CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-196
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTIC S REVIEW! S t
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS {OCPB} REVIEW
`
`NDA: 21-196
`
`Submission Date: 10/5/01,
`
`OCPB Receipt Date: 10/12/01
`
`Drug:
`
`Xyrem (y—hydroxybutyrate; sodium oxybate, GHB)
`
`Strength(s):
`
`500 mg/ml oral solution
`
`Indication:
`
`Cataplexy, Narcolepsy
`
`Applicant:
`
`Orphan Medical, Inc., Minnetonka, Minnesota
`
`Type:
`
`‘lP’ NDA
`
`Date of Review:
`
`2/28/02
`
`Primary Reviewer:
`
`Gerald J. Fetterly, Ph.D.
`
`Background and Summary of Current Submission:
`Orphan Medical, Inc. is seeking approval of Xyrem for the treatment of cataplexy
`attacks, resulting from patients with narcolepsy. Xyrem is an oral solution that is a
`neuroactive agent with a variety of CNS pharmacological properties. The species is
`present endogenously in many tissues, where it acts as a neurotransmitter on a GHB
`receptor and possesses neuromodulatory properties with significant effects on dopamine
`and GABA. As a result, studies have suggested that sodium oxybate improves REM
`sleep of narcoleptics in contrast to the antidepressant drugs. The recommended starting
`dose is 4.5 grams divided into 2 equal doses of 2.25 grams, the first taken at bedtime and
`the second taken 2.5-4 hours later while sitting in bed. The starting dosage can be
`decreased to 3.0 g/d or increased to as high as 9.0 g/d in increments of 1.5 g/d (0.75 g per
`dose). Two weeks are recommended between dosage adjustments to optimize reduction
`of daytime symptoms and to minimize side effects.
`Based on in vitro studies, the inhibitory potential of GHB on CYP450 isozymes
`
`was tested across a concentration range of 3 — 300 itM. The IC50 was determined to be
`
`greater than 300 uM (37.8 ug/ml) from these studies. Plasma concentrations that were
`
`achieved clinically following a dose of 4.5 g were approximately 100 ug/ml. Thus,
`further studies were requested by the Agency in order to assess completely the entire
`concentration range observed clinically. The original NDA was granted an approvable
`status on 7/2/01. This submission is a response to one of the Clinical Pharmacology
`deficiencies identified at that time. The other Clinical Pharmacology deficiencies will be
`addressed as Phase IV commitments following approval of the drug. The results of the
`additional study are as follows:
`
`

`

`1.
`
`In Vitro Studies
`
`Inhibitory Potential Of y-Hydroxybutyrate (GHB) Towards Human Hepatic
`Title:
`Microsomal Cytochrome P450 Isozymes.
`
`Objective:
`The goal of this study was to determine the potential inhibitory activity of GHB
`on various CYP450 enzymes in vitro.
`
`Study Design and Methods:
`Briefly, pooled, human liver microsomes from ten individuals were obtained
`~-~—\
`The activity of each isozyme was determined in the presence
`(concentrations ranging from 300 — 3000 pM) and absence of GHB. The positive control
`inhibitors used for each isozyme included 100 nM OL-naphthoflavone for CYP1A2, 5 11M
`sulfaphenazole for CYP2C9, 6O uM tranylcypromine for CYP2C19, 0.75 itM quinidine
`for CYP2D6, 100 HM diethyldithiocarbamate for CYPZEl, and 100 uM troleandomycin
`for CYP3A.
`
`Results:
`
`Table 1: Inhibitory Potential of Xyrem on Various CYP450 Enzymes.
`
`
`Assay
`7—Ethoxyresorufm O-deethylase
`Tolbutamide 4-methyl hydroxylase
`S-Mcphenytoin 4’—hydroxylase
`
`Dextromethorphan O-demethylase
`
`p-Nitrophenol hydroxylase
`
`Embromycin N—demethylase
`
`P450 lsoenzyme
`CYP1A2
`CYP2C9
`CYP2C l9
`
`CYP2D6
`
`CYPZEl
`
`CYP3A
`
`ICSO g EM?
`>3000
`>3000
`>3000
`
`>3 000
`
`>3000
`
`>3000
`
`For all of the CYP450 enzymes, the GHB concentration needed to inhibit 50% of
`
`the enzyme activity exceeded 3000 11M (378 ug/ml).
`
`Conclusion:
`
`Following a dose of 4.5 g (highest to be marketed dose), plasma concentrations of
`
`Xyrem are approximately 100 ug/ml. Thus, it appears that Xyrem will not inhibit any of
`the CYP450 enzymes (1A2, 2C9, 2Cl9, 2D6, 2131, and 3A) at concentrations that will be
`achieved clinically.
`
`Recommendation:
`
`The information supporting the lack of inhibitory potential of GHB on various CYP450
`isozymes is acceptable to the Office of Clinical Pharmacology and Biopharmaceutics.
`These findings should be incorporated into the proposed labeling.
`In addition,
`the
`labeling comments are attached at the end of this review. The sponsor is advised to
`incorporate the proposed labeling changes under the following sections of the label.
`
`

`

`Gerald J. Fetterly, PhD.
`
`
`
`RD/FT Initialed by Vanitha Sekar, PhD.
`
`
`
`cc: NDA 21,196, HFD-IZO (Harmonnay), HFD-86O (Mehta, Uppoor, Sekar, Fetterly),
`Central Document Room (Clin. PhaHn/Biopharm. File)
`
`

`

`2. OCPB Labeling Comments.
`
`Rx only
`
`CIII
`
`Xyrem® (sodium oxybate) oral solution
`
`CLINICAL PHARMACOLOGY
`
`PHARMACOKINETICS
`
`Sodium oxybate is rapidly but incompletely absorbed after oral administration;
`absorption is delayed and decreased by a high fat meal.
`It is eliminated mainly by
`metabolism with a half-life of 0.5-1 hour. Pharmacokinetics are nonlinear with blood
`
`levels increasing 3.7 fold as dose is doubled from 4.5 to 9 grams. The pharmacokinetics
`are not altered with repeat dosing.
`
`Absorption
`
`Sodium oxybate is absorbed rapidly following oral administration with an absolute
`bioavailability of about 25%. The average peak plasma concentrations (151 and 2nd peak)
`following administration of a 9 g daily dose divided into two equivalent doses given four
`hours apart were 78 and 142 micrograms/ml respectively. The average time to peak
`plasma concentration (Tmax) ranged from 0.5 to 1.25 hours in eight pharmacokinetic
`studies. Following oral administration, the plasma levels of sodium oxybate increased
`more than proportionally with increasing dose. Single doses greater than 4.5 grams have
`not been studied. Administration of sodium oxybate immediately after a high fat meal
`resulted in delayed absorption (average Tmax increased from 0.75 hr to 2.0 hr) and a
`reduction in peak plasma level (Cmax) by a mean of 58% and of systemic exposure (AUC)
`by 37%.
`
`Distribution
`
`Sodium oxybate is a hydrophilic compound with an apparent volume of distribution
`averaging 190-3 84 ml/kg. At sodium oxybate concentrations ranging from 3 to 300
`micrograms/m1, less than 1% is bound to plasma proteins.
`
`Metabolism
`
`Animal studies indicate that metabolism is the major elimination pathway for sodium
`oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and
`secondarily by beta—oxidation. The primary pathway involves a cytosolic NADP+~linked
`enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to
`
`

`

`succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme
`succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is
`metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase
`
`enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in
`the presence of alpha-ketoglutarate. An alternate pathway of biotransformation involves
`beta-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active
`metabolites have been identified.
`
`Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does
`not significantly inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9,
`CYP2C19, CYP2D6, CYP2E1 , or CYP3A up to the concentration of 3 mM (378
`micrograms/ml). These levels are considerably higher than levels achieved with
`therapeutic doses.
`
`Elimination.
`
`The clearance of sodium oxybate is almost entirely by biotransformation to carbon
`dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged
`drug appears in human urine within 6 to 8 hours afier dosing. Fecal excretion is
`negligible.
`
`Special Populations
`
`Geriatric
`
`The pharmacokinetics of sodium oxybate in patients greater than the age of 65 years have
`not been studied.
`
`Pediatric
`
`The pharmacokinetics of sodium oxybate in pediatric patients under the age of 18 years
`have not been studied.
`
`Gender
`
`In a study of 18 female and 18 male healthy adult volunteers, no gender differences were
`detected in the pharmacokinetics of sodium oxybate following a single oral dose of 4.5
`grams.
`
`Race
`
`There are insufficient data to evaluate any pharmacokinetic differences among races.
`
`

`

`Renal Disease
`
`Because the kidney does not have a significant role in the excretion of sodium oxybate,
`no pharmacokinetic study in patients with renal dysfiinction has been conducted; no
`effect of renal function on sodium oxybate pharmacokinetics would be expected.
`
`Hepatic Disease
`
`Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. The
`kinetics of sodium oxybate in 16 cirrhotic patients, half without ascites, (Child’s Class A)
`and half with ascites (Child’s Class C) were compared to the kinetics in 8 healthy adults
`after a single oral dose of 25 mg/kg. AUC values were double in the cirrhotic patients,
`with apparent oral clearance reduced from 9.1 in healthy adults to 4.5 and 4.1 ml/min/kg
`in Class A and Class C patients, respectively. Elimination half-life was significantly
`longer in Class C and Class A patients than in control subjects (mean Ty, of 59 and 32
`versus 22 minutes).
`It is prudent to reduce the starting dose of sodium oxybate by one—
`halfin patients with liver dysfunction (see Dosage and Administration).
`
`Drug-Drug Interaction
`
`Drug interaction studies in healthy adults demonstrated no pharrnacokinetic interactions
`between sodium oxybate and protriptyline hydrochloride, zolpidem tartrate, and
`modafinil. However, pharmacodynamic interactions with these drugs cannot be ruled
`out.
`
`INDICATIONS AND USAGE
`
`Xyrem® (sodium oxybate) oral solution is indicated for the treatment of cataplexy in
`patients with narcolepsy.
`
`In Xyrem clinical trials approximately 80% patients maintained concomitant stimulant
`use (see BLACK BOX WARNINGS).
`
`CONTRAINDICATIONS
`
`Sodium oxybate is contraindicated in patients being treated with sedative hypnotic
`
`WW»www.m¢w,’wo«w.mw...w...w«>9... “CNN-“w w
`agents,-
`"TWA
` -HVWF
`
`Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase
`deficiency. This rare disorder is an inborn error of metabolism.
`
`

`

`PRECAUTIONS
`
`Sodium Intake
`
`Daily sodium intake in patients taking sodium oxybate ranges from 0.5 g (for a 3 g
`sodium oxybate dose) to 1.6 g (for a 9 g sodium oxybate dose). This should be
`considered in patients with heart failure, hypertension or compromised renal function.
`
`Hepatic Insufficiency
`
`Patients with compromised liver function will have an increased elimination half-life and
`systemic exposure to sodium oxybate (see Pharmacokinetics W» The
`starting dose should therefore be decreased by one-half, and response to dose increments
`monitored closely (see Dosage and Administration).
`
`Renal Insufficiency
`
`Because less than 5% of
`No studies have been conducted in renal failure -
`sodium oxybate is excreted via the kidney, no dose adjustment should be necessary in
`patients with renal impairment. The sodium load associated with administration of
`sodium oxybate should be considered in patients with renal insufficiency.
`
`Information for Patients
`
`. w.-_.v----J --- ‘vurv‘AU‘.
`
`Drug Interactions
`
`Interactions between sodium oxybate and three drugs commonly used in patients with
`narcolepsy (zolpidem tartrate, protriptyline HCl, and modafinil) have been evaluated in
`formal studies. Sodium oxybate, in combination with these drugs, produced no
`significant pharmacokinetic changes for either drug (see Pharmacokinetics and
`Metabolism). However, pharmacodynamic interactions cannot be ruled out.
`Nonetheless, sodium oxybate should not be used in combination with sedative hypnotics
`or other CNS depressants.
`
`

`

`
`
`DOSAGE AND ADMINISTRATION
`
`Because food significantly reduces the bioavailability of sodium oxybate, consistent
`timing of dosing with relation to food is advised for each patient to minimize variability
`in response (see Pharmacokinetics and Metabolism). Whether sodium oxybate is
`taken in the fed 0r fasted state may affect both its efficacy and safety.
`
`Xyrem is required to be taken at bedtime and again 2.5-4 hours later. The recommended
`starting dose of Xyrem is 4.5 g/day divided into 2 equal doses of 2.25 g. The starting
`dosage can then be increased to a maximum of 9 g/day in increments of 1.5 g/d (0.75 g
`per dose). Two weeks are recommended between dosage increases to evaluate clinical
`response and minimize adverse effects. Xyrem is effective at doses of 6-9 g/day. The
`efficacy and safety of Xyrem at doses higher that 9 g/day have not been investigated, and
`doses greater than 9 g/day should ordinarily not be administered.
`
`Prepare both doses of Xyrem prior to bedtime. Each dose of Xyrem must be diluted with
`2 ounces (60mL) of water in the child resistant dosing cups provided prior to ingestion.
`The first dose is to be taken at bedtime and the second taken 2.5—4 hours later while
`
`need to set an alarm to awaken for the second dose. The
`sitting in bed. Patients
`second dose must be prepared prior to ingesting the first dose, and should be placed in
`close proximity to the patient’s bed. After ingesting each dose patients should then lie
`down and remain in bed.
`
`Hepatic Insufficiency
`
`Patients with compromised liver fiinction will have increased elimination half-life and
`systemic exposure along with reduced clearance. (see Pharrnacokinetics and
`Metabolism). As a result, the starting dose should be decreased by one-half and dose
`increments should be titrated to effect while closely monitoring potential adverse events.
`
`FEARS nus WAY
`A? on omeAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`———--_-_-—--—-u----—-——-——-——----_n-——---------—-—-—------—----------------------------------------------------------
`
`Gerald Fetterly
`3/5/02 04:15:29 PM
`BIOPHARMACEUTICS
`
`Vanitha Sekar
`3/5/02 04:20:47 PM
`BIOPHARMACEUTICS
`
`

`

` DEPARTMENT OF HEALTH AND
`
`
`
`HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`Clinical Pharmacology & Biopharmaceutics
`(HFD 860)
`Tracking/Action Sheet for Formal/Informal Consults
`
` To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`
`
`Please log-in this consult and review action for the
`
`specified IND submission
`
`
`IND No.2
`DATE OF DOCUMENT
`TREATMENT
` NDA NO.
`
`
`
`Serial NO.:
`21-196
`
`
`5/4/01
`Cataplexy
`
`1
`NAME OF DRUG
`“ :2 g 2‘
`PRIORITY CONSIDERATION
`Date ofFoml Consult:
`
`
`GHB (Xyrem) Oral Solution
`5/6/01
`__
`NAME OF THE SPONSOR: Orphan Medical, Inc.
`10 “ll PIf ”D JUN 2 9 2091
`
`.n: Gerald Fetterly, PhD.
`
`DATE: 6/29/01
`
`TYPE OF SUBMISSION
`
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`E] PREJND
`DANIMAL to HUMAN SCALING
`E] IN-VITRO METABOLISM
`D PROTOCOL
`E] PHASE II PROTOCOL
`C] PHASE [II PROTOCOL
`E] DOSING REGIMEN CONSULT
`E] PK/PD- POPPK ISSUES
`[J- PHASE IV RELATED
`
`I: DISSOLUTION/INcVITRO RELEASE
`D BIOAVAILABILITY STUDIES
`[:I IN-VIVO WAIVER REQUEST
`E] SUPAC RELATED
`[:1 CMC RELATED
`D PROGRESS REPORT
`E] SCIENTIFIC INVESTIGATIONS
`D MEETING PACKAGE (EOPZ/Pre-
`NDA/CMC/Pharmacometrics/Others)
`
`El FINAL PRINTED LABELING
`E] LABELING REVISION
`E] CORRESPONDENCE
`[:1 DRUG ADVERTISING
`[I ADVERSE REACTION REPORT
`[:1 ANNUAL REPORTS
`[:1 FAX SUBMISSION
`[3 OTHER (SPECIFY BELOW):
`Response to Biopharmaceutics Question
`Conveyed to Sponsor
`
`REVIEW ACTION
`
`[:1 Formal Review/Memo (attached)
`[:1 See cements below
`[3 See submission cover letter
`[:1 OTHER (SPECIFY BELOW:
`
`B Oral communication with
`E NAI (No action indicated)
`Name:
`[
`]
`El E-mail comments to:
`E] D Comments communicated in
`DMedicalDChemistDPharm—Tox
`MicroDPhannacometricsDOthers (Check
`meeting/Telecon. see meeting minutes dated:
`as appropriate and attach e-mail)
`[
`
`1 R
`
`EVIEW COMMENT(S)
`
`I: NEED TO BE COMMUNICATED TO THE SPONSOR
`
`U HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`COMMENTS/SPECIAL INSTRUCTIONS:
`
`The sponsor has responded to the agency’s question about ascertaining the potential pharrnacodynamic interactions in
`narcoleptic patients with other commonly used drugs in this patient population, such as methylphenidate. As a result, OMC—
`GHB-2 was the only controlled trial where the patients maintained stable doses Of stimulants. The Sponsor’s analysis Of the
`data concluded that 85% of the patient population were on stable stimulant doses. Since 85% of the patients with cataplexy in
`the sponsor’s major clinical trial (OMC-GHB-2) were on chronic stimulant therapy, the potential for pharmacodynarnic
`interactions between GHB and concomith-a ications cannot be ruled out.
`SIGNATURE OF REVIEWER: _
`. /3/
`Date
`SIGNATURE OF TEAM LEADER:
`Date
`
`
`1 M. Mehta
`. Up
`CC-t NDA 21-196; HFD-IZO; TL:
`1tral Document Room (Clin. PharmJBiOpharm, Files)
`
`/
`
`Elm
`
`
`
`Project Manager;
`
`

`

`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`JL' Gerald Fetterly, Ph.D.
`
`
`
`Clinical Pharmacology & Biopharmaceutics
`(HFD 860)
`
`
`
`
`
`Tracking/Action Sheet for Formal/Informal Consults
`
` To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`
`
`Please login this consult and review action for the
`
`
`specified IND submission
`
`
`
`IND No.:
`NDA No.
`DATE OF DOCUMENT
`TREATMENT
`
`
`
`
`
`Serial N°-=
`21-196, SN 058
`4/19/01
`Cataplexy
`PRIORrrY CONSIDERATION
`Date ofFormal Consult:
`g 2%”
`4/23/01
`
`DATE: 6/29/01
`
`NAME OF DRUG
`GHB (Xyrem) Oral Solution
`NAME OF THE SPONSOR: Orphan Medical, Inc.
`
`
`
`30“ 1
`'50 60 I” III EB JUN 2 9 208‘
`
`TYPE OF SUBMISSION
`
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`.
`
`[:1 PRE—IND
`DANIMAL to HUMAN SCALING
`[3 IN—VITRO METABOLISM
`D PROTOCOL
`E] PHASE II PROTOCOL
`[3 PHASE III PROTOCOL
`E] DOSING REGIMEN CONSULT
`CI PIUPD- POPPK ISSUES
`El PHASE IV RELATED
`
`[:I DISSOLUTION/IN-VITRO RELEASE
`E] BIOAVAILABILITY STUDIES
`[:1 IN-VIVO WAIVER REQUEST
`E] SUPAC RELATED
`E] CMC RELATED
`D PROGRESS REPORT
`[j SCIENTIFIC INVESTIGATIONS
`D MEETING PACKAGE (EOPZ/Pre-
`NDA/CMC/Pharmacometrics/Others)
`
`[:I FINAL PRINTED LABELING
`E] LABELING REVISION
`E] CORRESPONDENCE
`E] DRUG ADVERTISING
`[:I ADVERSE REACTION REPORT
`E] ANNUAL REPORTS
`[:1 FAX SUBMISSION
`E] OTHER (SPECIFY BELOW):
`Response to Biopharmaceutics Question
`Conveyed to Sponsor
`
`REVIEW ACTION
`
`[3 Formal Review/Memo (attached)
`1:] See comments below
`[I See submission cover letter
`[:1 OTHER (SPECIFY BELOW):
`
`[:1 Oral communication with
`E] NAI (No action indicated)
`Name:
`[
`]
`[:I E—mail comments to:
`DMedicalDChemistDPharm-Tox D E] Comments communicated in
`MicroDPharmacometricsDOthers (Check
`meeting/Telecon. see meeting minutes dated:
`as appropriate and attach e—mail)
`[
`
`] R
`
`EVIEW COMMENT(S)
`
`E] NEED TO BE COMMUNICATED TO THE SPONSOR
`
`[:I HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`COMMENTS/SPECIAL INSTRUCTIONS:
`
`The sponsor has provided an explanation regarding the agency’s question on the identical precision and accuracy observed in
`the three drug interaction studies. For clarification, the values obtained during the analyses of each study were similar but not
`identical in these three studies (See Attached Table 1). With respect to the method validation for GHB', a single report was
`prepared to describe the validation of the \ ' assay used in all three studies to measure GHB. This response is acceptable
`to the Office of Clinical Pharmacology and Biopharmaceutics.
`
`Date Mav I
`ISI!
`SIGNATURE OF REVIEWER: _
`l‘S/
`Date
`.1191? 9
`SIGNATURE OF TEAM LEADER:
`'
`" /
`'-
`Project Manager:
`CC.: NDA 21—196; HFD-120; TL: R. Upme: M. Mehta
`Central Document Room (Clin. Pharm./Biopharm. Files)
`
`

`

`__l__ page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`.n: Gerald Fetterly, Ph.D.
`
` DEPARTMENT OF HEALTH AND
`
`
`Clinical Pharmacology & Biopharmaceutics
`
`(HFD 860)
`
`
`Tracking/Action Sheet for Formal/Informal Consults
`
` To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`
`
`Please log-in this consult and review action for the
`specified IND submission
`
`
`DATE OF DOCUMENT
`NDA No.
`TREATMENT
`IND No.2
`
`
`
`Serial No.:
`
`
`
`
`21—196, SN 056
`4/11/01
`Cataplexy
`
`DATE: 6/28/01
`
`
`U“ 2 g L
`Date of Formal Consult:
`NAME OF DRUG
`3
`4/12/01
`_‘
`GHB (Xyrem) Oral Solution
`‘1' f3 '1
`.
`NAME OF THE SPONSOR: Orphan Medical, Inc.
`It) COMPI
`I u .,
`
`PRIORITY CONSIDERATION
`
`JUN 2 9 2801
`
`TYPE OF SUBMISSION
`
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`E] PRE-IND
`DANIMAL to HUMAN SCALING
`D IN-VITRO METABOLISM
`I:] PROTOCOL
`E] PHASE II PROTOCOL
`[:1 PHASE III PROTOCOL
`E] DOSING REGIMEN CONSULT
`Cl PK/PD- POPPK ISSUES
`[3 PHASE IV RELATED
`
`E] DISSOLUTION/IN-VITRO RELEASE
`I] BIOAVAILABILITY STUDIES
`E] IN—VIVO WAIVER REQUEST
`D SUPAC RELATED
`[:I CMC RELATED
`D PROGRESS REPORT
`E] SCIENTIFIC INVESTIGATIONS
`E] MEETING PACKAGE (EOPZ/Pre—
`NDA/CMC/Pharmacometrics/Others)
`
`[3 FINAL PRINTED LABELING
`E] LABELING REVISION
`E] CORRESPONDENCE
`[j DRUG ADVERTISING
`Ij ADVERSE REACTION REPORT
`[:I ANNUAL REPORTS
`E] FAX SUBMISSION
`E] OTHER (SPECIFY BELOW):
`Response to Biopharmaceutics Question
`Conveyed to Sponsor
`
`REVIEW ACTION
`
`E] Formal Review/Memo (attached)
`E] See comments below
`E] See submission cover letter
`E] OTHER (SPECIFY BELOW:
`
`NAI (No action indicated)
`[:1 E—mail comments to:
`Cl
`DMedicalDChemistEIPhann—Tox
`MicroDPharmacometricsDOthers (Check
`as appropriate and attach e—mail)
`
`I] Oral communication with
`Name:
`[
`]
`C] Comments communicated in
`meeting/Telecon. see meeting minutes dated:
`[
`
`I R
`
`EVIEW COMMENT(S)
`
`[:l NEED TO BE COMMUNICATED TO THE SPONSOR
`
`C] HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`COMMENTS/SPECIAL INSTRUCTIONS:
`
`As a result of the food effect on the bioavailability of GHB, we requested that the sponsor submit the calorie intake and food
`content of all meals consumed in the pharmacokinetic studies in order to support labeling recommendations about drug
`administration. The sponsor has stated that in the six studies conducted in healthy volunteers, subjects were fed in the same
`sequence and interval at which they were dosed. In all studies involving either multiple cohorts or crossover designs, the same
`menu was used for each period within a given study (See Attachments). Thus, food consumption effected the bioavailability
`of GHB in each phannacokinetic study. As a result of these findings, administration of Xyrem should be conducted in the
`fasted state in order to maximize efficacy or at least consistently (with or without food for both doses) throughout the treatment
`period.
`c
`
`. /
`SIGNATURE OF REVIEWER: _
`[3
`g1GNATURE 0F TEAM LEADER:
`g
`i.: NDA 21-196; HEB-120; TL: {Upm M. Mehta
`Central Document Room (Clin. PharmJBiopharm. Files)
`
`a”
`Date
`0
`Date .,&1
`Project Manager:
`
`Date
`
`

`

`Food Consumption in All Pharmacokinetic Studies.
`
`OMC—SXB~8
`
`(Gender Study):
`
`two hours after a
`Subjects were dosed beginning at 8 pm (20:00hr)
`dinner beginning at 6 pm (18:00hr) and consistin§‘8f?“"‘——‘—‘—"
`—-__——-h
`
`Hamburger patty (3 oz. ground beef)
`Hamburger bun
`Lettuce,
`tomato, condiments(est.)
`Pasta salad, X cup
`Caffeine—free soda, 12 oz.
`
`Total
`
`- 240 cal
`— 123
`—
`80
`- 189
`— 150
`782 cal
`
`The following morning at 7 am (07:06) a light breakfast was
`offered consisting of:
`
`raw, medium
`One apple,
`Milk, whole,
`8 oz.
`
`Total
`
`-
`81 cal
`
`- 150
`— 231 cal
`
`OMC-SXB—Q (Dose Proportionality Study):
`
`two hours after a
`Subjects were dosed beginning at 8 pm (20:00hr)
`f.-\_
`dinner beginning at 6 pm (18:00hr) and consisting of:
`f
`
`Hamburger patty (3 oz. ground beef)
`Hamburger bun
`Lettuce,
`tomato, condiments(est.)
`Pasta salad, % cup
`Caffeine-free soda, 12 oz.
`
`Total
`
`- 240 cal
`- 123
`—
`80
`- 189
`
`— 150
`782 cal
`
`The following morning at 7 am (07:00) a light breakfast was
`offered consisting of:
`
`raw, medium
`One apple,
`Milk, whole,
`8 oz.
`
`Total
`
`81 cal
`-
`
`- 150
`- 231 cal
`
`

`

`OMCvSXB-lo (Acute vs Chronic Study in Patients):
`
`The same standardized dinner was given to the patients prior to
`both the acute and 8 week test doses of Xyrem.
`The dinner was
`given beginning at 8 pm (20:00)
`tw§r2323§_2£i95;§9 beginning
`dosing at 10 pm (22:00).
`The dinn
`consisted o :
`
`KFC fried chicken, breast or leg & thigh
`Mashed potatoes & gravy,
`1 serving
`Cole slaw, 1 serving
`Biscuit,
`1 w/butter
`
`Total
`
`- 400
`— 120
`— 180
`- 180
`880 cal
`
`OMC—SXB-ll
`
`(Food Effect Study)
`
`(300 cal) and 8 oz. of
`A snack consisting of a cinnamon roll
`whole milk (150 cal) was given at 9 pm (21:00hr)
`the evening
`before dosing the next morning beginning at 7 am (07:00hr). On
`the study day when the high fat meal (breakfast) was served,
`the
`meal began at 6:30 am (06:30hr) thirty minutes prior to dosing
`and was consumed within 15 minutes.
`The meal consisted of:
`
`14g fat
`6g
`119
`89
`89
`_g
`47g fat
`
`— 184 cal
`-
`72
`- 160
`- 220
`- 150
`
`- 110
`896 cal
`
`2 2
`
`eggs fried in butter
`strips of bacon
`4 oz. hash browns, fried
`2 slices white toast, buttered
`8 oz. whole milk
`8 oz. orange juice
`
`Total
`
`Beginning at 11 am (11:00hr) after the 4 hour blood draw,
`subjects were given lunch which consisted of:
`
`the
`
`Smoked turkey croissant sandwich - 372 cal
`Soup, chicken noodle, 1.5 cup
`- 195
`
`Caffeine~free soda, 12 oz.
`- 150
`Total
`717 cal
`
`

`

`OMC—SXB-lz
`
`(Zolpidem Interaction Study):
`
`the night before dosing at
`A snack was offered at 9 pm (21:00hr)
`7 am (07:00hr)
`the following morning while fasted overnight.
`The
`snack consisted of one vanilla pudding cup (130 cal), a fruit bar
`(140 cal) and 8 oz of whole milk (150 cal).
`Four hours after
`
`lunch was served beginning at 11 am (11:00hr)
`(7am) dosing,
`consisting of the following:
`
`Lasagna, w/meat, ~12 oz.
`
`- S30 cal
`
`Scalloped potatoes, ~1 cup
`Lettuce salad w/dressing
`Roll w/butter
`8 oz. fruit punch
`
`Total
`
`— 211
`—
`90
`- 140
`
`- 110
`1081
`
`Dinner was given beginning at 5 pm (17:00hr) and consisted of:
`
`Smoked turkey croissant sandwich
`Potato chips,
`1 oz. bag
`Caffeine-free soda, 12 oz.
`
`Total
`
`- 272 cal
`- 150
`
`- 150
`572 cal
`
`OMC-SXB-l4 (Protriptyline Interaction Study):
`
`the night before dosing.
`A snack was offered at 10 pm (22:00hr)
`The snack consisted of one vanilla pudding cup (130 cal), a fruit
`bar (140 cal) and 8 oz of whole milk (150 Cal). At 6 am (06:00hr)
`a light breakfast was served two hours before dosing at 8 am
`(08:00)hr). This consisted of:
`
`» One cinnamon roll
`8 oz. whole milk
`
`- 300 cal
`
`- 150
`450 cal
`
`Total
`
`Five hours after the first (83m) dosing and one hour after the
`second (12 noon) dosing, if applicable,
`lunch was served
`beginning at 1 pm (13:00hr) consisting of the following:
`
`Lasagna, w/meat, ~12 oz.
`
`- 530 cal
`
`Scalloped potatoes, ~1 cup
`Lettuce salad w/dressing
`Roll w/butter
`8 oz. fruit punch
`
`- 211
`—
`90
`- 140
`
`- 110
`1081
`
`Total
`
`

`

`Dinner was given beginning at 5 pm (17:00hr) and consisted of:
`
`Smoked turkey croissant sandwich
`Potato chips, 1 oz. bag
`Caffeine-free soda, 12 oz.
`
`Total
`
`— 272 cal
`- 150
`
`- 150
`572 cal
`
`OMC-SXB-17 (Modafinil Interaction Study):
`
`the night before dosing at
`A snack was offered at 9 pm (21:00hr)
`7 am (07:00hr)
`the following morning while fasted overnight.
`The
`snack consisted of one vanilla pudding cup (130 cal), a fruit bar
`(140 cal) and 8 oz of whole milk (150 cal).
`Four hours after
`
`lunch was served beginning at 11 am (11:00hr)
`(7am) dosing,
`consisting of the following:
`
`Lasagna, w/meat, ~12 oz.
`
`- 530 cal
`
`Scalloped potatoes, ~1 cup
`Lettuce salad w/dressing
`Roll w/butter
`8 oz. fruit punch
`
`Total
`
`- 211
`—
`90
`- 140
`
`- 110
`1081
`
`Dinner was given beginning at 5 pm (17:00hr) and consisted of:
`
`Smoked turkey croissant sandwich
`Potato chips,
`1 oz. bag
`Caffeine—free soda, 12 02.
`
`Total
`
`— 272 cal
`— 150
`
`~ 150
`572 cal
`
`

`

` Office of Clinical Pharmacology and Biopharmaceutics
`New Drug Application Filing and Review Form
`M138 2% 28“
`
`\
`
`
`
`iiCllMPLizm T2 “ 7 2331
`
`General Information About
`
`the Submission
`
`lnfonnalion
`
`NBA Number
`OCPB Division I, II, 111
`Medical Division
`OCPB Reviewer
`OCPB Team Leader
`
`Date of Submission
`Estimated Due Date of OCPB Review
`PDUFA Due Date
`Division Due Date
`
`
`
`euro . harmacolo o
`erald Fetterl
`amana Uppoor
`
`‘0l30/00
`3/1 2/00
`\
`2/00
`
`
`__
`:5-1u=Q- 2waon
`
`—_
`
`
`
`Orhan Medical, Inc.
`Priorit 'Classificatwn W!-
`
`
`
`
`
`
`
`
`Dru Class —
`
`
`
`
`
`
`
`Starling dose: 4.5 glday.
`Dosing Regimen
`
`
`
`
`3, 4.5, 6, 7.5 and 9 glday
`divided into 2 equal doses
`
`
`administered 4 h apart.
`Route of Administration
`
`
`
`
`
`
`
`A. Clin. Pharm. and BiOoharm. Information
`
`“X” if included Number of
`Number of
`studies
`studies
`at filing
`submitted
`reviewed
`
`
`
`
`
`
`
`
`sufficient to locate reports, tables, data,
`
`
`
`
`
`
`ii
`E>
`
`
`
`
`
`STUDY TYPE
`Table of Contents present and
`
`I
`
`I
`
`Critical Comments If any
`
`0o-eP
`Tabular Listin o of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacol0o
`Mass balance:
`lsoz me characterization:
`Blood] olasma ratio:
`Plasma urotein bindin-z
`Pharmacokinetics (9.9., Phase I) -
`Healthy Volunteers—
`
`I
`—
`
`sinole dose:
`mullio Ie dose:
`Patients—
`
`sinole dose:
`multiole dose:
`
`-
`Dose ooroortionalit
`fasting / non—fasting single dose:
`fastino /non~fastino multiole dose:
`Dru-o-dru interaction studies -
`druo:
`ln-vivo effects on orima
`ln—vivo effects of primary drug:
`
`X
`
`X
`
`No
`gender: X
`
`
`pediatrics:
`geriatrics:
`renal imoairment:
`
`
`
`
`PD:
`
`X
`
`
` ln-vitro:
`
`
`

`

`Phase 2:
`
`Phase 3:
`
`X
`
`X
`
`Dose/Clinical Response (4
`studies were submitted in the
`Clinical Section
`
`PKIPD:
`Phase 1 and/or 2, oroof of concet:
`Phase 3 clinical trial:
`Po . ulation Anal ses -
`
`Data rich:
`
`:
`Absolute bioavailabili
`-
`Relative bioavailabili
`solution as reference:
`
`n—
`
`.vi‘I
`
`
`
`Solution is also the test
`formulation.
`
`Data sparse: I_—— ll. Bio aharmaceutics
`.r.
`
`Alternate formulation as reference:
`Bioe - uivalence studies -
`traditional desi-n; sin-le / multi dose:
`replicate design; sinole Imulti dose:
`Food-dru interaction studies:
`Dissolution:
`IVIVC :
`Bio-wavier re uest based on BCS
`808 class
`III. Other CPB Studies
`Geno ace/henot e studies:
`Chrono . harmacokinetics
`Pediatric develo - ment plan
`Literature References
`
`--
`
`Total Number of Studies
`included above
`
` Filabilit and QBR comments
`
`Comments sent tafirm ?
`
`X
`
`
`
`
`The sponsor
`A mass balance study was not performed.
`suggests that a radiolabeled mass balance and metabolic fate
`
`
`study in human volunteers would be unethical due to the
`possibility of the radiolabel becoming incorporated into the
`amino acid pool.
`
`
`1. What is the effect of food on the pharmacokinetics of GHB? As a result, does
`the timing of administration following food intake influence the bioavailability
`of the drug.
`.
`What is the effect of Hepatic impairment on the pharrnacokinetics of GHB?
`9’.”
`What is the effect of antacid administration on the bioavailability of GHB?
`
`Other comments or information not
`
`QBR questions (key issues to be
`considered)
`
`Primary reviewer Signature and Date
`
`Secondary reviewer Signature and Date
`
`/§2/
`
`3 Qé
`
`/3/ , 63 aé e
`
`/
`
`CC: NDA 21-196, HFD-850(Electr0nic entr) ,. Lee), HFD-120(CSO: Homonnay), RFD—860(Uppoor,
`
`Mehta), CDR(Clin. Pharm./Bi0pharm)
`
`'
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS (OCPB) REVIEW
`
`NDA: 21-196
`
`Submission Dates: 9/30/00,
`
`'
`
`10/13/00,
`
`12/7/00
`
`OCPB Receipt Dates: 11/1/00
`
`12/18/00
`
`Drug:
`
`Xyrem (y-hydroxybutyrate; sodium oxybate, GHB)
`
`Strength(s):
`
`500 mg/ml oral solution
`
`Indication:
`
`Applicant:
`
`Cataplexy, Narcolepsy
`
`Orphan Medical, Inc., Minnetonka, Minnesota
`
`Type:
`
`‘lP’ NDA
`
`Date of Review:
`
`3/12/01
`
`Primary Reviewer:
`
`Gerald J. Fetterly, Ph.D.
`
`Table of Contents.
`
`Executive Summary
`General Comments and Recommendations
`
`»
`
`Question Based Review
`
`Summary
`A. Pharmacokinetic Studies
`
`Synopses of Individual Studies
`A. In Vitro Studies
`
`4
`8
`
`10
`
`14
`14
`
`19
`19
`
`B. Multiple—Dose Pharmacokinetics of Xyrem in Narcoleptic Patients on Chronic
`Therapy
`20
`C. Single Dose Pharmacokinetic Study of Xyrem in Healthy Volunteers
`22
`D. Multiple-Dose Pharmacokinetics of Xyrem in Healthy Volunteers
`25
`E. Pharrnacokinetics of Xyrem after Single and Chronic Dosing
`29
`F. Effect of Food on the Pharmacokinetics of GHB
`32
`
`35
`G. Effect of Hepatic Impairment on the Pharmacokinetics of GHB
`38
`H. Pharmacokinetic Interaction of GHB with Ambien (Zolpidem)
`43
`I. Pharmacokinetic Interaction of GHB with Vivactil (Protriptyline)
`49
`J. Pharmacokinetic Interaction of GHB with Provigil (Modafinil)
`K. Literature (Protein Binding and Absolute Bioavailability via cross study
`comparison)
`54
`Labeling Comments and Draft Package Insert
`55
`
`

`

`Executive Summary:
`
`Orphan Medical, Inc. is seeking approval of Xyrem for the treatment of cataplexy
`attacks, resulting from patients with narcolepsy. Xyrem is an oral solution that is a
`neuroactive agent with a variety of CNS pharmacological properties. The species is
`present endogenously in many tissues, where it acts as a neurotransmitter on a GHB
`receptor and possesses neuromodulatory properties with significant effects on dopamine
`and GABA. As a result, studies have suggested that sodium oxybate impr