CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`APPLICATION NUMBER:
`
`
`103976Orig1s5211
`
`
`
`
`
`
`
`
`
`
`
`
`XOLAIR
` Trade Name:
`
`
`Generic or Proper omalizumab injection
`
` Name:
`
`Genentech
`
`Sponsor:
`
`Approval Date: March 21, 2014
`
`
`
`Indication:
` Moderate to severe persistent asthma in patients
`
`
` with a positive skin test or in vitro reactivity to a
`perennial aeroallergen and symptoms
`that are
`inadequately controlled with inhaled corticosteroids.
`
`
`idiopathic urticaria
`in
` adults
`and
` Chronic
`adolescents (12 years of age and above) who remain
`symptomatic despite H1 antihistamine treatment.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`103976Orig1s5211
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`
`X
`
`
`X
`X
`
`
`X
`X
`
`
`X
`X
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
`
`103976Orig1s5211
`
`
`
`APPROVAL LETTER
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`BLA 103976/5211
`
`Genentech
` 1 DNA Way
`
`South San Francisco, California 94080
`
`Attention:
`
`Cindy Wilson
`Regulatory Program Management
`
`Dear Ms. Wilson:
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`
` SUPPLEMENT APPROVAL
`
`Please refer to your Supplemental Biologics License Application (sBLA), dated July 25, 2013,
`
` received July 25, 2013, submitted under section 351(a) of the Public Health Service Act for
`Xolair (omalizumab).
`
`We acknowledge receipt of your amendments dated August 26, September 19, 26, and 30,
`
`October 14, and 30, November 4, 20, 21, and 27, and December 9, and 10, 2013, and January 8,
`
`and 16, February 11, and March 4, and 19, 2014.
`
`This Prior Approval supplemental biologics application proposes the use of Xolair (omalizumab)
`
`
`for the treatment of Chronic Idiopathic Urticaria.
`
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`
`WAIVER OF HIGHLIGHTS SECTION
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA
`
`automated drug registration and listing system (eLIST), the content of labeling
`
`[21 CFR 601.14(b)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`
`Reference ID: 3475329
`
`
`

`

`
` BLA 103976/5211
`
` Page 2
`
` identical to the enclosed labeling (text for the package insert and Medication Guide) and include
`
`
`
` the labeling changes proposed in any pending “Changes Being Effected” (CBE) supplements.
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this BLA, including pending “Changes Being Effected” (CBE) supplements, for which FDA
`has not yet issued an action letter, with the content of labeling [21 CFR 601.12(f)] in MS Word
`format that includes the changes approved in this supplemental application.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for ages zero to less than 12 years of age because
`there is evidence strongly suggesting that the drug product would be unsafe in this pediatric
`group. Clinical trials have not been conducted in patients less than 12 years of age due to safety
`concerns of anaphylaxis and malignancy associated with the use of Xolair.
`
`This product is appropriately labeled for use in ages 12 to 17 years for this indication. Therefore,
`no additional studies are needed in this pediatric group.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`
`
`proposed materials in draft or mock-up form with annotated references, and the package insert(s)
`to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion
`
` 5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
` As required under 21 CFR 601.12(f)(4), you must submit final promotional materials, and the
`
`
` package insert(s), at the time of initial dissemination or publication, accompanied by a Form
`FDA 2253. Form FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
`Reference ID: 3475329
`
`
`

`

`
` BLA 103976/5211
`
` Page 3
`
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`more information about submission of promotional materials to the Office of Prescription Drug
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`
`
`We remind you that you must comply with reporting requirements for an approved BLA (in
`
`21 CFR 600.80 and in 21 CFR 600.81).
`
`If you have any questions, call Colette Jackson, Senior Regulatory Health Project Manager, at
`(301) 796-1230.
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Badrul A. Chowdhury, M.D., Ph.D.
`Director
`Division of Pulmonary, Allergy, and Rheumatology Products
`Office of Drug Evaluation II
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`
`Content of Labeling
`
`Reference ID: 3475329
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`BADRUL A CHOWDHURY
`03/21/2014
`
`Reference ID: 3475329
`
`
`

`

`
`
` CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`
`103976Orig1s5211
`
`
`
`LABELING
`
`
`

`

`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` These highlights do not include all the information needed to use
`
`
`
`
`
` XOLAIR safely and effectively. See full prescribing information for
`
`XOLAIR.
`
`XOLAIR® (omalizumab) for injection, for subcutaneous use
`
`
`Initial U.S. Approval: 2003
`
`
`
`WARNING: ANAPHYLAXIS
`
`
`See full prescribing information for complete boxed warning.
`Anaphylaxis, presenting as bronchospasm, hypotension, syncope,
`
`
`urticaria, and/or angioedema of the throat or tongue, has been
`
`reported to occur after administration of Xolair. Anaphylaxis has
`
`
`
`occurred after the first dose of Xolair but also has occurred beyond
`
`
`
`
`1 year after beginning treatment. Closely observe patients for an
`
`
`
`
`
`
`
`appropriate period of time after Xolair administration and be
`
`
`
`
`
`
`prepared to manage anaphylaxis that can be life-threatening. Inform
`
`
`
`
`patients of the signs and symptoms of anaphylaxis and have them seek
`
`
`
`
`
`immediate medical care should symptoms occur. (5.1)
`
`
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`
`Indications and Usage (1.2, 1.3)
`3/2014
`
`
`
`
`Dosage and Administration (2.3)
`3/2014
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Xolair is an anti-IgE antibody indicated for:
`
`
`
`
`
`x Moderate to severe persistent asthma in patients with a positive skin test
`
`
`
`
`
`or in vitro reactivity to a perennial aeroallergen and symptoms that are
`
`
`
`
`
`
`
`inadequately controlled with inhaled corticosteroids (1 1)
`x Chronic idiopathic urticaria in adults and adolescents (12 years of age and
`
`
`
`
`
`above) who remain symptomatic despite H1 antihistamine treatment (1.2)
`
`
`
`
`
`
`Important Limitations of use:
`
`
`
`
`x Not indicated for other allergic conditions or other forms of urticaria. (1.1,
`
`
`
`
`
`
`1.2, 1.3)
`x Not indicated for acute bronchospasm or status asthmaticus. (1.1, 1.3, 5.3)
`
`
`
`
`x Not indicated for pediatric patients less than 12 years of age. (1.1, 1.2,
`
`
`
`
`
`
`1.3, 8.4)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`For subcutaneous (SC) administration only. (2.1, 2.3)
`
`
`
`Divide doses of more than 150 mg among more than one injection site to limit
`
`
`
`
`
`
`
`
`injections to not more than 150 mg per site. (2.4)
`
`
`
`
`
`
`
`
`x Allergic Asthma: Xolair 150 to 375 mg SC every 2 or 4 weeks.
`
`
`
`
`
`
`Determine dose (mg) and dosing frequency by serum total IgE level
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`WARNING: ANAPHYLAXIS
`
`INDICATIONS AND USAGE
`1
`1.1 Allergic Asthma
`
`1.2 Chronic Idiopathic Urticaria (CIU)
`
`
`
`1.3
`Important Limitations of Use
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dose for Allergic Asthma
`
`
`
`
`2.2 Dosing Adjustments for Allergic Asthma
`
`2.3 Dose for Chronic Idiopathic Urticaria
`
`
`Preparation and Administration
`2.4
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Anaphylaxis
`
`5.2 Malignancy
`
`
`5.3 Acute Asthma Symptoms
`
`
`
`5.4 Corticosteroid Reduction
`
`
`5.5
`Eosinophilic Conditions
`
`
`5.6
`Fever, Arthralgia, and Rash
`
`5.7
`Parasitic (Helminth) Infection
`
`
`5.8
`Laboratory Tests
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience in Allergic Asthma
`
`
`
`6.2 Clinical Trials Experience in Chronic Idiopathic Urticaria
`
`
`6.3
`Immunogenicity
`6.4
`Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`(IU/mL), measured before the start of treatment, and body weight (kg).
`
`
`See the dose determination charts. (2.1)
`
`
`x Chronic Idiopathic Urticaria: Xolair 150 or 300 mg SC every 4 weeks.
`
`
`
`Dosing in CIU is not dependent on serum IgE level or body weight. (2.3)
`
`
`
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`x Lyophilized, sterile powder in a single-use 5mL vial, 150 mg. (3)
`
`
`
`------------------------------CONTRAINDICATIONS-------------------------------
`x Severe hypersensitivity reaction to Xolair or any ingredient of Xolair. (4, 5.1)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`x Anaphylaxis—Administer only in a healthcare setting prepared to manage
`
`
`
`
`anaphylaxis that can be life-threatening and observe patients for an
`
`
`
`
`appropriate period of time after administration. (5.1)
`
`
`
`x Malignancy— Malignancies have been observed in clinical studies. (5.2)
`
`
`x Acute Asthma Symptoms—Do not use for the treatment of acute
`
`
`
`
`bronchospasm or status asthmaticus. (5.3)
`
`x Corticosteroid Reduction—Do not abruptly discontinue corticosteroids
`
`
`
`upon initiation of Xolair therapy. (5.4)
`
`
`x Fever, Arthralgia, and Rash— Stop Xolair if patients develop signs and
`
`
`
`
`symptoms similar to serum sickness. (5.6)
`
`
`
`x Eosinophilic Conditions—Be alert to eosinophilia, vasculitic rash,
`
`
`worsening pulmonary symptoms, cardiac complications, and/or
`
`
`
`neuropathy, especially upon reduction of oral corticosteroids. (5.5)
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------
`
`x Allergic Asthma: The most common adverse reactions (t1% more frequent
`
`
`
`
`
`in Xolair-treated patients) in clinical studies were arthralgia, pain
`
`(general), leg pain, fatigue, dizziness, fracture, arm pain, pruritus,
`
`
`
`
`
`
`dermatitis, and earache. (6.1)
`
`x Chronic Idiopathic Urticaria: The most common adverse events (t2% Xolair-
`
`
`
`treated patients and more frequent than in placebo) included the
`
`
`following: nausea, nasopharyngitis, sinusitis, upper respiratory tract
`
`
`
`infection, viral upper respiratory tract infection, arthralgia, headache,
`
`
`
`
`and cough. (6.2)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`
`
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------
`x No formal drug interaction studies have been performed. (7)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`Revised: 3/2014
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`8.3 Nursing Mothers
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Allergic Asthma
`
`
`14.2 Chronic Idiopathic Urticaria
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`Information for Patients
`17.1
`
`
`
`* Sections or subsections omitted from the full prescribing
`
`
`
`
`
`
`information are not listed.
`
`Xolair® (omalizumab) for subcutaneous use – Genentech, Inc.
`
`
`March 2014
`
`Reference ID: 3475329
`
`Page 1 of 26
`
`

`

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`2
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`3
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`4
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`5
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`6
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`7
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`8
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`9
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`10
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`12
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`13
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`14
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`15
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`16
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`17
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`18
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`19
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`20
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`21
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`22
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`23
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`24
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`25
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`26
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`27
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`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: ANAPHYLAXIS
`Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or
`angioedema of the throat or tongue, has been reported to occur after administration
`of Xolair. Anaphylaxis has occurred as early as after the first dose of Xolair, but
`
` also has occurred beyond 1 year after beginning regularly administered treatment.
` Because of the risk of anaphylaxis, observe patients closely for an appropriate period
`
`of time after Xolair administration. Health care providers administering Xolair
`should be prepared to manage anaphylaxis that can be life-threatening. Inform
`
`
`
`patients of the signs and symptoms of anaphylaxis and instruct them to seek
`immediate medical care should symptoms occur [see Warnings and Precautions
`
`(5.1)].
`
`1
`
`INDICATIONS AND USAGE
`
`1.1
`Allergic Asthma
`
`Xolair is indicated for adults and adolescents (12 years of age and above) with moderate to
`severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial
`
`aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.
`
`
`Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.
`
`1.2 Chronic Idiopathic Urticaria (CIU)
`
`Xolair is indicated for the treatment of adults and adolescents (12 years of age and above)
`
`with chronic idiopathic urticaria who remain symptomatic despite H1 antihistamine
`
`treatment.
`
`1.3 Important Limitations of Use:
`x Xolair is not indicated for treatment of other allergic conditions or other forms of
`
`
` urticaria.
`x Xolair is not indicated for the relief of acute bronchospasm or status asthmaticus.
`
`x Xolair is not indicated for use in pediatric patients less than 12 years of age.
`
`
`2
`
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1 Dose for Allergic Asthma
`
`Administer Xolair 150 to 375 mg by subcutaneous (SC) injection every 2 or 4 weeks.
`
` Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured
` before the start of treatment, and body weight (kg). See the dose determination charts below
`
`(Table 1 and Table 2) for appropriate dose assignment.
`
`Periodically reassess the need for continued therapy based upon the patient’s disease severity
`
`
`and level of asthma control.
`
`
` Xolair® (omalizumab) for subcutaneous use – Genentech, Inc.Page 2 of 26
`
` March 2014
`
`
`
`Reference ID: 3475329
`
`
`

`

` Table 1
`
`Administration Every 4 Weeks
`
`
`
` Xolair Doses (milligrams) Administered by Subcutaneous Injection
`
`Every 4 Weeks for Adults and Adolescents 12 Years of Age and Older
`
`
`for Allergic Asthma
`
`30í60
`150
`300
`
`300
`
`
`Body Weight (kg)
`
`
`
`> 60í70
`150
`300
`
`> 70í90
`150
`300
`
`
`SEE TABLE 2
`
`
`> 90í150
`300
`
`
`Pre-treatment
`
`
`
`Serum IgE
`
`
`(IU/mL)
`
`t 30í100
`
`> 100í200
`
`> 200í300
`
`> 300í400
`
`> 400í500
`
`> 500í600
`
`
` Table 2
`
`Administration Every 2 Weeks
`
`
` Xolair Doses (milligrams) Administered by Subcutaneous Injection
`
`Every 2 Weeks for Adults and Adolescents 12 Years of Age and Older
`
`
` for Allergic Asthma
`
`
`Pre-treatment
`
`
` Serum IgE
`
`(IU/mL)
`
`
`t 30í100
`
` > 100í200
`
` > 200í300
`
`
` > 300í400
`
`
` > 400í500
`
`
` > 500í600
`
`> 600í700
`
`Body Weight (kg)
`
`
`
`
`30í60
`
`> 60í70
`
`> 70í90
`
`> 90í150
`
`
`
` SEE TABLE 1
`
`225
`225
`300
`375
`
`225
`300
`300
`375
`
`225
`
`300
`
`
`225
`
` 300
`
`375
`
`DO NOT DOSE
`
`
` 2.2 Dosing Adjustments for Allergic Asthma
` Adjust doses for significant changes in body weight (see Table 1 and Table 2).
`
`
`Total IgE levels are elevated during treatment and remain elevated for up to one year after
`the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment
`
`cannot be used as a guide for dose determination.
`Interruptions lasting less than one year: Dose based on serum IgE levels obtained at
`x
`the initial dose determination.
`
`34
`
`35
`36
`37
`38
`39
`40
`41
`42
`43
`
`
` Xolair® (omalizumab) for subcutaneous use – Genentech, Inc.Page 3 of 26
` March 2014
`
`
`Reference ID: 3475329
`
`
`

`

`
`x
`
`Interruptions lasting one year or more: Re-test total serum IgE levels for dose
`determination.
`
`2.3 Dose for Chronic Idiopathic Urticaria
`Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.
`
`
`
` Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body
`weight.
`
`
`
`The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess
`the need for continued therapy.
`
`2.4 Preparation and Administration
`Prepare Xolair for subcutaneous injection using Sterile Water for Injection (SWFI), USP,
`ONLY. Each vial of Xolair is for single use only and contains no preservatives.
`
`Reconstitution
`The lyophilized product takes 15í20 minutes to dissolve. The fully reconstituted product
`will appear clear or slightly opalescent and it is acceptable if there are a few small bubbles
`or foam around the edge of the vial. The reconstituted product is somewhat viscous; in
`
`order to obtain the full 1.2 mL dose, ALL OF THE PRODUCT MUST BE WITHDRAWN
`
`
`
`
`from the vial before expelling any air or excess solution from the syringe.
`
`Use the solution within 8 hours following reconstitution when stored in the vial at 2í8ºC
`(36í46ºF), or within 4 hours of reconstitution when stored at room temperature.
`Reconstituted Xolair vials should be protected from sunlight.
`
`Preparation
`STEP 1: Draw 1.4 mL of SWFI, USP into a 3 mL syringe equipped with a 1 inch,
`18-gauge needle.
`STEP 2: Place the vial upright on a flat surface and using standard aseptic technique,
`
`insert the needle and inject the SWFI, USP directly onto the product.
`STEP 3: Keeping the vial upright, gently swirl the upright vial for approximately
`
`1 minute to evenly wet the powder. Do not shake.
`STEP 4: After completing STEP 3, gently swirl the vial for 5-10 seconds approximately
`
`every 5 minutes in order to dissolve any remaining solids. There should be no
`visible gel like particles in the solution. Do not use if foreign particles are
`
`present.
`
`Note: If it takes longer than 20 minutes to dissolve completely, repeat STEP 4
`until there are no visible gel-like particles in the solution. Do not use if the
`contents of the vial do not dissolve completely by 40 minutes.
`
`44
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`STEP 5:
`
`Invert the vial for 15 seconds in order to allow the solution to drain toward the
`stopper. Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle,
`insert the needle into the inverted vial. Position the needle tip at the very bottom
`
`
`of the solution in the vial stopper when drawing the solution into the syringe.
`Before removing the needle from the vial, pull the plunger all the way back to
`the end of the syringe barrel in order to remove all of the solution from the
`inverted vial.
`STEP 6: Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection.
`STEP 7: Expel air, large bubbles, and any excess solution in order to obtain the required
`1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution
`in the syringe.
`
`Administration
`Administer Xolair by subcutaneous injection. The injection may take 5-10 seconds to
`administer because the solution is slightly viscous. Each vial delivers 1.2 mL (150 mg) of
`Xolair. Do not administer more than 150 mg per injection site. Divide doses of more than
`150 mg among two or more injection sites (Table 3).
`
`Table 3
`
`Number of Injections and Total Injection Volumes
`
`
`
`Total Volume Injected
`Xolair Dose
`
` (mL)
` Number of Injections
`(mg)*
`1.2
`1
`150
`1.8
`2
`225
`2.4
`2
`300
`3.0
`3
`375
`
`*All doses in the table are approved for use in allergic asthma
`
`
`patients. The 150 mg and 300 mg Xolair doses are intended for use
`in CIU patients.
`
` DOSAGE FORMS AND STRENGTHS
`3
`
`
`150 mg of omalizumab as lyophilized, sterile powder in a single-use 5 mL vial.
`
`CONTRAINDICATIONS
`4
`The use of Xolair is contraindicated in the following:
`
`Severe hypersensitivity reaction to Xolair or any ingredient of Xolair [see Warnings and
`
`Precautions (5.1)].
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
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`160
`161
`162
`163
`
`5.1 Anaphylaxis
`Anaphylaxis has been reported to occur after administration of Xolair in premarketing
`clinical trials and in postmarketing spontaneous reports. Signs and symptoms in these
`reported cases have included bronchospasm, hypotension, syncope, urticaria, and/or
`angioedema of the throat or tongue. Some of these events have been life-threatening. In
`
`premarketing clinical trials in allergic asthma, anaphylaxis was reported in 3 of 3507
`
`(0.1%) patients in clinical trials. Anaphylaxis occurred with the first dose of Xolair in two
`patients and with the fourth dose in one patient. The time to onset of anaphylaxis was 90
`minutes after administration in two patients and 2 hours after administration in one patient.
`In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use
`
`was estimated to be at least 0.2% of patients based on an estimated exposure of about
`57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as
`early as after the first dose of Xolair, but also has occurred beyond one year after beginning
`regularly scheduled treatment.
`
`
`Administer Xolair only in a healthcare setting by healthcare providers prepared to manage
`
`
`anaphylaxis that can be life-threatening. Observe patients closely for an appropriate period
`
`of time after administration of Xolair, taking into account the time to onset of anaphylaxis
`seen in premarketing clinical trials and postmarketing spontaneous reports [see Adverse
`Reactions (6)]. Inform patients of the signs and symptoms of anaphylaxis, and instruct
`
`
`them to seek immediate medical care should signs or symptoms occur.
`
`Discontinue Xolair in patients who experience a severe hypersensitivity reaction
`
`[see Contraindications (4)].
`
`5.2 Malignancy
`Malignant neoplasms were observed in 20 of 4127 (0.5%) Xolair-treated patients compared
`witK  RI  

FRQWURO SDWLHQWV LQ FOLQLFDO VWXGLHV RI DGXOWV DQG DGROHVFHQWV • 12
`years of age) with asthma and other allergic disorders. The observed malignancies in
`Xolair-treated patients were a variety of types, with breast, non-melanoma skin, prostate,
`melanoma, and parotid occurring more than once, and five other types occurring once each.
`The majority of patients were observed for less than 1 year. The impact of longer exposure
`
`to Xolair or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is
`
`
`not known [see Adverse Reactions (6)].
`
`
`5.3 Acute Asthma Symptoms
`
`Xolair has not been shown to alleviate asthma exacerbations acutely. Do not use Xolair to
`treat acute bronchospasm or status asthmaticus.
`
`5.4 Corticosteroid Reduction
`Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Xolair
`therapy for allergic asthma. Decrease corticosteroids gradually under the direct supervision
`
`of a physician. In CIU patients, the use of Xolair in combination with corticosteroids has
`not been evaluated.
`
`
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`
`5.5 Eosinophilic Conditions
`
` In rare cases, patients with asthma on therapy with Xolair may present with serious
`systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent
`with Churg-Strauss syndrome, a condition which is often treated with systemic
`
`corticosteroid therapy. These events usually, but not always, have been associated with the
`reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia,
`vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy
`presenting in their patients. A causal association between Xolair and these underlying
`
`
`conditions has not been established.
`
`5.6 Fever, Arthralgia, and Rash
`In post-approval use, some patients have experienced a constellation of signs and symptoms
`including arthritis/arthralgia, rash, fever and lymphadenopathy with an onset 1 to 5 days
`after the first or subsequent injections of Xolair. These signs and symptoms have recurred
`after additional doses in some patients. Although circulating immune complexes or a skin
`biopsy consistent with a Type III reaction were not seen with these cases, these signs and
`symptoms are similar to those seen in patients with serum sickness. Physicians should stop
`Xolair if a patient develops this constellation of signs and symptoms [see Adverse
`Reactions (6.4)].
`
`
`5.7 Parasitic (Helminth) Infection
`Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient
`data are available to determine the length of monitoring required for geohelminth infections
`after stopping Xolair treatment.
`
`In a one-year clinical trial conducted in Brazil in patients at high risk for geohelminthic
`infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-
`treated patients experienced an infection, as diagnosed by standard stool examination,
`
`compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for
`infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study
`a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have
`received Xolair than a patient who did not have an infection. Response to appropriate anti-
`geohelminth treatment of infection as measured by stool egg counts was not different
`
`between treatment groups.
`
`5.8 Laboratory Tests
`Serum total IgE levels increase following administration of Xolair due to formation of
`Xolair:IgE complexes [see Clinical Pharmacology (12.2)]. Elevated serum total IgE levels
`
`
`
`may persist for up to 1 year following discontinuation of Xolair. Do not use serum total
`IgE levels obtained less than 1 year following discontinuation to reassess the dosing
`regimen for allergic asthma patients, because these levels may not reflect steady state free
`
`
`
`IgE levels.
`
`6
`ADVERSE REACTIONS
`
`Use of Xolair has been associated with:
`x Anaphylaxis [see Boxed Warning and Warnings and Precautions (5.1)]
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`
`x Malignancies [see Warnings and Precautions (5.2)]
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of a drug cannot be directly compared to rates in the
`
`clinical trials of another drug and may not reflect the rates observed in clinical practice.
`
`6.1 Clinical Trials Experience in Allergic Asthma
`
`
`
`Adult and Adolescent Patients 12 years of Age and Older
`The data described below reflect Xolair exposure for 2076 adult and adolescent patients
`
`ages 12 and older, including 1687 patients exposed for six months and 555 exposed for one
`
`year or more, in either placebo-controlled or other controlled asthma studies. The mean age
`of patients receiving Xolair was 42 years, with 134 patients 65 years of age or older; 60%
`were women, and 85% Caucasian. Patients received Xolair 150 to 375 mg every 2 or
`4 weeks or, for patients assigned to control groups, standard therapy with or without a
`placebo.
`
`The adverse events most frequently resulting in clinical intervention (e.g., discontinuation
`of Xolair, or the need for concomitant medication to treat an adverse event) were injection
`
`
`site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis
`
`(16%), headache (15%), and pharyngitis (11%). These events were observed at similar
`rates in Xolair-treated patients and control patients.
`
`Table 4 shows adverse reactions from four placebo-controlled asthma studies that
`occurred • 1% and more frequently in patients receiving Xolair than in those receiving
`placebo. Adverse events were classified using preferred terms from the International
`
`Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately
`from the reporting of other adverse events and are described following Table 4.
`
`
` Xolair® (omalizumab) for subcutaneous use – Genentech, Inc.Page 8 of 26
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`Reference ID: 3475329
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`

` Table 4
`
`Adverse Reactions • 1% More Frequent in
`
`Xolair-Treated Adult or Adolescent Patients 12 years of age and older
`
`
`Four placebo-controlled asthma studies
`
`
`Adverse reaction
`
`Body as a whole
`
`Pain
`Fatigue
`
`Musculoskeletal system
`Arthralgia
`Fracture
`
`Leg pain
`
`Arm pain
`
`Nervous system
`
`Dizziness
`
`Skin and appendages
`
`Pruritus
`Dermatitis
`Special senses
`Earache
`
`Xolair
`n = 738
`(%)
`
`Placebo
`n = 717
`(%)
`
`7
`3
`
`8
`2
`4
`2
`
`3
`
`2
`2
`
`2
`
`5
`2
`
`6
`1
`2
`1
`
`2
`
`1
`1
`
`1
`
`
`There were no differences in the incidence o