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`occurred in a patient who had had multiple suicide attempts in the past, and who had been
`on modafinil for at least 4 years. The acute delirium occurred in a 19 year old man who
`was discontinued from treatment after 3 months. The description of the event is unclear
`in the submission, but the sponsor felt assessment of the event was difficult because of
`“psychic disturbances and the use of therapeutic sedatives”. There is no firrther
`information about the case of visual disturbance, because it occurred in a compassionate
`use program in Canada, in which no CRstere kept.
`
`SERIOUS ADVERSE EVENTS
`
`A total of 27 patients in extensions of Studies 301 and 302 experienced serious adverse
`events who were not reported in the original NDA. As Dr. Freiman describes, none of
`these SAEs can be clearly related to treatment with modafrnil.
`
`Approximately 12 patients in Lafon sponsored studies had serious adverse events who
`were not reported previously in the NDA. Reports of interest included generalized
`epileptic attack and epileptic attack. No firrther information about these events is given,
`other than that Lafon tabular information summaries were used to generate the table
`(Sponsor’s Table 28, Vol 19, page IV-80 ofthe 6/30/98 submission) in which these
`events are included).
`
`OTHER ADVERSE EVENTS
`
`(
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`*
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`'
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`The only additional adverse event of interest relates to events subsumed under the
`COSTART term Dyskinesias. While this term is included in the label in the 1% Table of
`ABS in the RCTs (2% vs 0% in pbo patients), we have only recently (submission dated
`12/14/98) received detailed information about the events coded as dyskinesias.
`
`According to the sponsor, there were a total of 21 modaflnil treated patients who
`experienced a total of 26 events coded as dyskinesia; 12 (2%) of these subjects were in
`the Phase 3 controlled trials (or extensions), and 9 (1%) were in the foreign, non-
`Cephalon studies. Two of the events (both in the same patient) were considered serious;
`a 15 year old young woman who ingested an accidental overdose (1200 mg) and
`experienced “motoric crawling” and “abrupt movements”.
`
`'
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`Most of the investigator terms which were subsumed under the term Dyskinesia involved
`bucco-facial movements (e.g., facial tic, involuntary tongue movements, repetitive tongue
`rolling, jaw clenching, chewing lower lip, bruxism, rolling tongue).
`
`Five patients discontinued secondary to these events.
`
`The mean time fiom initiation oftreatment to onset of symptoms was 100 days in the
`Phase 3 trials, and the mean duration of symptoms was 111 days. Of the 11 events in the
`foreign database, all, save 1, occurred in studies of patients with mood and psychosocial
`disorders. The 1 other event occurred in 3 PK study.
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`The sponsor states that 18 ofthe AEs resolved without residual (I cannot tell if the drug
`was discontinued in some proportion of these cases) and 8 events were on-going, “at the
`time of discontinuation”. There is insufficient information to know how long afier
`discontinuation, if at all, any of these 8 events persisted. Of the 15 events of dyskinesia
`in 12 patients in the Phase 3 studies, 11 events (10 patients) spontaneously resolved with
`continued treatment, although 1 patient had involuntary tongue movements that lasted for
`1 month, spontaneously resolved, but then recurred 2 months later, and persisted for an
`additional 1 V2 months. The other events were persistent, but treatment was continued.
`
`Although Dyskinesia is listed in the Adverse Event table, I believe that additional
`explanation ofthe type of dyskinesia seen is worthwhile, given that most prescribers
`would not ordinarily understand this term to primarily refer to ore-facial abnormal
`movements (despite the fact that the phenomena noted here appear to resemble those seen
`in patients with tardive dyskinesia, there are other differences, including the much more
`rapid onset of these movements compared to TD, and the spontaneous resolution without
`change in the treatment). I believe an adequate solution would be to place an asterisk on
`the term Dyskinesia in the table, with a footnote stating *Oro-facial abnormal
`movements.
`
`FOREIGN LABORATORY DATA
`
`As Dr. Freiman notes in his review of 12/15/98, no significant laboratory abnormalities
`were “Oted In these patlentAPPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
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`Pharmacology
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`Biopharmaceutics
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` .-----------------------------------------------
`
`Labeling
`
`The sponsor proposed extensive changes to the labeling accompanying the Approvable
`letter. Division staff has had extensive discussions about labeling with the sponsor in
`several telephone conferences, which included stafi‘ fiom biopharmaceutics and, most
`notably, Dr. Klein of RFD-170, who reviewed the drug abuse data. The most recent
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`version of labeling was submitted to the Division in a fax dated 12/14/98. This version of
`labeling differs from the version attached to the Approvable letter in some important
`ways, partly because the sponsor has drafted sections that were relatively incomplete at
`the Approvable stage. In the following comments, I have highlighted the major changes.
`It should be noted that the sponsor disagrees vehemently with some ofthe language
`included in the labeling we are forwarding with this package; I will highlight which
`sections are still matters of controversy (we simply have not had sufficient time, given
`the rapidly approaching due dates, to enter into further negotiations with the sponsor on
`these points).
`
`N,
`
`Description Section
`
`In our original labeling, we included a statement that Modafinil is chemically unrelated,
`but pharmacologically related, to other CNS stimulants (i.e., methylphenidate and
`amphetamine). In reality, modafinil does share some pharmacological actions with the
`other stimulants, but also differs in some important aspects (striking a balance in
`describing these similarities and differences has been a major issue in various sections of
`labeling). In order to avoid a detailed explanation in this section, we have removed the
`original statement.
`
`Clinical Pharmacology Section
`
`Again, language describing that the effects ofmodafinil are similar, but not identical, to
`those ofthe other stimulants has been added. In addition, language about modafrnil’s
`effects at the dopamine receptor has been included, as has language fiirther describing its
`lack of sympathomimetic activity in various test systems, which is basically a slight
`expansion of our original wording.
`
`Finally, there is a brief discussion of a study which showed that CNS stimulants in the cat
`activated a wide array of brain systems, whereas modafinil activated discrete brain areas.
`This is followed by a statement that the relevance of this finding to humans is unknown.
`
`Pharmacokinetics
`
`Extensive changes have been made in the Absorption and Distribution and Metabolism
`and Elimination subsections. In particular, a more detailed description of the metabolism
`of modafinil and drug-drug interactions has been included, as has a discussion of the
`effects of age on the PK of modafrnil.
`
`Clinical Trials
`
`(-
`
`Minor changes have been made to this sub-section.
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`Precautions
`
`A paragraph on Abuse Potential, which is essentially repeated in the Drug Abuse section,
`was placed here in the Approvable letter, and is still here. Dr. Klein feels it should be in
`this position (given the potential for off label uses and his feeling that the drug
`intrinsically has considerable abuse potential; recall that his group originally proposed
`that the drug be Category III under the CSA), but the sponsor strongly objects to its
`placement here because similar language appears in the Drug Abuse and Dependence
`section, and labeling for other Schedule IV drugs does not include such language in the
`Precautions Section.
`
`Drug Interactions
`
`Extensive changes have been made to this section, particularly in the sub-section entitled
`Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by
`Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes.
`
`Adverse Events
`
`In our original label, we included a statement about a patient who experienced heart
`arrest, and we asked the sponsor for additional information. The sponsor submitted more
`details of this patient, who apparently had a history of syncopal episodes, and a
`subsequent episode of pain induced bradycardia. However, the episode of arrest referred
`to in labeling (a 9 second episode of asystole), was unaccompanied by any obvious
`stimulus (the patient was at the time being observed in a sleep lab). The sponsor has
`proposed language in this section that implies that the event is not drug related, because
`of the patient’s history.
`
`My view is that there is no evidence linking this event to previous syncopal attacks, and
`certainly no reason to link this event with the subsequent presumed vaso-vagal event.
`The language in the version we are sending up includes a description of the specific event
`and the fact that the patient had previous syncopal attacks. It implies nothing about the
`cause of this specific event.
`
`Drug Abuse and Dependence
`
`Extensive changes have been made here. Most of these changes are not substantive, and
`consist of some re-wording of statements in the Approvable drafl.
`
`However, the sponsor has proposed the inclusion of a brief description of 2 studies. In
`one, subjective effects were evaluate in normals who received a single dose of 300 mg
`modafmil, 300 mg of caffeine, and 15 mg of amphetamine. The sponsor concludes that
`modafmil was differentiated from amphetamine, but not from caffeine.
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`The second study evaluated the abuse potential of 3 doses of modafinil compared to that
`of2 doses of methylphenidate in in-patients experienced with drugs of abuse. The
`sponsor concludes that modafinil produced psychoactive and euphoric effects and
`feelings consistent with other CNS stimulants (methylphenidate). The section describing
`these 2 studies is followed by a statement that studies of these kinds are not known to
`reliably predict the abuse potential of these drugs.
`
`Dr. Klein feels very strongly that the description of the first study should not be included
`in labeling (see the attachment to his e-mail of 12/10/98). His conclusion is based on the
`following: 1) the use of a normal, not drug experienced, sample is an inappropriate
`sample in which to assess the abuse potential, 2) only a single dose was studied, 3) the
`dose was relatively low, 4) the response to caffeine is dependent upon the level of the
`tolerance ofthe subjects to it, which was unknown, 5) the methodology is inappropriate
`to assess craving, another stated objective of the study. For these reasons, he feels that
`the conclusions reached by the sponsor are wrong, and therefore that they should not be
`included in labeling because they are misleading. He does feel that the description of the
`second study should be in labeling.
`
`'r
`
`Of course, the sponsor wants the description ofthe first study in labeling, ostensibly
`because they believe it says something meaningful about the abuse potential in normals,
`and it provides “balance”. My inclination is to agree with our expert consultant, Dr.
`Klein.
`
`Dosage and Administration
`
`'
`
`Our original labeling stated the dose as 200 mg/day, given as a single dose in the
`morning.
`In a note to the sponsor, we informed them that an additional statement,
`describing that a single 400 mg/day dose was tolerated, but that there is no evidence to
`suggest that it confers additional benefit beyond that ofthe 200 mg dose, might be
`acceptable, if the requested safety information bore this out.
`
`I believe that such a statement is warranted, based on the sponsor’s submission.
`However, the sponsor requests that this section describe the 200 mg dose as the
`recommended starting dose, and that there is a suggestion that a daily dose of 400 mg
`might provide an additional benefit for some patients, and that:
`
`“Accordingly, whether or not to employ a dose of 400 mg is a matter of prescriber and
`patient preference.”
`
`
`
`
`The sponsor asserts that their proposed language is similar to the language in the Aricept
`label, which they believe is an appropriate comparison based on the Aricept data.
`
`The estimate ofthe treatment effect on one ofthe primary outcomes in the first study is
`slightly numerically greater for the 400 mg dose compared to the 200 mg close, but in the
`second study this ordering is reversed. For the proportion of patients improved on the
`global (the other outcome for which labeling displays estimates oftreatment effect), there
`
`*
`( ‘
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`——-——-J
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`8
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`was numerical superiority ofthe 400 mg dose compared to the 200 mg dose (72% vs
`64%) in the first study, and essential identity for the second study (60% vs 58%).
`Examination ofthe estimates ofthe treatment effect on other secondary measures
`revealed no consistent pattern.
`
`In my view, the data are weak for an advantage ofthe 400 mg dose compared to the 200
`mg dose. Inspection of the Aricept labeling suggests that there was consistent numerical
`superiority ofthe high dose compared to the low dose. Such a consistent relationship
`does not exist for the 400 and 200 mg groups in the modafinil studies. I recommend that
`our proposed language remain; the Clinical Trials section displays the results, and I do
`not believe the label need further interpret the data for the prescriber in the Dosage and
`Administration section.
`
`In summary, there are 5 portions ofthe labeling we wish to see approved with which the
`sponsor disagrees or which they have not yet seen: 1) the inclusion in the Precautions
`section of a statement about abuse potential, 2) the absence of a description of a single
`dose study in normals in the Drug Abuse and Dependence section, 3) the absence of a
`statement in the Dosage and Administration section that suggests that 400 mgday may
`provide a benefit to some patients beyond that conferred by the 200 mg/day dose, 4) the
`footnote in the Adverse Event table clarifying the type ofDyskinesias that were seen, and
`5) the altered description of the case of asystole. As I described above, we have had
`numerous telephone negotiations over labeling with the sponsor. Given the rapidly
`approaching PDUFA due date, I do not believe that we have the time, at the divisional
`level, to fiirther negotiate the language in these sections.
`I recommend that the
`application be approved with the label as we have forwarded it, although, of course, we
`will be available for discussion of these points.
`
`/S/
`
` Russell Katz, M.D.
`
`Cc:
`
`NDA 20-717
`
`HFD-120
`
`HFD-120/Katz/Freiman/Fitzgerald/Atrakchi/Homanny
`HFD~1 70/Klein
`
`ADDENDUM
`
`(“‘ ,
`‘ “
`
`
`
`(
`
`I have discussed these issues with Dr. Temple, Director, ODE I (conversation of
`12/17/98). We agree that the paragraph on Abuse Potential in the Precautions
`Section maybe removed. The changes described in points 2-5 above will remain
`
`.
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`-.
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`as I have proposed, with a slight change in the Dosage and Administration, which
`will now state that there is no consistent evidence of increased benefit of the 400
`mg dose compared to the 200 mg dose, and will refer the reader to the Clinical
`Trials sub—section.
`
`/S/
`
`5/
`
`Russell Katz, MD.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
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`\
`
`December 16, 1998
`
`(yephaloni Inc_
`
`Paul Leber, MD
`Director, Division of Neurophannacological
`Drug Products (HFD-120)
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Woodmont 11 Building
`1451 Rockville Pike
`Rockville, MD 20857
`
`.
`CENTER FOR DRUG EVALUATION
`AND RESEARCH
`
`DEC 1 7 1998
`
`145 Brondywine Parkway
`West Chester, PA 193804245
`(610) 3440200
`Fax (610) 3440065
`
`RECEIVED HFD-120
`
`NDA NO. 20—717
`PROVIGILm (modafinil) Tablets
`
`Response to FDA Request
`
`Dear Dr. Leber:
`
`,‘
`( ‘
`
`Reference is made to our pending New Drug Application (NDA) No. 20—717, Provigil® (modafinil)
`Tablets, for the improvement of wakefulness in patients with excessive daytime sleepiness associated
`with narcolepsy, dated December 27, 1996 and our submission to the NDA of June 4, 1998
`containing dose finding results for the reproductive toxicology studies. Further reference is made to
`the December 15, 1998 request by Anna Marie Homonnay—Weikel, Project Manager, to provide
`written commitment, including timing of final reports, for the post-approval conduct of the TG.AC
`dermal transgenic mouse bioassay and development and reproductive toxicology studies in the rat for
`general reproductive performance/fertility and teratology.
`
`Cephalon, Inc. will conduct the_ for modafinil as requested in the December 31, 1997
` .
`approvable letter. Assuming approval of the protocol by the Carcinogenicity Assessment Committee
`(including doses and vehicle for the positive control) within the first quarter of 1999, Cephalon will
`initiate the trial in the second the quarter of 1999 and submit the final report to the Agency in the
`second quarter of 2000.
`
`initiate the rat general reproductive performance/fertility and teratology studies,
`Cephalon will
`conducted in compliance with GLP regulations, in the first quarter of 1999. Final reports will be
`submitted to FDA in the third quarter of 1999.
`
`‘
`
`“5"
`
`If you have any questions, please contact me at (610) 738—653 1.
`
`Sincerely,
`
`@7: 2%
`
`Kenneth L. White, PharmD.
`Vice President, Regulatory Affairs
`
`,» ’
`
`(
`
`,
`
`KLW/rp
`cc:
`
`Anna Marie Homonnay-Weikel
`
`jzwmismomnmmm
`
`
`
`

`

`October 30, 1998
`
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`
`
`Cephalon, Inc.
`
`‘
`
`Paul Leber, M.D.
`.
`.
`.
`.
`Director, Dmsron ofNeuropharmacological O R l G ‘ N A L
`Drug Products (HFD-IZO)
`Food and Dmg Administration
`Woodmont 11 Building
`1451 Rockville Pike
`Rockville, MD 20857
`
`v
`
`145 Brundywine Parkway
`west Chem, PA 193804245
`(610) 3440200
`Fox (610) 3440065
`
`Dear Dr. Leber:
`
`NBA 20-71‘7
`Provigil (modafinil) Tablets
`
`NEW CORRESP
`
`Reference is made to our pending New Drug Application (NDA) 20-717, Provigil®
`(modafinil) tablets, for the improvement ofwakefiilness in patients with excessive daytime
`sleepiness associated with narcolepsy, which was dated December 27, 1996.
`
`Further reference is made to the approvable letter dated December 29, 1997 and to our
`subsequent meeting on September 23, 1998 to discuss metabolic drug-drug interaction
`studies with modafinil.
`
`( ‘
`
`The purpose ofthis submission is to forward minutes of the September 23, 1998 meeting,
`along with two articles and a final study report requested by Dr. Yuan, “Evaluation of the
`Inhibition of Cytochrome P450 2C19 by Modafinil, Modafinil Sulfone and Modafinil Acid
`in Human Liver Microsomes.” A Table of Contents is attached for your reference.
`
`Ifyou have any questions regarding this information, please contact me at 610-738-6531.
`
`j/regafl71538/20717/1981030.doc
`
`Sincerely,
`( /g,,’.
`2WM
`Kenneth L. White, PharmD.
`Vice President
`Regulatory Affairs
`
`CENTER FOR DRUG EVALUATION
`AND RESEARCH
`
`NOV 02 1998
`
`(7
`RECEIVED HFD-12_O
`
`
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`FDA Meeting Report
`Modafinil
`Division ofNeuropharmacological Drug Products
`September 23, 1998
`
`The purpose ofthe September 23rd meeting was to discuss Cephalon’s plans for
`metabolic drug-drug interaction studies with modafinil. The meeting is a condition ofthe
`approvable letter ofDecember 30, 1997, for PROVIGIL®.
`
`m“
`
`In attendance:
`
`FDA
`
`Anna Marie Homonnay-Weikel
`Chandra Sahajwalla Pharmacokinetics
`Rae Yuan, Pharmacokinetics
`
`Cephalon
`James Cappola, Medical Affairs
`Richard Civil, Clinical Research
`George McCormick, Drug Safety and Disposition
`Philmore Robertson, Pharmacokinetics
`Kenneth L. White, Regulatory Affairs
`
`interactions ofmodafinil that had been obtained since the proposal was submitted
`(March, 1998). The items were:
`
`1) Anselmino et al. Effect ofModafinil, an Antinarcoleptic Drug, and its Metabolites on
`Human CYP 2C. Abstract and poster presented at the 12th International Symposium
`on Microsomes and Drug Oxidations, 1998
`2) Grozinger et a1. Interaction ofModafinil and Comipramine as Comedication in a
`Narcoleptic Patient. Clinical Neuropharmacology, vol. 21, no. 2, pp. 127 — 129,
`l 998.
`3) Report DM-98-009. Evaluation ofthe Inhibition ofCytochrome P450 2Cl9 by
`Modafinil, Modafinil Sulfone and Modafinil Acid in Human Liver Microsomes
`4) Report 01538a/112/PK/UK, “A Balanced Latin Square, Randomized, Crossover
`Study to Investigate the Single-Dose Pharmacokinetics ofModafinil 200 mg and
`Dexamphetanune 10 mg When Given Either Alone or in Combination in Healthy
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`supply a report as requested. As noted above, the results of the modafinil-
`dextroamphetamine interaction study had already been provided. We were also asked
`whether we planned other inhibition studies with the sulfone and answered that these
`studies were underway at the present time, but no results are yet available.
`In subsequent discussion, the following topics were addressed. They are organized by
`study, not by their chronological order in the discussion.
`
`In vitro interaction study - CYP2C19 inhibition
`
`Both modafinil and modafinil sulfone are planned for inclusion in the in vitro interaction
`study. At steady state for modafinil (400 rug/day) and modafinil sulfone, the total
`inhibition ofCYP2C19 at Tmax is estimated to be as much as 65% to 75% with the
`contribution of the sulfone estimated to be 10% to 15%.
`The selection of diazepam as a stande substrate for CYP2C19 was briefly discussed,
`with a question being raised as to the relationship ofthe concentration selected (10 11M)
`to the KM ofthe compound for CYP2C19. The KM is ca. 24 1.1M (Jung et al., 1997),
`compared to a KM of ca. 80 M for CYP3A4. Use of 10 M should provide sufficient
`analytical sensitivity while ensuring that we are targeting primarily the CYP2C19-derived
`metabolism. FDA asked about the concentrations of modafinil to be used. Proposed
`concentrations were given as 10, 30, 100 and 300 pM, which were acceptable.
`In response to questions, Dr. Robertson reviewed the metabolic pathways of
`clomipramine and fluoxetine. CYP2D6 is responsible for important metabolic pathways
`for both ofthese compounds (as it is for most tricyclic antidepressants and selective
`serotonin reuptake inhibitors), with CYP2C19 generally having a rather smaller role.
`However, in CYP2D6 poor-metabolizers, CYP2C19-dependent pathways can take on
`greater prominence. The primary goal ofthe inclusion of clomipramine, des-
`methylclomipramine and fluoxetine in this study is to determine the relative contributions
`of CYP2C19 in their metabolism by using liver microsomes from CYP2D6-deficient, -
`normal and -super-metabolizer subgroups. This is particularly important given the lack
`of agreement in reports in the literature regarding the contributions of CYP2C19 to the
`metabolism of these compounds.
`
`The information derived from the in vitro study can then be used to enable a decision as
`to whether additional clinical study is warranted.
`
`Clinical interaction studies - CYP enzyme induction/suppression
`In response to a request from the reviewers, Dr. Robertson presented an overview ofthe
`results from the in vitro induction study (human hepatocytes) recently completed at
`
`XenoTech. Most ofthe information presented had bee '
`with the proposal, but
`
`some elements had been only recently received from
`‘ orrnation,
` .
`
`primarily the pictures 0
`erived from
`was
` .
` .
` .
`esults demonstrated that the concentrations ofthe
`presented. Th
`an
`CYP3A4, CYP
`2B6 enzymes were increased in the microsomes from the
`modafinil-treated he
`'
`me induction, not just enzyme activation had
` .
`
`occurred. Themsults forCYP2C9were equivocal. Dr. Yuan
`asked if CYP3
`was r
`it
`y the sulfone. Dr. Robertson answered that, given the
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`poor inhibition ofCYP3A4 by parent modafinil (Ki z 632 uM) and the greater polarity of
`the sulfone metabolite, it would not be expected that modafinil sulfone would be an
`inhibitor of CYP3A4.
`
`Because ofthe relatively small number of important pharmaceutical products that have
`CYP1A2 or CYP2B6 as primary metabolic pathways, Cephalon proposed that it would
`be unnecessary to conduct clinical drug-drug interaction trial testing those pathways.
`From the discussions that ensued, it is our beliefthat the proposal was accepted.
`Dr. Yuan asked whether CYP2B6 constitutes a primary metabolic pathway for
`ketoconazole. Dr. Robertson answered that he thought not, but would check.
`Subsequently Dr. Robertson has been able to ascertain that ketoconazole is not only a
`potent inhibitor of CYP3A4/5, but is also a substrate primarily for those enzymes
`(Spatzenegger and Jaeger, 1995). Consistent with that conclusion, concurrent
`administration ofketoconazole with rifampin, a potent CYP3A4 inducer, caused marked
`reduction in serum ketoconazole levels (McEvoy (ed.), 1998). Hence, the contribution, if
`any, ofCYP2B6 to the metabolism ofketoconazole would not appear to be a major one.
`
`‘
`
`“‘“’
`
`CYP3A4 Study - The basic design ofthe study was accepted, and the difficulty inherent
`in performance ofsuch a study acknowledged. Our rationale (as summarized in the
`written proposal) for the length ofthe dosing period with modafinil was briefly presented
`and accepted as reasonable.
`
`Given the high inter- and intraindividual variability expected for ethinylestradiol, Dr.
`Yuan suggested that a second, less variable marker substrate (e.g., triazolam or
`midazolam) also be included. Even taking into account the potential effects ofthe
`steroidal contraceptive on the pharmacokinetics ofthese compounds, use ofone ofthem
`would seem likely to give a less equivocal result than would the steroidal contraceptives.
`We agreed and said that we would try to work such a second marker substrate into the
`protocol.
`
`CYP2C9 - The rationale for the study was briefly discussed and accepted as reasonable.
`The rationale centers on the fact that there was a decrease in CYP2C9 activity when
`human hepatocytes were cultured in the presence of high concentrations of modafinil. It
`is not known whether this rather unusual finding will correlate with any findings in viva;
`however, due to the low therapeutic index for warfarin, a study was considered to be
`warranted.
`
`The timecourse ofthe suppression effect, ifit occurs in vivo, is not known, and FDA
`commented that time could then be a problem with this study. Dr. Robertson replied that
`we recognize this fact and, by analogy to the induction study, have proposed a relatively
`long period oftreatment with modafinil in order to ensure that we have optimized the
`probability that we can detect even a relatively small change in CYP2C9 activity.
`Many ofthe points raised in the context ofthe discussion ofthe CYP3A4 study were, of
`course, directly applicable also to the CYP2C9 study. However, as noted above, there is
`no information available regarding CYP suppression by modafinil in viva.
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`The FDA reviewers also pointed out that with multiple pathway for metabolism available
`in the cytochrome system, we should emphasize proper dose to prevent escape
`metabolism from masking inhibition ofa particular pathway. Dr. Robertson replied that,
`due to the fact that this study will be in normal subjects, we will have to keep the dose of
`Coumadin® low. However, given the selectivity of CYP2C9 for (S)-warfarin and given
`our intention to use a stereoselective assay to monitor the reaction, the study should
`provide a definitive result.
`.fl
`
`The Reviewers present accepted the plans proposed for drug interaction studies and the
`basic design of the trials.
`
`Cephalon was requested to submit the new data presented during the meeting. Abstracts
`and articles presented will be attached to the minutes ofthe meeting and submitted to
`FDA The results ofthe study of modafinil sulfone inhibition of CYP2C19 will be
`submitted to FDA in October.
`
`Cephalon was asked for the timelines for initiation and completion ofthe proposed
`studies.
`
`1.
`
`In vitro study in human hepatocytes is scheduled to be initiated in December and
`completed 6 months later
`2. The ethinylestradiol study is scheduled to be completed no earlier than 3rd Quarter of
`1999. A draft protocol should be available in November.
`3. The study of warfarin is scheduled to be completed by 2ud Quarter of 1999. A draft
`protocol should be available in November.
`
`J/regafl7cep15381nda207l7/fdameetingxepm4
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`MEMORANDUM OF TELECON
`
`DATE: 12/18/98
`
`NDA: 20-717
`
`N‘DRUG: PROVIGIL (modafinil) Tablets
`
`BETWEEN:
`
`Bantam
`
`‘
`
`Ken White
`
`Earl Henry
`Man Miller
`
`Rich Civil
`
`Pliji Robertson
`Nancy Kribbs
`George McCormick
`Wayne Schuck
`Paul Kirsch
`
`AND:
`
`we
`Rusty Katz, M.D.
`Joel Freiman, MD.
`Anna M. Homonnay-Weikel, R.Ph.
`
`SUBJECT: Inform Cephalon of DNDP’s final decisions on the aspects of the proposed
`labeling that were subject to recent discussions between Cephalon, Inc. and DNDP.
`
`DISCUSSION:
`
`.
`
`.
`
`-
`
`-
`
`The 'Abuse Potential’ subsection will be deleted from the ‘Precautions'
`section.
`
`The Division decided not to include information about the single dose study
`in normals in the ‘Abuse Potential’ section.
`
`r
`
`The ‘Dosage and Administration’ section will remain the same as the
`12/29/97 approvable labeling except for new inclusions concerning dosing
`in certain patient populations.
`
`The comparisons in the ‘Carcinogenicity’ and ‘Fertility’ sections will be
`based on the 200 mg dose versus the 400 mg dose.
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`Cephalon, Inc. seemed agreeable to these final decisions regarding the
`proposed labeling.
`
`/S/
`
`
`
`omonnay-Weik l, R.Ph.
`.
`Project Manager
`
`CCZ
`
`Orig IND
`Div File
`
`HFD-120/Katz/Freiman
`HFD-120/Homonnay
`
`APPEARS THIS WAY ON ORIGINAL
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`