`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`- 21-450
`
`Trade Name:
`
`Zomig Nasal Spray
`
`
`
`Generic Name:
`
`zolmitriptan
`
`Sponsor:
`
`AstraZeneca Pharmaceuticals LP
`
`Approval Date:
`
`September 30, 2003
`
`Indications:
`
`For the acute treatment of migraine.
`
`

`

`RESEARCH
`
`CENTER FOR DRUG EVALUATION AND
`
`APPLICATION NUMBER:
`
`21-450
`
`CONTENTS
`
`
`
`Reviews / Information Incluits I
`Review.
`
`_—
`A roval Letter
`__
`A rovable Letter
`——
`Final Printed Labelin_
`Medical Review s
`
`
`
`Chemistr Review 3
`
`Pharmacolo_ Review 5)
`Statistical Review s
`
`Microbiolo 3 Review
`Clinical Pharmacology and Biopharmaceutics
`Review s
`
`!i
`
`Administrative Document s
`
`Corres - ondence
`
`>4
`
`x
`
`
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-450
`
`APPROVAL LETTER
`
`

`

`
`
`a"
`
`a. {( DEPARTMENTOFHEALTH& HUMANSERVICES
`0""‘0-
`
`*l'hla
`
`PUb'iC”93"“SBWiCE
`
`Food and Drug Administration
`Rockville, MD 2085?
`
`NBA 21-450
`
`Judy W. Firor
`
`US Regulatory Affairs
`AstraZeneca Pharmaceuticals LP
`
`1800 Concord Pike
`PO Box 8355
`
`Wilmington, DE 19850-8355
`
`Dear Ms. Firor:
`
`Please refer to your new drug application (NDA) dated March 27, 2003, received March 28, 2003,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Zomig (zolmitriptan)
`
`Nasal Spray.
`
`We acknowledge receipt of your submissions dated April 17, April 25, August 29, and September 30,
`2003 .
`
`The March 27, 2003 submission constituted a complete response to our December 19, 2002 action
`letter.
`
`This new drug application provides for the use of Zomig (zolmitriptan) Nasal Spray for the acute
`treatment of migraine.
`
`It is approved, effective on the date of this
`We completed our review of this application, as amended.
`letter, for use as recommended in the agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert, .
`text for the patient package insert, immediate container and carton labels). Marketing the product with
`FPL that is not identical to the approved labeling text may render the product misbranded and an
`unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format — NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed.
`Individually mount 15
`of the copies on heavy-weight paper or similar material- For administrative purposes, designate this
`submission “FPL for approved NDA 21-450.” Approval of this submission by FDA is not required
`before the labeling is used.
`
`We acknowledge your phase 4 commitment, as discussed in a teleconference held on August 28, 2003
`and in your letter dated August 29, 2003, to provide the following information to support approval of
`(b)(4)—————————————————————————————————————— spray devices.
`
`
`
`

`

`
`
`
`
`l. The results of an open-label. mdmd, two-period crossover bioequivalence study
`comparing two single 5 mg doses ofzoknitriptan (ZOMIGO) administered to healthy
`voh'rnteers1n the two meal aptly devices used1n the clinical development program. The study
`will assess the bioequrvahee of the two devices after single dose administration of
`zolm‘itriptln to healthyW with particular regard to AUC, Cm, and tmx. You commit
`tosubmitthe results offltiaélilwithintimonths ofthe date ofthis letter
`
`2.. Additional data in support of the(b)(4)—-——--—---—--—----——-{details to be subsequently agreed to
`with the FDA) and I) submit the-——-—----------—-—---——-he submission of the 5 mg
`bioequivdence study.
`
`,
`"‘i
`
`'7 Inflammhtnit three copies of the introductory promotional materials that you propose to use for
`: mm Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division andtwo copies ofboth the promotional materials and the package insert(s) directly to:
`
`Q
`"{
`
`'
`
`:
`
`'
`
`.
`
`Division of Drug Marketing, Advertising,
`and Commutation, BED-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Roekville, MD 20857
`
`-*
`
`. " .. Please submit one market package ofthe drug product when it is available.
`
`We rem'md you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`'
`
`The MedWetch—to—Manut’actu‘er Program provides manufacturers with copies of serious adverse event
`repute fiat are received directly by the FDA. New molecular entities and important new biologics
`, qulit'y for inclusion for three years after approval. Your firm13 eligible to receive copies of reports for
`are product. To participate in the program, please see the enrollment instructions and program
`description details atWest-n1-
`
`1ny have any questions, call Lana Chen, Regulatory Project Manager, at (301) 594-5529.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division of Neuropharrnacological Drug Products
`Ofice of Drug EvaluatiOn I
`Centerfor Drug Evaluation and Research
`
`Enclosure
`
`
`
`

`

`
`
` yaw record that was signed electronically and
`
`. icflfic electronic signature.
`
`—--————_____-—-w-.__._..
`
`Rucsell Katz
`9/30/03 12:40:35 PM
`
`
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-450
`
`APPROVABLE LETTER
`
`
`
`

`

`
`
`‘9
`
`6 DEPARTMENT OFHEALTH & HUMANSERVICES
`
`PUb'lCHealth39Wi€e
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21—450
`
`Judy W. Firor
`US Regulatory Affairs
`AstraZeneca Pharmaceuticals LP
`
`1800 Concord Pike
`PO Box 8355
`
`Wilmington,DE 19850—8355
`
`Dear Ms. Firor:
`
`'-
`
`Please refer to your new drug application (NDA) dated February 27, 2002, received February 27,
`submitted under section 505 (b)of the Federal Food, Drug, and Cosmetic Act for Zomig (zolmitriptan)
`Nasal Spray.
`
`' We acknowledge receipt of your submissions dated the following:
`
`February 27, 2002
`March 6, 2002
`April 15, 2002
`June 27, 2002
`August 12, 2002
`
`August 14, 2002
`September 26, 2002
`October 9, 2002
`November 5, 2002
`November 11, 2002
`
`November 12, 2002
`November 22, 2002
`November 25, 2002
`December 10, 2002
`
`We have completed our review of this application, as amended, and it is approvable. Before the
`application may be approved, however,
`it will be necessary for you to submit additional data to
`demonstrate the bioequivalence of the clinical and commercial (i.e., “to be marketed”) spray devices.
`
`As you know, we communicated the deficiency of the in vitro testing of the commercial device in a
`teleconference on 10/9/02 (see enclosure). You submitted a response, in writing, on November ll,
`2002. That submission essentially contained two arguments to support bioequivalence of the two
`devices: one that relies on the existing in vitro data, and another based on clinical data from the long-
`term study 0078. We conclude that your argument relying on the existing in vitro data provides no
`new compelling evidence to support the bioequilvalence of the two devices.
`
`We also find the clinical argument problematic. We believe that it is impossible to compare the results
`contained in part 2 of study 0078 (during which all subjects received the best optimal dose) with those
`obtained in part 1 (during which subjects were randomized to 0.5mg, 1mg, 2.5mg, or 5mg) because of
`the potential bias resulting from the fact that investigators knew (and could communicate to the
`subjects) that subjects were being switched to the best optimal dose. They also knew when this switch
`occurred, which was coincident with the change to the commercial device. This potential bias would,
`in our opinion, favor the commercial device. Furthermore, the results from that study are based on
`efficacy data across multiple attacks; We do not accept such analyses to demonstrate efficacy as we
`believe that a subject's experience with the study medication from a previous attack can influence the
`
`'
`
`

`

`
`
`NDA 21—450
`
`Page 2
`
`response rate for subsequent attacks. We believe that these issues preclude the acceptance of these
`data as evidence of efficacy of Zomig Nasal Spray when delivered using the commercial device.
`
`In order to address this deficiency, you may consider one of the following:
`
`1. Repeat the in vitro testing using either mechanical actuation or have the break ring re-manufactured
`with more narrow specifications before repeating the study.
`
`(We remind you that Cmax
`2. Provide in viva pharmacokinetic data to demonstrate bioequivalence.
`and AUC should be bioequivalent. Furthermore, since a drug delivered via a commercial device
`that results in a longer Tm“, compared to the Tum of the clinical device, may be less efficacious in
`the treatment of an acute clinical syndrome like migraine, we will also look carefully at Trm as
`supportive evidence).
`
`3. Provide efficacy data from a well-designed, randomized controlled trial.
`
`In addition, it will be necessary for you to submit revised draft labeling. The attached approvable
`labeling contains annotations of areas that require further clarification or editing.
`If additional
`information relating to the safety or effectiveness of this drug becomes available, further revision of
`the labeling may be required.
`
`Finally, we provide this additional comment, which does not affect
`application:
`
`the approvability of this
`
`The zolmitriptan drug substance specification provided in the current submission
`
`
`incorrectly lists the acceptance criterion for
`as not more than (NMT)
`We remind you that, per your October 21,1997 submission to NDA 20- 768, the limit for
`
`-
`is NMT -"'” Please ensure that all applicable documents reflect the correct
`limit.
`
`include a safety update as described in 21 CFR
`When you respond to the above deficiency,
`314.50(d)(5)(vi)(b). The safety update should include data from all non-clinical and clinical studies of
`the drug under consideration regardless of indication, dosage form, or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows:
`
`0 Present new safety data from the studies for the proposed indication using the same format as the
`original NDA submission.
`
`0 Present tabulations of the new safety data combined with the original NDA data.
`it
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`
`II For indications other than the proposed indication, provide separate tables for the frequencies of
`adverse events occurring in clinical trials.
`
`

`

`NDA 21-450
`
`Page 3
`
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating the drop-
`outs from the newly completed studies. Describe any new trends or patterns identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide narrative
`summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
`
`6. Provide a summary of worldwide experience on the safety of this drug.
`estimate of use for drug marketed in other countries.
`
`Include an updated
`
`7. Provide English translations of current approved foreign labeling not previously submitted.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, RFD-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 2085?
`
`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110. If you do not
`follow one of these options, we will consider your lack of reSponse a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you have any questions, call Lana Chen, Regulatory Project Manager, at (301) 594-5529
`
`APPEARS IHIR was
`(ij CM 3:?th
`"
`"'
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Kata, M.D.
`Director
`
`, u» -
`
`Division of Neuropharrnacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure
`
`

`

`2i Page(s) Withheld
`
`_;_______ § 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`/ § 552(b)(5) Draft Labeling
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`.
`Russell Katz
`12/19/02 04:16:32 PM
`
`Aryng‘i‘fii‘ Fur-r4 .3
`u
`» mun: Hui ”.313,
`
`
`
`
`
`