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`CONCLUSIONS.
`
`Modafinil, 2-[ldiphenyl, ethyl)sulfinyll-acetamide, is pharmacologically related to the stimulants
`d-amphetamine, methylphenidate, and cocaine. In vivo studies have demonstrated that
`Modafinil increases locomotor,activity and promotes wakefulness. Like other CNS stimulants,
`in vitro studies have revealed that modafinil has some binding affinity for the dopamine uptake
`sites. Modafinil's affinity for the uptake site was approximately five-fold lower than cocaine‘s
`affinity and 16-fold lower than d-amphetamine.
`-
`
`Evaluation of modafinil’s dependence in a preclinical self-administration study and clinical study
`has suggested that its dependence capacity is equivalent to that of CNS stimulants. Results
`from the self-administration study showed that modafinil possesses reinforcing properties li.e.,
`functions as a positive reinforcer) in primates. Modafinil maintained self~administration behavior
`in primates trained to self-administer cocaine.
`in the preclinical
`animal model
`(drug
`discrimination study) for evaluating a drug' subjective effects, modafinil elicited partial
`
`Human abuse liability evaluation indicated that modafinil may possess stimulant-like
`dependence producing properties. Modafinil was shown to have stimulant-like pharmacological
`
`
`
` .
`
` .
`
` .
`
`2. CLINICAL PHARMACOLOGiI'
` .
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`IPage 1, Consider addin
` .
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`h
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` .
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`3.
`
`It is as
`Information summarized under Clinical Pharmacology is not the most relevant.
`important to add information from the self-administration and drug discrimination studies
`as well. See scheduling document.
`
`More than pk differences (Females > > >Males).
`4. AGE/GENDER DIFFERENCES:
`Metabolism in females is evidently less than in males.
`
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`CONCLUSIONS.
`
`Modafinil, 2-[ldiphenyl, ethyl)sulfinyll-acetamide, is pharmacologically related to the stimulants
`d-amphetamine, methylphenidate, and cocaine. In vivo studies have demonstrated that
`Modafinil increases locomotor,activity and promotes wakefulness. Like other CNS stimulants,
`in vitro studies have revealed that modafinil has some binding affinity for the dopamine uptake
`sites. Modafinil's affinity for the uptake site was approximately five-fold lower than cocaine‘s
`affinity and 16-fold lower than d-amphetamine.
`-
`
`Evaluation of modafinil’s dependence in a preclinical self-administration study and clinical study
`has suggested that its dependence capacity is equivalent to that of CNS stimulants. Results
`from the self-administration study showed that modafinil possesses reinforcing properties li.e.,
`functions as a positive reinforcer) in primates. Modafinil maintained self~administration behavior
`in primates trained to self-administer cocaine.
`in the preclinical
`animal model
`(drug
`discrimination study) for evaluating a drug' subjective effects, modafinil elicited partial
`
`Human abuse liability evaluation indicated that modafinil may possess stimulant-like
`dependence producing properties. Modafinil was shown to have stimulant-like pharmacological
`
`
`
` .
`
` .
`
` .
`
`2. CLINICAL PHARMACOLOGiI'
` .
`
`IPage 1, Consider addin
` .
`
`h
`
` .
`
`3.
`
`It is as
`Information summarized under Clinical Pharmacology is not the most relevant.
`important to add information from the self-administration and drug discrimination studies
`as well. See scheduling document.
`
`More than pk differences (Females > > >Males).
`4. AGE/GENDER DIFFERENCES:
`Metabolism in females is evidently less than in males.
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`5. ADVERSE REACTIONS:
`
`follows:
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`DRUG ABUSE AND DEPENDENCE
`
`Controlled Substance Class
`
` .
`
`Abuse Potential and Dependence
`
`45
`
`
`
` .
`
`
`
`7. Recommend deletion of Withdrawal section (Page 22). because subjects were on
`concomitant medications during withdrawal of modafinil.
`
`8. Recommend deletion of Clinical Dependence section (Page 21), because the U.S. study
`(Jasinski, FSK Med Ctr., Johns Hopkins) demonstrated that modafinil at above therapeutic
`doses was recognized as amphetamine-like, was ”liked”, produced euphoria in post addict
`volunteers in a single dose study. Study was placebo controlled, and used methylphenidate
`as positive control. A significant gender difference was observed in which the stimulant-
`like response in females was more intense than observed in males.
`
`9. Under OVERDOSAGE section (Page 22). should state that modafinil and modafinil acid
`exhibited linear 'pharmacoklnetics over a dose range of 40-499 mg. Also, females (35%)
`appeared to excrete less modafinil acid in urine than males (51%).
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`/S/
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`/S/
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`(,
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`_
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`Igor Cerny, Pharm.D.
`
` .
`
`IZ ag/$7
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`pg?»
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`Brand Name:
`
`Provigil
`
`Generic Name:
`
`Modafinil
`
`Sponsor:
`
`Cephalon
`
`Indication:
`
`Narcolepsy
`
`NDA Number:
`
`20-217
`
`Original Receipt Date:
`
`6/30/98
`
`Clinical Reviewer:
`
`Joel Freiman, MD
`
`'
`
`Review Completed:
`
`12/15/98
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`BACKGROUND
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`NDA 20-717 was submitted by Cephalon, Inc. on 12/30/96, for the use of modafinil as a
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`treatment for patients with excessive daytime sleepiness associated with narcolepsy. An
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`approvable letter was issued on 12/29/97 requesting additional clarification of labeling, safety,
`
`and other issues. The sponsor resubmitted NDA-717 on 6/30/98 with responses to most of the
`issues in the12/2‘§/97 approvable letter. This review will address only the sponsor’s response
`
`to the safety issues raised in the 12/29/97 approvable letter. A separate clinical review will
`
`address the sponsor’s update ofthe integrated summary ofsafety.
`
`desire to suggest a maximal daily dose of 400 mg/day even though the data from two
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`efiectiveness trials do not demonstrate any consistent,
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`increased benefit of 400 mg/day
`
`compared to 200 mg/day.
`
`In addition, the sponsor did not submit sufficiently detailed data
`
`regarding the long-term exposure to 400 mg/day given as a single daily dose to permit a
`statementin labeling about the long term safety of this dose.
`
`For the purpose of this review the specific safety issue question as stated in the 12/29/97
`
`approvable letter will be followed by this reviewer’s summary of the sponsor’s response then
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`followed by the reviewer’s comments to the sponsors response.
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`SAFETY ISSUES
`
`2
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`1. You state that you cannot be certain that the numbers of patients in the
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`dose/duration cells in your tables of foreign data represent separate discrete
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`individuals, raising the question of the accuracy of your statements that 2305
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`subjects have been exposed to modafmil.
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`Before we can approve your application, we must have as complete and accurate an
`
`accounting of} subjects/patients exposed to modafinil as possible, with accurate
`1
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`corresponding dose/duration data for this cohort. Your re-submission should address
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`this issue clearly and completely. Our stafi' will be happy to discuss with you the way in
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`which this data should be submitted.
`
`SUMMARY OF SPONSORS RESPONSE
`
`SOURCE: VOL. 1 OF 67 ATTACHMENT 2
`
`NON-CEPHALON SPONSORED STUDIES
`
`METHODS
`
`The sponsor re-evaluated all non-Cephalon case report forms (CRFs) to identify the
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`number of unique patients exposed to modafinil worldwide among the 81 non—Cephalon-
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`sponsored foreign studies with CRFS.
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`Among the non-Cephalon-sponsored studies there was no miform subject identification
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`system across studies. To determine the number of 1mique, identifiable subjects among
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`METHODS
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`The sponsor did not have to make any assumptions to calculate the number of unique
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`exposures in the Cephalon sponsored-studies.
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`RESULTS
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`The sponsor; identified 760 unique modafinil-exposed subjects. Among the 760 unique
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`I
`
`subjects, 600 subjects were fi'om the blinded studies and fi'om open label studies. An
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`additional 160 subjects, initially in the placebo group ofthe double blind studies subsequently
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`were exposed to modafinil in the open-label extensions.
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`DOSING INFORMATION (CEPHALON-SPONSORED AND NON-CEPHALON-SPONSORED STUDIES)
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`. For each unique modafinil exposed subject who participated in a foreign (non-Cephalon—
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`sponsored trial), his or her exposures were condensed into one composite exposm'e, with a
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`duration equal to the sum ofthe individual exposures. Average daily dose was calculated over
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`made among exposures classified as either “clusters” or “linkers”, these exposures are not
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`included in Table 1.
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`SPONSORS CONCLUSIONS
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`,t
`COMMENTS
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`The sponsor has conducted a reasonable re-evaluation ofthe non-Cephalon-
`
`sponsored and Cephalon-sponsored studies to identify the number ofunique subject
`
`exposures to modafinil worldwide. The total number of unique exposures (2265) is
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`similar to the number (2305) cited in the original NDA.
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`other at 400 mg/day, thus this subject would be classified with an average daily dose of
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`300 mg/day).
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`( V
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`With respect to the evaluation of safety to long term modafinil exposure it must
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`be kept in mind that subjects participating in more than one trial may not have had
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`continuous exposure.
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`From the sponsor’s Table 1, among participants in the Cephalon sponsored studies
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`with an average tlaily dose of 375-424 mg/day, 31 subjects had duration of exposure of 180-
`l
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`364 days and 12 subjects had duration of exposure greater than or equal to 365 days. No
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`subjects had exposure too greater than 425 mg/day ofmodafinil for greater than 28 days.
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`From the sponsor’s Table 1, among participants in the foreign non-Cephalon
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`sponsored studies with a average daily dose of 375-424 mg/day, 47 subjects had a duration of
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`exposure of 180-364 days and 86 subjects had a duration of exposure greater than or equal to
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`365 days. Among subjects with an average daily dose greater than or equal to 425 mg/day, 4
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`subjects had duration of exposure of 180-364 days and 42 subjects had duration of exposure
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`greater than or equal to 365 days.
`
`_’ ‘
`
`Overall exposure to an average daily dose of modafinil greater than or equal to 375
`
`mg/day is limited.
`
`2. Please clearly present accurate duration (and corresponding safety experience) data
`
`for subjects who have received single daily doses of 400 mg or greater; this information
`
`is currently unobtainable from your submission. In addition, please present duration
`
`- _
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`and corresponding safety data separately for subjects who have received daily doses of
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`400 mg or greater as twice a day dosing; there may be some overlap in these 2 cohorts
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`(single daily dose and twice a day dosing).
`
`SUMMARY OF SPONSORS RESPONSE
`
`SOURCE: VOLUME 1 OF 67 ATTACHMENT 3A
`
`l1 M
`
`ETHODS
`
`The sponsor utilized databases from both Cephalon-sponsored (through a data cutoff of
`
`June 2, 1997) and non-Cephalon-sponsored clinical studies for which Cephalon had access to
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`the study data. The sponsor sub-snatified the safety data for modafinil exposed subjects with
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`greater than or equal to 400 mg/day into subjects with exposure to 400 mg/day and subjects
`
`with exposure to greater than 400 mg/day. The sponsor’s rationale for this sub-stratification
`
`relates to the fact that the highest proposed dose in the draft labeling is 400 mg/day and
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`therefore this dose should be the primary focusofthe analysis.
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`The method for computing dose and duration varied by whether or not the study was
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`conducted by the sponsor
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`collected. Only adverse experiences that occurred on a study day in which the dose was at
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`least 400 mg/day are included. Adverse experiences are categorized by onset on study days for
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`which the total daily dose was 400 mg and on study days for which total daily dose was
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`greater than 400 mg.
`
`Among the 81 non-Cephalon-sponsored studies with CRFs, only five studies had
`information linking dosage and study day. Only two of these 5 studies (studies 1424 and
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`1513) had any modafinil dosing with greater than or equal to 400 mg /day and are therefore
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`included in this analysis of safety data Categorization of exposure and adverse experience
`
`was handled in the same manner as for the Cephalon—sponsored studies.
`
`Among the remaining 76 non-Cephalon-sponsored studies with CRFs, 24 had any dosing
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`with total daily modafinil doses of at least 400 mg/day. Start and stop dates for study drug,
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`dosing and date of adverse experience were not known. Since dose could not be linked to
`
`study day in these 24 studies the following methods were followed to determine dosing days
`
`greater than or equal to 400 mg/day of modafiful:
`
`NON-CEPHALON-SPONSORED STUDIES WITH FIXED DAILY DOSAGES
`
`0 Duration of exposure was ascertained from the CRF
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`o Dosage the subject was supposed to have received was determined fi'om the protocol
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`instrucu'ons
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`9
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`Subjects were characterized to total days ofexposure to either 400 mg/day ofgreater than
`400 mg/day.
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`Adverse experiences occurring at any time during the study are included in the analysis
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`NON-CEPHALON-STUDIES wrm VARIABLE DAILY DOSAGES
`
`mg/day were further analyzed.
`
`Subjects were categorized into those with modal total daily doses of400 mg/day and those
`
`with modal total daily dose greater than 400 mg/day.
`
`Adverse experience data was categorized by dose (400 mg/day and greater than 400
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`mg/day) and dosing frequency (once daily and twice daily doses). The sponsor included a
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`third category; a heterogeneous group of non-Cephalon-sponsored studies with variable
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`>364
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`93‘”) _
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`698 subjects received doses of 400 mg/day and 146 received doses of greater than 400
`
`mg/day. Among subjects exposed to 400 mg/day, 326 subjects were dosed for more than 90
`
`
`
`
`
`days, 275 subjects for at least 180 days, and 93 subjects for at least 365 days. Nearly all
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`exposure at greater than or equal to 400/mgday for more than 90 days is from Cephalon-
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`sponsored Phase 3 studies 301 and 302 (314 subjects). Among subjects treated with greater
`than 400 mg/dayj only 9 subjects were dosed more than 14 days. Total exposure to once daily
`
`dosing was much greater than total exposure to twice daily dosing (127 subjects). The total
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`number of subjects participating in studies with twice daily dosing was obtained by adding
`
`together the numbers of patients exposed to twice daily dosing (V01. 1, Tables 3.2b and 3.3b,
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`p. 87 and 89).
`
`’1"\
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`SINGLE DAILY DOSE AT FIXED DOSAGE
`
`Cephalon-Sponsored Clinical Pharmacology Studies (excluding study 201 AB) sponsor’s
`
`Table 2.
`
`In the Cephalon-sponsored clinical pharmacology studies, a total of 34 subjects received
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`modafinil doses of 400 mg/day and 36 subjects received modafinil doses of >400 mg/day.
`
`Many adverse experiences,
`
`including headache, asthenia, nausea, anorexia,
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`insomnia,
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`nervousness, and abnormal thinking were more frequent at >400 mg/day than at 400 mg/day.
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`Only euphoria was noticeably more frequent at 400 mg/day than at >400 trig/day.
`
`Cephalon-Sponsored Clinical Pharmacology Study 201 AB sponsor’s Tables 3A and 3B
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`
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`In the only single (once) daily dose non-Cephalon—sponsored study with known start and
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`stop dates for study drug and adverse experiences a total of 12 subjects received modafinil at
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`400 mg/day for 1-2 days. Two subjects (17%) experienced headache.
`
`Non-Cephalon-Sponsored Studies With Unknown Start and Stop Dates for Study Drug
`
`and Adverse Experiences (one study, short duration) sponsor’s Table 4.
`1
`
`.s
`In this single (once) daily dose non-Cephalon-sponsored study with unknown start and
`
`stop dates for study drug and adverse experiences, 30 subjects received 400 mg/day and no
`
`subjects received > 400 mg. This was a short-term study (no more than 2 days exposure) and
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`the most common adverse experience was headache (23%).
`
`SINGLE DAILY DOSE AT VARIABLE DAILY DOSES
`
`Cephalon-Sponsored Phase 3 Studies; Open-Label Phases sponsor’s Table 5
`
`In the Cephalon—sponsored open-label studies a total of 405 subjects received doses of
`modafinil of 400 mg/day and only 15 subjeéts received at least one daily dose of
`
`modafinil > 400 mg/day. No subject received modafinil > 400 mg/day for more than 13
`
`days. The most common adverse experience at 400 mg/day was headache (46%). The
`
`next most common adverse experiences (with frequencies > 10%) were infection (31%),
`
`rhintis (17%), pain (16%), dyspepsia (15%), flu syndrome (14%), tooth disorder (13%),
`
`accidental injury (12%), back pain (11%), and sinusitis (11%).
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`TWICE DAILY DOSE AT FIXED DAILY DOSAGES
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`Non-Cephalon—Sponsored Study With Known Start and Stop Dates for Study Drug and
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`Adverse Experiences (protocol 1424) sponsor’s Table 6.
`
`In the only twice daily dosing non Cephalon-sponsored study with known start and stop
`
`dates for study drug and adverse experiences, 8 subjects received modafinil 400 mg and 22
`received modafihil > 400 mg. The most common adverse experience with 400 mg/day dosing
`
`was the adverse reaction term CNS stimulation (88%). Headache was the second most
`
`common adverse experience (63%). At > 400 mg/day, headache and the adverse reaction term
`
`personality disorders were the most common adverse experiences, with fi‘equencies of 59%
`
`and 50%, respectively. In this study, the number of adverse experiences that were more
`
`common with 400 mg/day of modafinil was nearly equal
`
`to the number of adverse
`
`experiences that were more frequent at > 400 mg/day.
`
`Non-Cephalon-Sponsored Studies With Unknown Start and Stop Dates for Study Drug
`I
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`and Adverse Experiences sponsor’s Table 7.
`
`V;
`
`In the twice daily dose non-Cephalon—sponsored studies with unknown start and stop dates
`
`for study drug and adverse experiences, 80 subjects received modafinil 400 mg/day and 17
`
`subjects received modafinil > 400 mg/day. No subject received >400 mg/day for more than
`
`seven days. For all the adverse experiences in this table, the fiequency of the adverse
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`experience was higher with > 400 mg/day. Unlike other studies, the fiequency of headache at
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`400 mg/day was very low, 3%.
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`Non-Cephalon-Sponsored Studies with Unknown Start and Stop Dates for Study Drug
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`In the multiple daily dose non-Cephalon-sponsored studies with unknown start and stop
`
`dates for study drug and adverse experiences, 42 subjects received modafinil 400 mg/day and
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`28 received modafinil > 400 mg/day. The most common adverse experience in the 400
`
`mg/day and > 400 mg/day group was insomnia with a frequency of 21% and 62%,
`
`respectively. The majority of adverse experiences were more fi'equent at > 400 mg/day of
`
`modafinil than at 400 mg/day.
`
`SPONSOR’S CONCLUSIONS
`
`Treatment with total modafinil doses of 400 mg/day was well tolerated in all categories of
`
`studies. Further evidence that 400 mg/day is well tolerated is provided by the fact that of 302
`
`subjects who received modafinil 400 mg/dayzzt‘or more than 90 days in the open-label phases
`
`of study 301 and 302, the rate of discontinuation for adverse experiences was 3%, while
`
`overall discontinuation rate for all subjects in the open-label phases Ofthese studies was 10%.
`
`and Adverse Experiences, sponsors Table 8.
`
` MULTIPLE (VARIABLE) DOSE ADMINISTRATION LEVELS
`
`Almost all of the modafinil dosing at a dosage of 400 mg/day in studies other than studies
`
`301 and 302 (including their open-label phases) was short-term.
`
`In studies with short-term modafinil dosing (<90 days) at dosages >400 mg/day, the types
`
`of adverse experiences that were most commonly observed were generally similar across
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`
`
`17
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`TWICE DAILY DOSE AT FIXED DAILY DOSAGES
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`Non-Cephalon-Sponsored Study With Known Start and Stop Dates for Study Drug and
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`Adverse Experiences (protocol 1424) sponsor’s Table 6.
`
`In the only twice daily dosing non Cephalon-sponsored study with known start and stop
`
`dates for study drug and adverse experiences, 8 subjects received modafinil 400 mg and 22
`received modafibil > 400 mg. The most common adverse experience with 400 mg/day dosing
`
`was the adverse reaction term CNS stimulation (88%). Headache was the second most
`
`common adverse experience (63%). At > 400 mg/day, headache and the adverse reaction term
`
`personality disorders were the most common adverse experiences, with frequencies of 59%
`
`and 50%, respectively. In this study, the number of adverse experiences that were more
`
`common with 400 mg/day of modafinil was nearly equal
`
`to the number of adverse
`
`experiences that were more fi'equent at > 400 mg/day.
`
`Non-Cephalon-Sponsored Studies With Unknown Start and Stop Dates for Study Drug
`l
`
`and Adverse Experiences sponsor’s Table 7.
`
`'1
`
`In the twice daily dose non—Cephalon-sponsored studies with unknown start and stop dates
`
`for study drug and adverse experiences, 80 subjects received modafinil 400 mg/day and 17
`
`subjects received modafinil > 400 mg/day. No subject received >400 mg/day for more than
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`seven days. For all the adverse experiences in this table, the frequency of the adverse
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`experience was higher with > 400 mg/day. Unlike other studies, the frequency of headache at
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`400 mg/day was very low, 3%.
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`MULTIPLE (VARIABLE) Dose ADMINISTRATION LEVELS
`
`Non-Cephalon-Sponsored Studies with Unknown Start and Stop Dates for Study Drug
`
`and Adverse Experiences, sponsors Table 8.
`
`In the multiple daily dose non-Cephalon-sponsored studies with unknown start and stop
`
`dates for study drug and adverse experiences, 42 subjects received modafinil 400 mg/day and
`
`28 received modafinil > 400 mg/day. The most common adverse experience in the 400
`
`mg/day and > 400 mg/day group was insomnia with a frequency of 21% and 62%,
`
`respectively. The majority of adverse experiences were more frequent at > 400 mg/day of
`
`modafinil than at 400 mg/day.
`
`SPONSOR’S CONCLUSIONS
`
`Treatment with total modafinil doses of 400 mg/day was well tolerated in all categories of
`
`studies. Further evidence that 400 mg/day is well tolerated is provided by the fact that of 302
`
`subjects who received modafinil 400 mydayiifor more than 90 days in the open-label phases
`
`of study 301 and 302, the rate of discontinuation for adverse experiences was 3%, while
`
`overall discontinuation rate for all subjects in the open-label phases ofthese studies was 10%.
`
`~ r
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`Almost all of the modafinil dosing at a dosage of 400 mg/day in studies other than studies
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`301 and 302 (including their open-label phases) was short-term.
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`In studies with short-term modafinil dosing (<90 days) at dosages >400 mgday, the types
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`of adverse experiences that were most commonly observed were generally similar across
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`study categories and desing fi'equency. Mth confinued (long-term) treatment, the new
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`adverse experiences seen were to a large extent those of daily life.
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`Adverse experience fi'equencies observed with total daily modafinil doses of >400 mg/day
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`were generally greater than those seen with 400 mg/day and were usually ofthe same type.
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`The subject exposure to 400 mg/day of modafinil was much greater than the exposure to
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`>400 mg/day. This was true both for the number of subjects exposed (698 at 400 mg/day and
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`146 at >400 mg/day) and also the duration of exposure (409 subjects at 400 mg/day for more
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`than 28 days vs. 4 subjects at >400 mg/day for more than 28 days).
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`The total exposure to once daily modafinil closing at dosages greater than or equal to 400
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`mg/day was much greater than exposure to subjects to twice daily dosing. No valid
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`comparison could be made of the adverse experience profiles of once daily vs. twice daily
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`dosing for atleast two reasons. All the dosing in US. studies was once daily, while most
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`European studies were twice daily and therefore confounded by cultural differences in adverse
`experience reporting, Secondly, the adverse experience fi‘equencies were too variable within
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`both the once daily and twice dosing categories to allow meaningful comparisons between
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`them.
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`REVIEWER’S COMMENTS
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`In general the quality and completeness of data from non-Cephalon-sponsored studies
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`(foreign) used by the sponsor in this submission are inferior to that of the Cephalon sponsored
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`studies (U.S.). Limitations in the comparison of Cephalon-sponsored versus non-sponsored
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`studies may be more due to differences in data collection and quality rather than cultural
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`differences in adverse experience reporting as the sponsor suggests.
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`Nearly all the long term safety data is fi'om the open-label phases of studies 301 and 302
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`which were conducted with a once daily dosing schedule. The overall number of subjects
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`exposedtomodafinilatdosesgreaterthanorequalto400mgadayforgreaterthan 1 yearis
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`93. There is limited data on subjects exposed to twice daily dosing (127 subjects, only 8 of
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`whom completed more than 28 days oftreatment).
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`For the non-Cephalon-sponsored studies in which subject eligibility for analysis was
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`determined by the subject’s modal dose of modafinil over the course of the study, the potential
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`exists for including adverse experiences with onset at times for which the total daily modafinil
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`dose was less than 400 mg/day. The sponsor considers inclusion of all adverse experiences for
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`subjects in such studies to be a conservau've approach to data analysis. While to some extent
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`this assumption is reasonable, the inclusion of events at all dose levels blurs any qualitative or
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`quantitative differences among specific dose levels.
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`The sponsor states that long term safety is further evidenced by the fact that the
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`discontinuation rate due to adverse experiences was only 3% in subjects exposed to 400
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`mg/day for more than 90 days verses a 10% discontinuation rate for all subjects in the open-
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`label phase of studies 301 and 302. While reassuring, a declining discontinuation rate due to
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`adverse experiences as the study progresses might normally be expected. Discontinuation of
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`subjects early in the course of a study due to adverse experiences pre-selects for a more
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`medication tolerant cohort which is then able to progress further on in the study and may be
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`able to tolerate higher doses ofthe study drug.
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`Overall there is a limited degree ofexperience with modafinil exposure at greater than or
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`equal to 400 mg/day for more than 90 days (326 subjects 314 of which are from the open-label
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`phases of studies 301 and 302) and at greater than 364 days (93 subjects). The sponsor has not
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`specifically stratified adverse experiences by duration of therapy, nor has the sponsor
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`categorized reports by level of seriousness. The majority of the long-term experience is
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`derived from the open-label phases of studies 301 and 302. A more detailed review of these
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`studies will be accomplished in the review ofthe updated integrated summary of safety.
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`3. Please submit available laboratory data for the foreign studies. Describe in detail
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`how often laboratory measurements were assessed in the various foreign cohorts.
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`SUMMARY OF SPONSORS RESPONSE
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`SOURCE VOL. 3 OF 67,
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`_,
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`METHODS
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`All non-Cephalon-sponsored clinical study reports, data summaries, subject listings,
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`available databases, and all case report forms, were reviewed to determine the studies in which
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`laboratory data had been collected. Laboratory data fiom 25 studies sponsored by_
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`-were identified Five of these studies only had laboratory data collected at baseline.
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`Only those 20 studies containing laboratory data for on- or post-treatment assessments are
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`included by the sponsor in this review.
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`The analysis of clinical laboratory tests was preformed by study. The integrated
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`analyses focuses on clinically significant abnormalities only. The criteria for the clinically
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`significant
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`abnormalities
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`is based on the
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`cut points
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`from FDA Division of
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`Neuropharmacological Drug Products and modified by Cephalon (V01. 3, Appendix 2.0, p.
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`62). Patients with clinically significant laboratory values on modafinil treatment that were also
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`present before modafinil
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`treatment are not discussed in the narrative section for each
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`individual study.
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`The sponsor performed 100% quality control checks on all data entered into the
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`laboratory database. Those errors identified were corrected.
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`RESULTS
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`A total of 686 subjects are summarized, 525 with modafinil treatment and 161
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`placebo-treated subjects. There were 452 male and 230 female patients ranging in age from
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`12-90 years.
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`‘
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`' t
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`The most fi'equently occurring clinically significant abnormal laboratory values for all
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`.
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`assessments were hematocrit (149 values), hemoglobin (87 values), red blood cells (76
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`values), lymphocytes (42 values), bicarbonate (36 values), glucose (34 values), WBC (34
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`values), and BUN (32 values). All other clinically significant abnormal values had a fi-equency
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`of less than 25.
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`SPONSORS CONCLUSIONS
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`Review of all
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`laboratory data from non-Cephalon-sponsored studies revealed no
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`clinically meaningful average laboratory values or trends in the occurrence of abnormal
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`laboratory values.
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`COMMENTS
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`‘i‘
`At the request of the FDA the sponsor provided additional information on patients
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`with clinically significant elevations of liver enzymes (total bilirubin, GGT, alkaline
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`phosphatase, ALT and AST). This information is provided in a Response to FDA Request for
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`Information Dated December 14, 1988.
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`A total of 27 patients participating in 10 studies conducted by Laboratoire L. Lafon
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`experienced a clinically significant liver enzyme elevation either pre-treatment, on placebo or
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`while receiving modafanil. Among these 27 patients only 10 had documented clinically
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`significant liver enzyme elevations either priorto and during modafanil treatment (Attachment
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`2).
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`Four patients had clinically significant elevations prior to modafanil treatment. Two of these 4
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`patients with clinically significant elevations were enrolled in study MOD-021, a PK study in
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`patients with severe chronic hepatic insufliciency. There did not appear to be any consistent
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`treatment related trends among these patients.
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`(
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`Six patients developed new onset clinically significant liver enzyme elevations. In
`three patients the liver enzyme was elevated prior to treatment. In four patients enzyme
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`elevations appeared to be resolving at endpoint.
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`The abnormalities of hematocrit, hemoglobin and RBC are co-related and of uncertain
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`significance as are several instances of low lymphocyte values. The sponsor appears to have
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`made a reasonable efiort to abstract and present the available laboratory data from the non-
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`Cephalon—sponsored studies. No clinical concern is raised from the available data.
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`/S/
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`
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`Joel Freiman, M.D
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`R.Katz
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`RFD-120
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`NDA, 20-217
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`HFD-120, Freiman, K212, Hommonay
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