actions needed to correct
`and prevent recurrence of nonconforming product and other quality problems, as
`required by 21 CFR 820.100(a)(3).
`3. Failure to establish and maintain adequate procedures for implementing corrective
`and preventive action (CAPA) to include verifying or validating the corrective
`and preventive action to ensure that such action is effective and does not
`adversely affect the finished device as required by 21 CFR 820.100(a)(4).
`4. Failure to establish and maintain adequate procedures to ensure that complaints
`are evaluated to determine whether the complaint represents an event which is
`required to be reported to FDA under part 803, Medical Device Reporting, as
`required by 21 CFR 820.198(a)(3). Procedures for receiving, reviewing, and
`evaluating complaints by formally designated unit had not been adequately
`established. The sponsor provided a revised Commercial Product Complaint
`Handling Process in January 2012 to add instruction for employees who could
`potentially receive a complaint to gather or obtain information associated with
`medical events. However, CDRH did not consider this response adequate because
`the sponsor had not provided evidence that it implemented systemic corrective
`actions to include analyzing past complaints to verify that all adverse events have
`been reported according to the new procedure.
`5. Failure to establish adequate procedures for identifying training needs and to
`ensure that all personnel are trained to adequately perform their assigned
`responsibilities, and have training documented, as required by 21 CFR 820.25(b).
`6. Failure to develop, maintain and implement Medical Device Reporting (MDR)
`procedures, as required by 21 CFR 803.17. The sponsor provided a revised
`procedure for Postmarketing Safety Reporting in January 2012. However, CDRH
`did not consider the response adequate because the sponsor had not provided
`evidence that it had implemented systemic corrective actions to include analyzing
`past complaints to verify that all adverse events have been reported according to
`the new procedure.
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`4.1 CMC Review (DPP): David Claffey, PILD.
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`5. Safety Update
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`In the Class 2 Complete Response Resubmission of June 20, 2012 (received date: June
`21, 2012), the sponsor included a safety update as required in accordance with 21 CFR
`314.50(d)(5)(iv)(b). The sponsor reports that no clinical studies have been ongoing or
`initiated in the period since the last patient was administered ADASUVE in the clinical
`program described in the original submission of NBA 22549. Therefore, there are no new
`clinical safety data to report in this resubmission.
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`The safety update also includes an updated literature search relevant to the safety of
`loxapine. No new clinical or nonclinical safety information was found from the updated
`search.
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`6. Updated labeling
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`6.1 FDA Revised Labeling:
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`The Division’s Complete Response Letter of May 2, 2012 included FDA revisions to the
`sponsor’s proposed labeling. In addition to formatting changes for clarity and to avoid
`redundancy, FDA included the following important revisions:
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`l. Broadening of contraindications to include current diagnosis (in addition to
`history) of asthma, COPD, or other lung disease associated with bronchos asm.
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`2.
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`Under Section 6.1, Clinical Trials Ex erience, deletion of the hrase,
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`from the Healthy Volunteers section. FDA considers that this statement is not
`re evant, because a finding of decreased FEVl/FVC ratio occurs only with severely
`decreased FEVl (>20% decreases in most of the subjects) as demonstrated in the asthma
`study.
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`Un er Section 6.1, Clinical Trials Experience, changing the last paragraph of the
`section describing the COPD trial (COPD Patients section) to read that rescue
`medication was administered “to 11% of patients in the placebo group.” The
`sponsor’s report of 15% was believed by FDA to be incorrect, resulting from
`double counting of the patient who received rescue afier both the first and second
`dose.
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`5. Changing the y-axis of Figure 7, “LS Mean Change from Baseline in FEVl in
`Patients with Asthma” from mL to L.
`6. Deletion—
`because FDA considers this figure unnecessary.
`7. Un er Section 8.3, Nursing Mothers, revision of wording to conform to required
`regulatory language.
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`Thus, FDA revisions to the sponsor’s proposed labeling, including some formatting and
`editing changes, are as follows (base document: sponsor’s labeling version of 4/ 17/12;
`FDA additions/deletions in track changes):
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`Reviewer’s Comments: The sponsor’s proposed REMS has been extensively reviewed by
`DRISK and DPP during this Cycle. As the final labeling has been agreed upon with the
`sponsor, the focus has been to ensure that the final REMS adequately aligns with the final
`labeling. The proposed REMS as negotiated with the sponsor and including the elements
`summarized above is acceptable.
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`8. Proposed Post-Marketing Study
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`As part of the resubmission of the NDA in Cycle 2, the Division requested that a
`prospective observational study be conducted to better understand the safety,
`effectiveness, and treatment patterns associated with the real world use of Staccato
`Loxapine. Therefore, the sponsor’s Cycle 2 submission included a synopsis of a proposed
`postmarketing study entitled, “A Postmarketing Observational Study to Evaluate the
`Safety and Effectiveness of Staccato Loxapine in Agitated Patients with Schizophrenia or
`Bipolar Disorder Treated in Real World Emergency Settings.” At the
`Psychopharmacologic Drugs Advisory Committee Meeting on December 12, 2011, the
`overall goals and design of the study were discussed, and the FDA clarified that the
`primary interest was in getting additional safety data as opposed to getting comparative
`data. Alexza stated that they would be agreeable to changing the study design to assess
`the safety of ADASUVE alone.
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`On April 5, 2012, the sponsor submitted a complete protocol titled, “A Post-marketing
`Observational Study to Evaluate the Safety of ADASUVE (Staccato Loxapine for
`Inhalation) in Agitated Patients with Schizophrenia or Bipolar Disorder.” Since the
`protocol was submitted late in Cycle 2, and since a complete response action was taken, a
`complete review of the proposed protocol was deferred to Cycle 3.
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`9. Reviews from other Disciplines
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`9.1 Division of Epidemiology
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`During this Cycle, Cary Parker, M.P.H, of the Division of Epidemiology (DEPI)
`completed a review of the proposed postmarketing observational study. In her review
`(November 27, 2012), DEPI recommended that the sponsor address concerns regarding
`the sampling plan, study population (inclusion/exclusion criteria and loss to follow-up),
`exposure measures, outcome measures, covariates, s
`1e size, and recruitment.
`Re ardin stud
`o ulation, DEPI recommended that‘
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`9.2 Division of Medication Error Prevention and Analysis (DMEPA)
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`The Division of Medication Error Prevention and Analysis (DMEPA) reviewed the
`device label, pouch labeling, carton labeling, and instructions for use submitted by the
`sponsor on June 21, 2012. The reviewer, Loretta Holmes, BSN, PharmD, noted that the
`sponsor’s labels and labeling submitted on June 21, 2012 were compared against the
`previous recommendations contained in OSE reviews dated March 12, 2012 and April 9,
`2012 as well as follow-up label and labeling negotiations with the sponsor. DMEPA
`concluded that the sponsor “has implemented all of our previous recommendations and
`agreed upon changes to the labels and labeling.” No additional recommendations were
`made.
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`DMEPA also conducted a proprietary name review. In her consult dated October 5, 2012,
`Dr. Holmes noted that the proposed name, ADASUVE, was previously reviewed in OSE
`Reviews in the previous cycles and found to be acceptable. In addition, the Office of
`Prescription Drug Promotion (OPDP) determined the proposed name to be acceptable
`from a promotional perspective. DMEPA and the Division of Psychiatry Products (DPP)
`concurred with the findings of OPDP’s promotional assessment of the proposed name.
`DMEPA conducted name simulation studies, solicited comments from other review
`disciplines, and conducted failure mode and effects analysis of similar names. DMEPA
`concluded that the proposed proprietary name is acceptable from both a promotional and
`safety perspective.
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`9.3 Division of Pulmonary, Allergy, and Rheumatology Products
`(DPARP)
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`The Division of Pulmonary, Allergy, and Rheumatology Products completed a briefing
`package review (Cycle 3) on November 26, 2012. During the previous review cycles,
`DPARP had been extensively involved in assessing the pulmonary risk associated with
`ADASUVE administration. In addition, DPARP provided significant input in the
`development of accurate labeling to reflect pulmonary data and in development of
`effective REMS.
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`In the Cycle 3 review, Theresa Michele, M.D. of DPARP agreed that, if approved, a post-
`marketing study to evaluate the safety of ADASUVE in a real-world setting, using the
`REMS, will be required. Dr. Michele noted that there is significant risk of post-inhalation
`bronchospasm following administration of ADASUVE, particularly in patients with
`underlying airway hyperresponsiveness caused by conditions such as asthma and COPD.
`Dr. Michele pointed out that characteristics of the patient population, including a high
`prevalence of smoking and inability to give a reliable history, increase the risk of
`bronchospasm following ADASUVE inhalation. However, Dr. Michele further noted that
`during this review cycle, DPARP recommendations regarding communication of risk and
`mitigation strategies are incorporated into the proposed product labeling, REMS, and
`PMC study. DPARP concluded that these strategies are expected to mitigate, but not
`eliminate, the risk of severe bronchospasm with inhalation of ADASUVE.
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`9.4 Office of Compliance
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`In a review entitled “REMS Memorandum” dated November 1, 2012, Kendra Biddick,
`Consumer Safety Officer for the REMS Compliance Team, Office of Compliance (0C)
`noted that 0C had participated in meetings (during Cycle 2) between DPP, the Office of
`Surveillance and Epidemiology (OSE), and the sponsor. In the meetings, it was made
`clear to the sponsor that in order to prevent deaths, healthcare facilities must have
`immediate access on-site to equipment and personnel trained to provide advanced airway
`management, including intubation and mechanical ventilation.
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`On February 16, 2012, FDA sent an e-mail to the sponsor which included a REMS
`document that DRISK had drafted. At that time, the following important comments to
`improve enforceability of the REMS were provided by OC to the sponsor:
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`The documentation needs to be required. As a result, 0C requested
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`changing the wording from
`to “must” as follows: “This training-
`be documented and is sub'ect to audi .”
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`requested addition of the following: “These procedures, protocols, and/or order
`sets must be documented and are sub'ect to audi .”
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`Therefore, 0C requires modification of this section to read as follows: “The
`health care facility will meet requirements in b. through j. above prior to
`certification.”
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`requested addition of the following: “This training must be documented and is
`subject to audi .”
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`In the REMS Memorandum of November 1, 2012, OC noted that agreement has been
`reached between Compliance and OSE on REMS assessment and audit plans and
`concluded that “all Office of Compliance concerns have been adequately addressed.”
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`10. Discussion
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`In this review cycle (Cycle 3), there are no new issues from a clinical standpoint. The
`sponsor reports that no clinical studies have been ongoing or initiated in the period since
`the last patient was administered ADASUVE in the clinical program described in the
`original submission of NDA 22549. Therefore, there are no new clinical safety data to
`report in this resubmission.
`
`As I noted in my Cycle 2 Review (April 9, 2012), the sponsor’s claim for efficacy in the
`treatment of acute agitation associated with schizophrenia or bipolar disorder is supported
`by the results of the two pivotal trials: Trial 004-301 in the acute treatment of agitation
`associated with schizophrenia, and Trial 004-302 in the acute treatment of agitation
`associated with bipolar disorder. However, significant pulmonary adverse events,
`particularly in subjects with asthma or COPD, were reported during the clinical program
`and are a major safety concern. In both the asthma (Trial 004-105) and COPD (Trial 004-
`108) trials, in which two doses of ADASUVE were given 10 hours apart, airflow
`obstruction was worse after the second dose.
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`In Cycle 3, the sponsor and the FDA have reached agreement on labeling and a REMS
`which should substantially decrease the risk of serious respiratory adverse events and
`facilitate safer and more effective management of serious respiratory adverse events
`should they occur. Important agreements between FDA and the sponsor in this regard
`include:
`
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`1. limiting dosing of ADASUVE to a single dose in 24 hours;
`2. broadening of contraindications to include current diagnosis (in addition to
`history) of asthma, COPD, or other lung disease associated with bronchospasm;
`3. requiring that ADASUVE be administered only in an enrolled healthcare facility
`that has immediate access on-site to equipment and personnel trained to manage
`acute bronchospasm, including advanced airway management (intubation and
`mechanical ventilation);
`4. requiring that healthcare providers: 1) screen all patients for a history of asthma,
`COPD, or other pulmonary disease prior to administering ADASUVE; 2)
`examine patients (including chest auscultation) for respiratory signs (e.g.
`wheezing) prior to administering ADASUVE; and 3) monitor patients for
`symptoms and signs (i.e., vital signs and chest auscultation) of bronchospasm at
`least every 15 minutes for a minimum of one hour following treatment with
`ADASUVE; and
`5. ensuring that relevant staff from healthcare facilities and wholesalers/distributors
`is adequately trained on the ADASUVE REMS program and procedures; and
`ensuring that this training is adequately documented and subject to audit.
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`As noted by DPARP, these strategies are expected to mitigate, but not eliminate, the risk
`of severe bronchospasm with inhalation of ADASUVE. Therefore, the proposed
`postrnarketing observational study is very important because it will provide important
`information about utilization and safety of ADASUVE in a real-world setting.
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`11. Recommendations for Postmarketing Study
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`I am in agreement with the recommendations made by the Division of Epidemiology as
`detailed in their final review (November 27, 2012) of the proposed postmarketing study.
`Based on my review, I have the following additional comments:
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`1.
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`12. Conclusions and Final Recommendations
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`In conclusion, from a clinical standpoint, I recommend approval of ADASUVE for the
`acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.
`The negotiated labeling and REMS are acceptable.
`
`As I discussed in detail in my Cycle 2 Review (April 9, 2012), ADASUVE provides a
`non-invasive, rapid treatment of acute agitation associated with schizophrenia or bipolar
`disorder. Therefore, it will provide an alternative to current medications approved for this
`indication which are either invasive (eg, intramuscular) or may be of slower onset (eg,
`oral medications). Acute agitation is a severe, disruptive complication of schizophrenia
`and mania. It may progress from inner distress (nervousness, restlessness, panic) to an
`outwardly apparent dysfunctional state with cursing, hostility, difficulty controlling
`impulses, uncooperative behavior, and increased potential for violence. The rapid onset
`and proven efficacy of ADASUVE will quickly prevent escalation of agitation
`symptoms, decreasing the likelihood of injuries to the patient or medical personnel
`associated with having to physically restrain the patient.
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`There is significant risk of bronchospasm associated with ADASUVE use, especially in
`patients with asthma or COPD. However, the REMS will serve to decrease the risk of
`respiratory adverse events, increase the likelihood of early detection of respiratory
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`adverse events should they occur and, ensure that appropriate respiratory support and
`treatment is available on-site. Although the REMS will not completely eliminate the risk
`of severe bronchospasm associated with administration of ADASUVE, it will
`substantially mitigate this risk and ensure that appropriate management of bronchospasm
`is readily available on-site if needed.
`
` A
`
` post-marketing observational study as outlined above and including the Division of
`Epidemiology recommendations should be required and will be important in identifying
`safety issues associated with use of ADASUVE in a clinical setting. At the time of this
`writing, final recommendations from DRISK and CDRH are pending. Therefore, my
`recommendation is contingent on approval recommendations from these divisions.
`
`
`
` ___________________________
` Francis E. Becker, M.D., F.A.C.P.
` November 27, 2012
`
`
` Medical Officer,
`
`
`
`
` FDA CDER ODE1 DPP HFD 130
`
`
`
`
`
`
`
`cc: NDA 22549
`
`HFD 130
`
`T Laughren
`
`M Mathis
`
`R Levin
`
`K Updegraff
` K Lehrfeld
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3222256
`
`36
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`FRANCIS E BECKER
`11/27/2012
`
`ROBERT L LEVIN
`11/27/2012
`See Cross-Discipline Team Leader review memo to follow.
`
`Reference ID: 3222256
`
`

`

`DIVISION OF PULMONARY, ALLERGY, and RHEUMATOLOGY PRODUCTS
`BRIEFING PACKAGE REVIEW
`
`
`Date:
`To:
`
`
`
`
`From:
`
`Through:
`
`Through:
`
`Subject:
`
`November 13, 2012
`Thomas Laughren, MD
`Director, Division of Psychiatry Products
`Theresa M. Michele, MD
`Clinical Team Leader, Division of Pulmonary, Allergy, and
`Rheumatology Products
`Sally Seymour, MD
`Deputy Director for Safety, Division of Pulmonary, Allergy, and
`Rheumatology Products
`Badrul A. Chowdhury, MD, PhD
`Director, Division of Pulmonary, Allergy, and Rheumatology Products
`Pulmonary safety evaluation of Adasuve (loxapine) inhalation powder for
`New Drug Application (NDA) 22-549 at a dose of 5 mg or 10 mg every 2
`hours as needed to a maximum dose of 30 mg per day for the treatment of
`agitation associated with schizophrenia or bipolar disorder in adults
`
`
`General Information
`NDA#:
`22-549
`Sponsor:
`Alexza Pharmaceuticals
`Drug Product: Adasuve (loxapine) inhalation powder
`Materials Reviewed: NDA 22-549 SD#1, original submission dated December 11, 2009;
`NDA 22-549 SD#28, complete response dated August 4, 2011;
`NDA 22-549 SD#45, second complete response dated June 21, 2012;
`various labeling and REMS submissions
`
`
`1. Executive Summary
`This is a consult review from the Division of Pulmonary, Allergy, and Rheumatology
`Products (DPARP) regarding the second complete response for NDA 22-549. This
`consult further addresses labeling and REMS related to the pulmonary safety of loxapine
`inhalational powder, proposed for treatment of adult patients with agitation associated
`with schizophrenia and bipolar disorder. Loxapine is a typical first generation
`antipsychotic drug, similar to haloperidol. It was approved as an oral formulation in 1975
`and an intramuscular formulation in 1979, although only the oral dosage form is currently
`marketed.
`On June 21, 2012, Alexza submitted a complete response to the Division's May 2, 2012
`action letter for NDA 022549 which provides for the use of Adasuve (loxapine)
`inhalation powder for the treatment of agitation associated with schizophrenia or bipolar
`disorder in adults. The original NDA was submitted on December 11, 2009. The Division
`issued the initial CR