CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-794
`
`MEDICAL REVIEW
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`1 of 7
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`Almirall EXHIBIT 2042
`
`Amneal v. Almirall
`IPR2019-00207
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`Clinical Team Leader Interdisciplinary Summary
`NDA 21-794 ACZONE (dapsone) Gel, 5%
`
`June 29, 2005
`
`The Clinical Team Leader concurs with the Primary Clinical Reviewer, as per her
`careful review, that this application for ACZONE (dapsone) Gel, 5%, for the treatment of
`acne vulgaris should be approved. Certain specific issues regarding the nature of this
`product nave arisen during review and discussion about ACZONE Gel, 5% with other
`review disciplines. The intent.of this briefreview is to summarize these concerns.
`
`Safety of Drug Product
`
`The main issue of discussion with the applicant for labeling was whether patients
`to be treated with ACZONE Gel, 5%, should have glucose 6-phosphate dehydrogenase
`(G6PD) and complete blood count evaluations. This evaluation of safety was approached
`by the clinical team from two main avenues.
`
`The first approach was whether there was a potential for adverse events given the
`level of systemic exposure of dapsone with this topical product. The clinical team
`expected a low level of exposure relative to the oral form of.this drug and this was
`confrrmed by the FDA clinical pharmacologist, Dr. Tapash Ghosh. Following this line of
`thought, what is the threshold level of dapsone exposure that would lead to a concern
`(i.e., for hemolysis). Given prior clinical experience with dapsone, a lower threshold of
`dapsone exposure could be concern for sensitive individuals ( e.g., G6PD deficient
`patients and methemoglobin reductase deficient patients according to the oral dapsone
`label). The applicant was asked this question directly, but was unable to answer this
`definitively. In fact, the data provided by the sponsor regarding ACZONE Gel treated
`patients in their study DAP0I 10 suggest a drop in hematocrit (see graph below). The
`drop in hematocrit was attributed by the applicant to be possibly due to loss of Q.lood
`from blood draws. It is not clear to this reviewer that the amount of blood drawn for this
`study would lead to such a drop in hematocrit. The sponsor had not provided any
`supportive evidence (e.g., placebo.treated patients and their change in hemoglobin with
`the same amount of blood draws). Loss of blood due to hemolysis remains a viable
`explanation for these changes.
`
`It will be important to have any further studies conducted to carefully address this
`by evaluating dapsone levels along with documenting changes in hematocrit, reticulocyte
`count, and other hematologic parameters.
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`Change in Hemoglobin from Baseline by G6PD Activity in Study DAP011 O (Amend 15)
`
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`LLN ·················-··················-····-···--· :····-·····--·········--·········
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`Change in Hemoglobin (G/DL)
`LLN = Lower Limit of Normal
`
`The second approach was a data driven analysis of patients exposed to topical
`dapsone and a separate evaluation of G6PD deficient patients.
`
`As was noted by the Primary Reviewer, the monitoring for dapsone related
`hemolysis was not the most careful or thorough (for example, reticulocyte counts were
`not available for all patients with complete blood counts and dapsone levels were
`available for very few patients).
`
`A well known fact regarding dapsone hemolysis is that patients with glucose 6-
`phosphate dehydrogenase deficiency are more sensitive to the oxidative stress and
`dapsone related hemolysis. The applicant did not enroll adequate numbers of subjects
`with glucose 6-phosphate dehydrogenase (G6PD) deficiency in the clinical studies to be
`able to make reasonable conclusions about the safety of ACZONE Gel in this population.
`Only 25 G6PD deficient subjects were treated with ACZONE were enrolled in Q!e
`clinical studies.
`
`For this reason, the label should include the concerns in.the PRECAUTIONS and
`INDICATIONS AND USAGE sections outlining this concern and informing
`practitioners to obtain G6PD levels and baseline CBC prior to treatment with ACZONE
`Gel, 5%. Additionally, a post-marketing commitment to evaluate the safety in sufficient
`numbers of G6PD deficient patients is recommended by the Primary Reviewer. The
`clinical TL is in agreement with such a required commitment.
`
`Carcinogenicity
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`The current oral dapsone label sates that dapsone is a carcinogen, but was based
`on older data than what was submitted to this NDA.
`
`The pharmacologist/toxicologist, Dr. Norman See, states in his review that
`dapsone is not carcinogenic in rats, nor was there evidence of any potential to induce
`carcinogenicity in a 26 week dermal study conducted in Tg.AC mice. In addition,
`dapsone topical gel did not increase the rate of formation of UV induced skin tumors
`when applied topically to hairless mice in a 12-month photocarcinogeni.ity study.
`
`This assessment of lack of carcinogenicity was based on review of the latest
`proprietary studies conducted by this applicant.
`
`Efficacy and Risk vs. Benefit
`
`This product appears to have limited efficacy as per the observed difference in
`efficacy vs. vehicle in the two pivotal studies conducted. However, this difference is
`statistically significant (see Dr. Kathy Fritsch's statistics review). The benefit achieved
`with this product may be relatively small but appear in the estimate of this reviewer to be
`sufficient to counter the perceived risks associated with the use of this product. The
`somewhat unknown risks of use in the G6PD deficient population will be mitigated by
`the recommended closer monitoring of the patients' hematocrit and the language in the
`labeling proposed.
`
`Mechanism of Action
`
`The mechanism of action of dapsone for the treatment of acne vulgaris has been
`postulated to be via an anti-inflammatory mechanism of some sort. However, this has not
`been adequately characterized nor its clinical relevance evaluated.
`
`A non-committal attempt by the applicant at evaluating the anti-microbial effect
`of dapsone on acne was conducted (see Clinical Microbiology review by Mr. Harold
`Silver). There is not sufficient evidence submitted in the NDA to introduce any
`information regarding anti-microbial claims into labeling.
`
`Chemistry, Manufacturing, and Controls Concerns
`
`I) A sample of the drug product was sent to the Agency by the applicant. On
`evaluation, the substance was gritty with crystals or particles dispersed in the gel.
`According to the CMC review, these particles are drug substance (dapsone).
`Discussion regarding this aspect of the product was held between CMC,
`Biopharm, and Clinical reviewers. It was determined that this product's
`grittines~, while possibly a reflection of poor formulation design, did not impact
`safety and effectiveness so long as the marketed product met the same
`specifications on particle size distribution as the product that was investigated in
`the clinical and pharmacokinetic studies.
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`2) The product packaging (container) is translucent to light. Apparently, the drug
`substance is also photo labile. This apparently was not well-thought out by the
`applicant. Recommending that the drug product be placed into the opaque
`cardboard container each time after use appears to be a stop gap measure until a
`better product with an opaque container is used. Apparently, the professional
`sample tube is opaque and will not need to be placed in a light-tight box.
`According to the Chemistry reviewer, Mr. Ernie Pappas, having a marketed
`product placed in a larger tube of the same material as the professional sample
`tube would not require extensive regulatory evaluation.
`
`3) The applicant stated they had produced at their own risk approximately -...
`professional sample tubes with labeling prior to Agency evaluation and approval
`(see graphic below).
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`This is acceptable from a clinical perspective for a one time exception for this
`current printed batch of 3 gram physician samples only. The next printing or in 6
`months, which ever comes first, should use the approved label.
`
`Pediatric Waiver Request
`
`·
`
`The applicant requested a pediatric waiver for subjects under that age of 12.
`While acne does occur in patients younger than age 12, a waiver to study patienrs with
`acne younger than age 12 has been routinely granted for products intended to treat acne:
`No extenuating circumstances exist with regard to this product from our review so
`granting of a waiver appears to be reasonable.
`
`Conclusion
`
`Thus, in conclusion, this NDA is recommended for approval with the labeling that
`addresses the concerns described above {see Primary Clinical Review) and with the post(cid:173)
`marketing commitment to address the need for additional safety data in G6PD deficient
`patients.
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`Markham C. Luke, M.D., Ph.D.
`Lead Medical Officer, Dermatology
`
`APPEARS THIS WAY
`ON ORIGINAL
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`·-------------------------------
`
`/s/
`
`Markham Luke
`6/30/05 09:03:25 AM
`MEDICAL OFFICER
`
`Interdisciplinary summary for NDA
`
`Stanka Kukich
`7/5/05 10:56:16 AM
`MEDI.CAL OFFICER
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