CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212690Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Division of Risk Management (DRM)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA 021196
`NDA 212690
`July 21, 2020
`2020-124
`2020-1537
`Yasmeen Abou-Sayed, PharmD
`Joan E. Blair, RN, MPH
`Shelly Harris, ScD, MPH
`Jacqueline Sheppard, PharmD
`Cynthia LaCivita, PharmD
`July 21, 2020
`
`
`Application Type/Numbers
`
`Action Date
`OSE RCM #
`
`Reviewer Names
`
`
`Acting Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`
`Trade Name
`Name of Applicant
`Therapeutic Class
`
`Evaluation REMS modification for Xyrem; Evaluation of REMS
`Submission for Xywav
`
`Sodium oxybate (Xyrem); calcium, magnesium, potassium, and
`sodium oxybates (Xywav)
`
`Xyrem; Xywav
`Jazz Pharmaceuticals, Inc.
`
`Central Nervous System (CNS) Depressant
`
`0.5g/ml sodium oxybate (Xyrem); 0.5 g/mL total salts equivalent
`to 234 mg/mL calcium oxybate, 96 mg/mL magnesium oxybate,
`130 mg/mL potassium oxybate, and 40 mg/mL sodium oxybate
`equivalent to 0.413 g/mL of oxybate
`For Adult Patients:
`•
`Initiate dosage at 4.5 grams (g) per night orally, divided
`into two doses 2.5 to 4 hours apart
`• Titrate to effect in increments of 1.5 g per night at
`weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5
`to 4 hours later)
`• Recommended dosage range: 6 g to 9 g per night orally
`
`1
`
`Formulation
`
`
`
`Dosing Regimen
`
`
`
`Reference ID: 4643955
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`

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`For Pediatric Patients:
`
`
`
`
`Initial Dosage
`
`Patient
`Weight
`
`< 20 kg
`
`Maximum Recommended
`Maximum Weekly Dosage
`Dosage
`Increase
`Take 2.5 to 4
`Take at
`Take 2.5 to 4
`Take at
`Take 2.5 to 4
`Take at
`Hours Later:
`Bedtime:
`Hours Later:
`Bedtime:
`Hours Later:
`Bedtime:
`There is insufficient information to provide specific dosing recommendations for patients
`who weigh less than 20 kg.
`
`20 kg to < 30 ≤ 1 g
`≤ 1 g
`
`
`30 kg to < 45 ≤ 1.5 g
`≤ 1.5 g
`
`>45 kg
`≤ 2.25 g
`≤ 2.25 g
`
`0.5 g
`0.5 g
`0.75 g
`
`0.5 g
`0.5 g
`0.75 g
`
`3 g
`3.75 g
`4.5 g
`
`3 g
`3.75 g
`4.5 g
`
`
`
`Reference ID: 4643955
`
`2
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`

`

`
`EXECUTIVE SUMMARY ............................................................................................................................... 4
`
`Table of Contents
`
`1
`2
`
`Introduction ...................................................................................................................................... 5
`Background ....................................................................................................................................... 5
`2.1
`PRODUCT INFORMATION ................................................................................................... 5
`2.2
`CURRENTLY APPROVED XYREM REMS ........................................................................ 6
`2.3
`REGULATORY HISTORY ..................................................................................................... 7
`Therapeutic Context and Treatment Options ............................................................................. 7
`3.1
`DESCRIPTION OF THE MEDICAL CONDITION ............................................................. 7
`3.2
`DESCRIPTION OF CURRENT TREATMENT OPTIONS ................................................ 8
`Benefit Assessment .......................................................................................................................... 8
`Risk Assessment and Safe-Use Conditions .................................................................................. 9
`Expected Postmarket Use ............................................................................................................. 10
`Review of Proposed REMS ............................................................................................................ 10
`7.1
`GENERAL ............................................................................................................................... 10
`7.2
`REMS GOAL ........................................................................................................................... 10
`7.3
`REMS DOCUMENT ............................................................................................................... 11
`7.4
`REMS REQUIREMENTS ...................................................................................................... 11
`REMS Participant Requirements and Materials ........................................................... 11
`7.4.1
`7.4.2
`REMS Materials and Key Risk Messages ....................................................................... 11
`7.5
`REMS ASSESSMENT TIMETABLE ................................................................................... 13
`Supporting Document.................................................................................................................... 13
`8
`REMS Assessment Plan .................................................................................................................. 13
`9
`10 Summary of Office of Prescription Drug Promotion Recommendations on REMS
`Materials ................................................................................................................................................... 13
`11 Discussion ........................................................................................................................................ 15
`12 Conclusions and Recommendations ........................................................................................... 16
`13 Appendix .......................................................................................................................................... 16
`A. Xywav and Xyrem REMS Assessment Plan ....................................................................................... 16
`B. Appended REMS Materials ................................................................................................................ 23
`14 References ....................................................................................................................................... 24
`
`3
`
`4
`5
`6
`7
`
`
`
`
`
`Reference ID: 4643955
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`3
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`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRM) evaluates the risk evaluation and mitigation
`strategy (REMS) for Xywav (calcium, magnesium, potassium, and sodium oxybates), submitted on
`January 21, 2020, and amended on July 7, 2020, July 13, 2020, July 16, 2020, and July 20, 2020 and the
`REMS modification for Xyrem (sodium oxybate), submitted on July 16, 2020 and amended on July 20,
`2020. Jazz (the “Applicant”) submitted a New Drug Application (NDA) 212690 under Section 505(b)(2) of
`the Federal Food, Drug and Cosmetic Act, for Xywav with the proposed indication for the treatment of
`cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.
`The reference listed drug Xyrem (sodium oxybate) is approved with a REMS with elements to assure safe
`use (ETASU) to mitigate the risks of serious adverse outcomes resulting from inappropriate prescribing
`misuse, abuse, and diversion of Xyrem.
`The Applicant has proposed a REMS for Xywav and Xyrem. Xywav and Xyrem contain the same active
`moiety, have the same risks and will use the same risk mitigation strategies. The Applicant submitted a
`full REMS proposal, including REMS document, REMS supporting document, and all REMS appended
`materials, that incorporates Xywav into the existing Xyrem REMS forming the new Xywav and Xyrem
`REMS. In addition, the following new materials – Xywav Patient Quick Start Guide, Xywav Brochure for
`Pediatric Patients and their Caregivers, and Xywav Prescription Form were created, and an optional
`Takeback program for the return of unused drug was added.
`The goal of the XYWAV and XYREM REMS is to mitigate the risks of serious adverse outcomes resulting
`from inappropriate prescribing, misuse, abuse, and diversion of XYWAV and XYREM by:
`1.
`Informing prescribers, pharmacists, and patients of:
`a. The risk of significant CNS and respiratory depression associated with XYWAV and
`XYREM
`b. The contraindication of use of XYWAV and XYREM with sedative hypnotics and alcohol
`c. The potential for abuse, misuse, and overdose associated with XYWAV and XYREM
`d. The safe use, handling, and storage of XYWAV and XYREM
`2. Ensuring that pharmacy controls exist prior to filling prescriptions for XYWAV and XYREM that:
`a. Screen for concomitant use of sedative hypnotics and other potentially interacting
`agents
`b. Monitor for inappropriate prescribing, misuse, abuse, and diversion of XYWAV and
`XYREM
`c. Notify prescribers when patients are receiving concomitant contraindicated medications
`or there are signs of potential abuse, misuse, or diversion
`
`
`DRM finds the proposed Xywav and Xyrem REMS to be acceptable for approval. This REMS proposal, if
`approved, will require a modification to the existing Xyrem REMS (NDA 021196) to the new Xywav and
`Xyrem REMS.
`The Timetable for submission of assessments of the Xywav and Xyrem REMS remains the same as that
`approved on February 27, 2015 in the Xyrem REMS. The REMS Assessment Plan was changed to capture
`metrics for both products in this REMS.
`
`
`
`
`Reference ID: 4643955
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`

`

` 1
`
` Introduction
`This review by the Division of Risk Management (DRM) evaluates the proposed risk evaluation and
`mitigation strategy (REMS) for Xywav (calcium, magnesium, potassium, and sodium oxybates). Jazz
`Pharmaceuticals, Inc. (Jazz) submitted a New Drug Application (NDA) 212690 under Section 505(b)(2) of
`the Federal Food, Drug and Cosmetic Act, for Xywav with the proposed indication for the treatment of
`cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.1
`This application is under review in the Division of Neurology 1 (DN1). The reference listed drug is Xyrem
`(sodium oxybate) NDA 021196. Xyrem is approved with a REMS to mitigate the risks of serious adverse
`outcomes resulting from inappropriate prescribing, misuse, abuse, and diversion of Xyrem. The
`Applicant has proposed a REMS for Xywav and Xyrem, as these products contain the same active moiety,
`have the same risks and will has the same goals and REMS requirements. A corresponding REMS
`modification submitted as a prior approval supplement (PAS) 34 for Xyrem is under review in DN1, to
`incorporate Xywav into the existing Xyrem REMS forming the Xywav and Xyrem REMS.2 The applicant’s
`proposed REMS consists of elements to assure safe use (ETASU), an implementation system, and a
`timetable for submission of assessments to ensure the benefits of Xywav and Xyrem outweigh the risks.3
`
`
` 2
`
` Background
`2.1 PRODUCT INFORMATION
`Xywav (calcium, potassium, magnesium, and sodium oxybates) oral solution contains the active moiety
`oxybate (4-hydroxybutanoate), a central nervous system depressant, and belongs to the same
`pharmacologic class as Xyrem® (sodium oxybate), a Schedule III controlled substance. Oxybate is also
`known as gamma-hydroxybutyrate (GHB), an endogenous compound and metabolite of the
`neurotransmitter gamma-amino butyric acid (GABAB), that acts as a potent central nervous system
`(CNS) depressant. Oxybate is a CNS depressant, however, the exact mechanism of action of oxybate in
`the treatment of narcolepsy is unknown. It is hypothesized that the therapeutic effects of Xywav on the
`symptoms of narcolepsy (cataplexy and EDS) are mediated through GABAB actions during sleep at
`noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.
`Xywav is a non-new molecular entity, submitted under section 505(b)(2) of the Food, Drug, and
`Cosmetic Act (FDCA).a The intent of the Xywav formulation is to reduce sodium content by replacing
`most of the sodium with other cations, i.e., calcium, potassium, and magnesium.
`Although Xyrem and Xywav both contain the same concentration of the active moiety and have the
`same dosing regimenb; the products were not deemed bioequivalent. Therefore, the Applicant was
`required to perform a clinical study to demonstrate efficacy of Xywav.4
`The dosing for Xywav aligns with current Xyrem dosing. The recommended starting dose in adult
`patients is 4.5 grams (g) per night administered orally in two equal divided doses: 2.25 g at bedtime and
`2.25 g taken 2.5 to 4 hours later. The dose should be increased by 1.5 g per night at weekly intervals
`(additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 to 9 g
`per night orally. Doses higher than 9 g per night have not been studied in either Xyrem or Xywav and
`
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
`
`
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`Reference ID: 4643955
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`

`

`should not ordinarily be administered. Xywav is also proposed for use in pediatric patients, and the
`proposed dosing regimen in the table below aligns with current Xyrem dosing.
`Table 1 – Xywav and Xyrem Dosage for Pediatric Patients 7 Years of Age and Older
`
`Initial Dosage
`Maximum Weekly Dosage
`Maximum Recommended
`Increase
`Dosage
`Patient
`Weight
`
`< 20 kg
`
`Take 2.5 to 4
`Take at
`Take 2.5 to 4
`Take at
`Take 2.5 to 4
`Take at
`Hours Later:
`Bedtime:
`Hours Later:
`Bedtime:
`Hours Later:
`Bedtime:
`There is insufficient information to provide specific dosing recommendations for patients
`who weigh less than 20 kg.
`
`20 kg to < 30 ≤ 1 g
`≤ 1 g
`
`
`30 kg to < 45 ≤ 1.5 g
`≤ 1.5 g
`
`>45 kg
`≤ 2.25 g
`≤ 2.25 g
`
`0.5 g
`0.5 g
`0.75 g
`
`0.5 g
`0.5 g
`0.75 g
`
`3 g
`3.75 g
`4.5 g
`
`3 g
`3.75 g
`4.5 g
`
`
`
`2.2 CURRENTLY APPROVED XYREM REMS
`Xyrem was approved in 2002 with a Risk Minimization Action Plan (RiskMAP) that required the
`following:
`• Prescribers enrolled in the RiskMAP in order to prescribe Xyrem
`• Patients enrolled in the RiskMAP in order to receive Xyrem
`• A single, central, specialty pharmacy dispensed Xyrem only via direct shipment to an enrolled
`patient pursuant to a prescription written by an enrolled prescriber
`Xyrem was identified as a product deemed to have in effect an approved REMS because there were
`elements to assure safe use in effect on the effective date of the Food and Drug Administration
`Amendments Act of 2007 (FDAAA). The REMS was approved on February 27, 2015 consisting of a
`Medication Guide, elements to assure safe use (ETASU), an implementation system, and a timetable for
`submission of assessments. The goal of the Xyrem REMS is to mitigate the risks of serious adverse
`outcomes resulting from inappropriate prescribing, misuse, abuse, and diversion of Xyrem by: c,d
`1.
`Informing prescribers, pharmacists, and patients of:
`• The risk of significant CNS and respiratory depression associated with XYREM.
`• The contraindication of use of XYREM with sedative hypnotics and alcohol.
`• The potential for abuse, misuse, and overdose associated with XYREM.
`
`
`c The goal of mitigating diversion in this REMS refers to preventing the sale or transfer of the drug outside the
`framework of the REMS in order to mitigate the risks of central nervous system depression, respiratory depression,
`abuse, and misuse.
`d The goal of mitigating diversion in this REMS refers to preventing the sale or transfer of the drug outside the
`framework of the REMS in order to mitigate the risks of CNS depression, respiratory depression, abuse, and
`misuse.
`
`
`
`Reference ID: 4643955
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`

`• The safe use, handling, and storage of XYREM.
`2. Ensuring that pharmacy controls exist prior to filling prescriptions for XYREM that:
`• Screen for concomitant use of sedative hypnotics and other potentially interacting agents.
`• Monitor for inappropriate prescribing, misuse, abuse, and diversion of XYREM.
`• Notify prescribers when patients are receiving concomitant contraindicated medications or
`there are signs of potential abuse, misuse, or diversion.
`The ETASU in the Xyrem REMS include:
`• Healthcare providers who prescribe Xyrem must be certified by reviewing the training materials
`and enrolling in the REMS.
`• The pharmacy that dispenses Xyrem must be specially certified by reviewing the training
`materials. Pharmacists who dispense Xyrem must counsel new patients and those restarting
`treatment after 6 months or longer. They also need to document patient and prescriber
`behavior that may be indicative of abuse, misuse, or diversion.
`• Patients who receive Xyrem must review the educational materials and be enrolled in the REMS
`by their provider.
`
`
`2.3 REGULATORY HISTORY
`The following is a summary of the regulatory history relevant to this review:
`• 6/30/2020: The Agency held a teleconference with the Applicant to notify them of the need to
`modify the Xyrem REMS, to align with the proposed Xywav and Xyrem REMS.
`• 7/16/2020: The Applicant submitted a REMS modification for Xyrem NDA 021196 under prior
`approval supplement (PAS) 34, in response to the June 30, 2020 teleconference with the Agency
`on June 30, 2020, to update the REMS materials to incorporate Xywav into the existing REMS
`materials, and to add new REMS materials specific to Xywav, including the Xywav Patient Quick
`Start Guide, Xywav Brochure for Pediatric Patients and their Caregivers, and Xywav Prescription
`Form.
`• 7/17/2020: The Agency provided feedback on the Applicant’s 7/16/2020 submissions (the REMS
`modification for Xyrem and REMS amendment for Xywav), including revisions to the REMS
`materials to align with the proposed Prescribing Information (PI) for both products, and updates
`to the REMS assessment plan.
`• 7/20/2020: The Applicant submitted REMS amendments, consisting of a full REMS proposal, to
`NDAs 021196 and 212690, Xywav, incorporating the Agency’s comments from 7/17/2020.
`
`
`
` 3
`
` Therapeutic Context and Treatment Options
`
`
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Narcolepsy is a chronic neurological disorder characterized by EDS, cataplexy (attacks of loss of muscle
`tone precipitated by emotional gestures lasting for several minutes), sleep paralysis and hypnagogic
`
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`Reference ID: 4643955
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`

`hallucinations.e,5 The prevalence of narcolepsy with cataplexy is between 25 and 50 per 100,000 people
`(incidence 0.74 per 100,000 patient years).f,6 Narcolepsy patients, compared to the general US
`population, have a higher incidence of obstructive sleep apnea (50-68%)7; major depressive disorder
`(17%), social anxiety disorder (21%), and panic disorder (12%).8 Pediatric narcolepsy is associated with
`several co-morbid conditions, including metabolic diseases (including diabetes), obesity, precocious
`puberty and psychiatric comorbidities.9
`In pediatric patients diagnosed with narcolepsy, the onset of narcolepsy symptoms was noted in as
`many as 11.7% of children prior to age 510, and 59% of children prior to age 15.11 The diagnosis of
`narcolepsy is often delayed as the disorder is rare with low general awareness relative to other chronic
`diseases. While the median age of diagnosis has been reported as 33 years, the corresponding median
`age of symptom onset was 16 years.12
`
`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`Management of narcolepsy includes pharmacological and nonpharmacological approaches. Currently,
`Xyrem is the only approved drug for cataplexy.
`FDA approved drugs used to treat EDS include modafinil and methylphenidate.
`
` 4
`
` Benefit Assessment
`The clinical benefit of Xywav was established in a pivotal Phase 3 study, study 15-006 (National Clinical
`Trial [NCT] 03030599), in adults with cataplexy and EDS in narcolepsy.13 Study 15-006 is a two-part
`randomized, double blind, placebo controlled, random withdrawal study, designed to evaluate the
`efficacy and safety of Xywav in adult patients with cataplexy and EDS in narcolepsy. Study 15-006
`enrolled 201 subjects, with a median age of 38 years, and majority female (61%). At study entry, 52
`subjects were being treated with Xyrem, 23 subjects with Xyrem plus other anti-cataplectic, 36 subjects
`with a non-Xyrem anti-cataplectic, and 90 subjects were treatment-naïve. All subjects started treatment
`with Xywav in a 12-week open label, optimized treatment and titration period (OTTP), followed by a 2-
`week stable dose period then a 2-week, double blind, placebo controlled, randomized withdrawal
`period. Figure 1 demonstrates the flow of study 15-006:
`
`
`
`
`
`
`
`
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
`f Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
`
`
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`Reference ID: 4643955
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`

`Figure 1 – Study 15-006 Design
`
`
`The primary efficacy endpoint was the change in the average weekly number of cataplexy attacks from 2
`weeks of the stable dose period to 2 weeks of the double blind, randomized withdrawal period. The key
`secondary efficacy endpoint was the change in the Epworth Sleepiness Scale (ESS) score from the end of
`the stable dose period to the end of the double bind, randomized withdrawal period.
`Study 15-006 achieved the primary efficacy endpoint demonstrating clinical efficacy of Xywav for
`treatment of cataplexy and EDS in narcolepsy. Patients randomized to placebo during the double blind,
`randomized withdrawal period showed significant increase (worsening) in the average weekly number
`of cataplexy attacks compared with subjects randomized to continue treatment with Xywav (median of
`2.35 on placebo versus 0.0 on Xywav; p < 0.0001). There was no change in the median average weekly
`number of cataplexy attacks in patients who remained on Xywav during the same period.
`With regards to the secondary endpoint, subjects randomized to placebo during the double-blind
`randomized withdrawal period showed a significant increase (worsening) in the ESS score compared
`with subjects randomized to continue treatment with Xywav (median 2.0 on placebo versus 0.0 on
`Xywav, p < 0.0001). There was no change in the median ESS score in subjects remaining on Xywav
`treatment during the double randomized withdrawal period.
`Overall, adult patients on stable doses of Xywav had fewer cataplexy attacks and experienced less
`worsening in the ESS than did patients withdrawn from Xywav and randomized to placebo.14,g The
`effectiveness of oxybate in the treatment of cataplexy and excessive daytime sleepiness in pediatric
`patients 7 years of age and older with narcolepsy was established with Xyrem and not repeated in this
`study.15
`
` 5
`
` Risk Assessment and Safe-Use Conditions
`Sodium oxybate is a Schedule III controlled substance, as it is a salt of gamma hydroxybutyrate (GHB), a
`Schedule I controlled substance. Abuse or misuse of illicit GHB is associated with CNS adverse reactions,
`
`
`g Section 505-1 (a) of the FD&C Act: FDAAA factor (C): The expected benefit of the drug with respect to such disease
`or condition.
`
`
`
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`Reference ID: 4643955
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`

`including seizure, respiratory depression, decreased consciousness, coma, and death.h Because of the
`risks of inappropriate prescribing, misuse and abuse sodium oxybate, currently marketed as Xyrem, is
`available only through a REMS.i Because Xywav references Xyrem as a basis for its approval, and shares
`the same active moiety, oxybate, the Agency determined Xywav will be subject to the same REMS
`requirements and should be incorporated into the currently approved Xyrem REMS.16
`
` 6
`
` Expected Postmarket Use
`Xywav is proposed to be prescribed and dispensed in the same manner as Xyrem for use in the
`outpatient setting. Prescribers of Xywav are likely to be specialist providers who are knowledgeable of
`the risks associated with Xyrem and therefore should be familiar with the Xywav and Xyrem REMS
`requirements.
`
` 7 Review of Proposed REMS
`
`7.1 GENERAL
`The Applicant submitted a full REMS proposal, including REMS document, REMS supporting document,
`and all REMS appended materials, that incorporates Xywav into the existing Xyrem REMS creating the
`new Xywav and Xyrem REMS.
`
`
`7.2 REMS GOAL
`The Applicant has updated the goals to include the addition of Xywav to the modified Xyrem REMS. The
`new goals will state:
`The goal of the XYWAV and XYREM REMS is to mitigate the risks of serious adverse outcomes
`resulting from inappropriate prescribing, misuse, abuse, and diversion of XYWAV and XYREM by:
`3.
`Informing prescribers, pharmacists, and patients of:
`a. The risk of significant CNS and respiratory depression associated with XYWAV and
`XYREM
`b. The contraindication of use of XYWAV and XYREM with sedative hypnotics and alcohol
`c. The potential for abuse, misuse, and overdose associated with XYWAV and XYREM
`d. The safe use, handling, and storage of XYWAV and XYREM
`4. Ensuring that pharmacy controls exist prior to filling prescriptions for XYWAV and XYREM that:
`
`
`h Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-
`threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a
`persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that
`may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug
`experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may
`require medical or surgical intervention to prevent one of the outcomes listed in this definition.
`i Section 505-1 (a) of the FD&C Act: FDAAA factor (E): The seriousness of any known or potential adverse events
`that may be related to the drug and the background incidence of such events in the population likely to use the
`drug.
`
`
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`Reference ID: 4643955
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`

`a. Screen for concomitant use of sedative hypnotics and other potentially interacting
`agents
`b. Monitor for inappropriate prescribing, misuse, abuse, and diversion of XYWAV and
`XYREM
`c. Notify prescribers when patients are receiving concomitant contraindicated medications
`or there are signs of potential abuse, misuse, or diversion
`Reviewer’s Comments: We agree with the proposed goal for the Xywav and Xyrem REMS.
`
`7.3 REMS DOCUMENT
`The Applicant submitted a REMS document based on the existing Xyrem REMS document and updated
`to be consistent with the Agency’s draft Format and Content of a REMS Document Guidance for
`Industry17. The proposed REMS document has been revised to include Xywav in the current Xyrem
`REMS, and to include proposed Xywav specific REMS materials.
`Reviewer Comment: We agree with the Applicant’s proposed REMS document.
`
`7.4 REMS REQUIREMENTS
`
`7.4.1 REMS Participant Requirements and Materials
`In order to include Xywav into the Xyrem REMS, the Applicant incorporated Xywav into existing
`materials or provided Xywav specific materials when needed. The Applicant also proposed a ‘Takeback’
`Program whereby a patient may dispose of unused or expired drug using a Drug Enforcement Agency
`(DEA) compliant mailer obtained via the Certified Pharmacy. No other changes were made to the
`existing Xyrem ETASU. See below for specific REMS materials changes.
`
`7.4.2
`
` REMS Materials and Key Risk Messages
`7.4.2.1 General
`The key risk messages for the Xywav and Xyrem REMS remain the same as in the currently
`approved Xyrem REMS.
`The Applicant proposes revising the existing Xyrem REMS materials for use in the Xywav and
`Xyrem REMS and adding three Xywav-specific REMS materials. The current Xyrem REMS
`materials that were revised include:
`
`1. Prescriber Enrollment Form
`2. Patient Enrollment Form
`3. Prescriber Brochure
`4. Certified Pharmacy Training Program – Modules A and B
`5. Modules A and B Knowledge Assessment
`6. Xyrem Prescription Form
`7. Xyrem Patient Quick Start Guide
`8. Xyrem Brochure for Pediatric Patients and their Caregivers
`9. Patient Counseling Checklist
`10. Risk Management Report
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`Reference ID: 4643955
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`11
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`11. REMS Website
`
`The new REMS materials specific to Xywav include:
`
`1. Xywav Patient Quick Start Guide
`2. Xywav Brochure for Pediatric Patients and their Caregivers
`3. Xywav Prescription Form
`
`7.4.2.2 Prescriber Enrollment Form
`Patient Enrollment Form
`Module A Knowledge Assessment
`Module B Knowledge Assessment
`Risk Management Report
`Xyrem Prescription Form
`Editorial revisions to these materials have been proposed to incorporate Xywav into the REMS.
`Reviewer Comment: We find the proposed Prescriber Enrollment Form, Patient Enrollment Form,
`Module A and Module B Knowledge Assessments, Risk Management Report and, Xyrem
`Prescription Form acceptable.
`
`7.4.2.3 Prescriber Brochure
`Certified Pharmacy Training Program
`Editorial revisions to these materials have been proposed to incorporate Xywav into the REMS.
`Additional language has been added to educate Prescribers and Pharmacy staff, respectively, on
`transitioning patients between the two drugs and detailing the drug-specific Prescription Forms
`and patient educational materials. The Applicant accepted the Agency’s comment to remove
`promotional language
` and to align
`the content of the material with the draft PI.
`Reviewer Comment: We find the proposed Prescriber Brochure and Certified Pharmacy Training
`Program acceptable.
`
`7.4.2.4 Patient Counseling Checklist
`Editorial revisions to this material have been proposed to incorporate Xywav into the REMS
`and to align the content of the material with the draft PI.
`Reviewer Comment: We find the proposed Patient Counseling Checklist acceptable.
`
`7.4.2.5 Xywav Prescription Form
`This new material was proposed to incorporate Xywav into the REMS.
`Reviewer Comment: We find the proposed Xywav Prescription Form acceptable.
`
`7.4.2.6 Xyrem Patient Quick Start Guide
`Xyrem Brochure for Pediatric Patients and their Caregivers
`
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`12
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`Reference ID: 4643955
`
`(b) (4)
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`

`

`
`
`Editorial revisions to these materials have been proposed to incorporate Xywav into the REMS.
`The Applicant accepted the Agency’s comment to remove promotional language
`and to align the content of the material with the
`
`draft PI.
`Reviewer Comment: We find the proposed Xyrem Patient Quick Start Guide and Xyrem Brochure
`for Pediatric Patients and their Caregivers acceptable.
`
`7.4.2.7 Xywav Patient Quick Start Guide
`Xywav Brochure for Pediatric Patients and their Caregivers
`These new materials were proposed to incorporate Xywav into the REMS. The Applicant accepted
`the Agency’s comment to remove promotional language
`
`and to align the content of the material with the draft PI.
`Reviewer Comment: We find the proposed Xywav Patient Quick Start Guide and Xywav Brochure
`for Pediatric Patients and their Caregivers acceptable.
`
`
`7.5 REMS ASSESSMENT TIMETABLE
`The timetable for submission of assessments of the REMS remains the same as that approved on
`February 27, 2015 in the Xyrem REMS.
`
` 8
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` Supporting Document
`The Applicant made editorial revisions throughout the REMS Supporting Document (SD) to incorporate
`Xywav into the Xyrem REMS. Additionally, the attestations for the REMS stakeholders were updated to
`correlate with the new REMS document format.
`
`Reviewer Comment: We agree with the Applicant’s proposed REMS supporting document.
`
` 9
`
` REMS Assessment Plan
`The REMS Assessment Plan is summarized in the REMS Supporting Document and will be included in the
`Xywav Approval letter and Xyrem REMS Modification Approval letter. The proposed REMS Assessment
`Plan (AP) is based off the most recent Xyrem REMS AP, and the following revisions were made to:
`
`
`1. Align with the 2019 Draft Guidance for Industry - REMS Assessment: Planning and Reporting
`2. To add metrics to clarify existing metrics in the current Xyrem REMS (in the areas of Program
`Implementation and Operations, Program Compliance, Safe Use, and Health Outcomes)
`3. To add metrics related to the transition to a Shared REMS with Xywav and Xyrem
`
`
`The revised REMS Assessment Plan is attached as Appendix A.
`Reviewer Comment: We