Subject: Tolvaptan (Jynarque ) Tablet

Transcription

1 09-J Original Effective Date: 09/15/18 Reviewed: 08/08/18 Revised: 00/00/00 Subject: Tlvaptan (Jynarque ) Tablet THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION. Dsage/ Administratin Psitin Statement Billing/Cding Reimbursement Prgram Exceptins Definitins Related Guidelines Other References Updates DESCRIPTION: Jynarque (tlvaptan) is an ral, selective vaspressin V2-receptr antagnist apprved by the FDA in April 2018 t slw kidney functin decline in adults at risk f rapidly prgressing autsmal dminant plycystic kidney disease (ADPKD). Prir t FDA apprval, Jynarque was granted rphan drug designatin fr the treatment f ADPKD in April Jynarque is the first drug t be apprved by the FDA fr the management f patients with ADPKD. Tlvaptan inhibits vaspressin-stimulated cyst grwth in vitr and chlride-dependent fluid secretin int cysts. In animal mdels, decreased camp cncentratins are assciated with decreases in the ttal kidney vlume grwth rate and the rate f frmatin and enlargement f kidney cysts. Tlvaptan, as brand name Samsca, was initially apprved by the FDA in May 2009 fr the treatment f clinically significant hypervlemic and euvlemic hypnatremia. Samsca is initiated in a hspital setting due t frequent serum sdium mnitring requirements (t help prevent verly rapid crrectin and risk f smtic demyelinatin). In additin, due t the risk f hepatic injury, tlvaptan use when treating hypnatremia is limited t n mre than 30 days at a maximum dsage f 60 mg daily. Tlvaptan use in ADPKD requires cntinuus treatment at a higher dsage. As such, Jynarque is available nly thrugh a restricted distributin prgram under a Risk Evaluatin and Mitigatin Strategy (REMS) called the JYNARQUE REMS Prgram. Plycystic kidney disease is an inherited disease that causes lifelng grwth in kidney cysts and kidney vlume, leading t prgressive and irreversible decline in kidney functin. It may be inherited as an autsmal dminant r recessive trait. The autsmal dminant frm (ADPKD) is the mst cmmn genetic cause f chrnic kidney disease. ADPKD ccurs in all races and has a reprted prevalence f 1:400 t 1:1,000. Mst individuals eventually prgress t end-stage renal disease (ESRD) requiring dialysis and/r kidney transplant. ADPKD is the underlying cause f kidney disease in apprximately 5% f patients wh initiate dialysis each year in the US. Renal functin remains intact fr mst patients until

2 the furth decade f life; hwever, nce the glmerular filtratin rate (GFR) starts t decline, the average reductin is abut 4.5 ml/min per year. ADPKD is caused by tw knwn (and pssibly mre unknwn) genetic mutatins: PKD1 and PKD2. The PKD1 mutatins are mre cmmn (71% t 85%) than the PKD2 mutatins (15%). Patients with PKD2 have a less severe phentype (mean age f ESRD is 74 years) than thse with PKD1 (54 years). Diagnsis primarily relies upn assessment f family histry f ADPKD and imaging f the kidneys; ultrasngraphy is mst cmmnly used. In patients with a family histry, the number f renal cysts (depending n the patient s age) can generally cnfirm a diagnsis. Hwever, genetic testing is the nly way t establish a definitive diagnsis, and testing is particularly useful in patients withut a family histry f ADPKD. Genetic testing results are als useful in determining patients at higher risk fr rapid prgressin t ESRD. Other characteristics such as kidney size and early nset f symptms r hypertensin are als useful predictrs. The PROPKD (predicting renal utcmes in ADPKD) scre is a recently develped scring algrithm that stratifies ADPKD patients int lw, intermediate, r high risk fr rapid prgressin t ESRD. Prir t the apprval f tlvaptan, there were n FDA-apprved treatments fr patients with ADPKD. Treatment included nnspecific measures, such as strict bld pressure cntrl, dietary prtein restrictin, increased fluid intake, a lwsalt diet, and statins (t reduce cardivascular mrtality). Once a patient prgresses t ESRD the ptins are either dialysis r renal transplantatin. Jynarque was shwn t slw the rate f decline in renal functin in patients at risk f rapidly prgressing ADPKD in tw trials; TEMPO 3:4 in patients at earlier stages f disease and REPRISE in patients at later stages. The findings frm these trials, when taken tgether, suggest that Jynarque slws the lss f renal functin prgressively thrugh the curse f the disease, and led t the apprval by the FDA. In TEMPO 3:4, 1,445 adult patients with early (estimated creatinine clearance [ 60 ml/min), rapidly-prgressing (ttal kidney vlume [TKV] 750 ml and age <51 years) ADPKD were randmized 2:1 t treatment with tlvaptan r placeb. Patients received treatment twice a day (first dse n waking, secnd dse apprximately 9 hurs later). Patients were initiated n 45 mg/15 mg, and up-titrated weekly t 60 mg/30 mg and then t 90 mg/30 mg as tlerated. Patients were t maintain the highest tlerated dse fr 3 years. All patients were encuraged t drink adequate water t avid thirst r dehydratin and befre bedtime. The primary endpint was the difference fr rate f change f TKV nrmalized as a percentage. The ther key endpints were ADPKD-related events the slpw f EGFR during treatment. and At baseline, average egfr was 82 ml/min/1.73 m 2 and mean TKV was 1,692 ml (height adjusted 972 ml/m). The subjects mean age was 39 years, 48% were female, and 84% were Caucasian. Of the 770 subjects wh submitted t genetic analysis in TEMPO 3:4 s pen-label extensin, 749 (97%) had an identifiable mutatin in the PKD1 (656 r 88%), r PKD2 (93 r 12%) gene. The trial met its prespecified primary endpint f 3-year change in TKV (p<0.0001). The difference in TKV between treatment grups mstly develped within the first year, the earliest assessment, with little further difference in years tw and three. Tlvaptan has little effect n kidney size beynd what accrues during the first year f treatment. The relative rate f ADPKD-related events was decreased by 13.5% in tlvaptan-treated patients, (44 vs. 50 events per 100 persn-years; hazard rati, 0.87; 95% CI, 0.78 t 0.97; p=0.0095). The estimated difference in the annual rate f change in thse wh cntributed t the analysis was 1.0 ml/min/1.73m 2 /year (95% CI, 0.6 t1.4).

3 REPRISE was a duble-blind, placeb-cntrlled randmized withdrawal trial in adult patients (age 18 t 65) with CKD) with an egfr between 25 and 65 ml/min/1.73m 2 if yunger than age 56; r egfr between 25 and 44 ml/min/1.73m 2, plus egfr decline >2.0 ml/min/1.73m 2 /year if between age 56 t 65. Subjects were t be treated fr 12 mnths; after cmpletin f treatment, patients entered a 3- week fllw-up perid t assess renal functin. The primary endpint was the treatment difference in the change f egfr frm pre-treatment baseline t pst-treatment fllw-up, annualized by dividing by each subject s treatment duratin. Prir t randmizatin, patients were required t cmplete sequential single-blind run-in perids during which they received placeb fr 1 week, fllwed by tlvaptan titratin fr 2 weeks, and then treatment with tlvaptan at the highest tlerated dse achieved during titratin fr 3 weeks. During the titratin perid, tlvaptan was up-titrated every 3-4 days frm a daily ral dse f 30 mg/15 mg t 45 mg/15 mg, 60 mg/30 mg and up t a maximum dse f 90 mg/30 mg. Only patients wh culd tlerate the tw highest dses f tlvaptan (60 mg/30 mg r 90 mg/30 mg) fr the subsequent 3 weeks were randmized 1:1 t treatment with tlvaptan r placeb. Patients were maintained n their highest tlerated dse fr a perid f 12 mnth. All patients were encuraged t start drinking an adequate amunt f water at screening and cntinuing thrugh the end f the trial t avid thirst r dehydratin. A ttal f 1519 subjects were enrlled in the study. Of these, 1370 subjects successfully cmpleted the pre-randmizatin perid and were randmized and treated during the 12-mnth duble-blind perid. Because 57 subjects did nt cmplete the ff-treatment fllw-up perid, 1313 subjects were included in the primary efficacy analysis. Fr subjects randmized, the baseline, average egfr was 41 ml/min/1.73 m 2. Subjects mean age was 47 years, 50% were female, and 92% were Caucasian. In the randmized perid, the change f egfr frm pretreatment baseline t pst-treatment fllw-up was 2.3 ml/min/1.73 m2/year with tlvaptan as cmpared with 3.6 ml/min/1.73 m2/year with placeb, crrespnding t a treatment effect f 1.3 ml/min/1.73 m2/year (p <0.0001). The key secndary endpint (egfr slpe in ml/min/1.73 m2/year assessed using a linear mixed effect mdel f annualized egfr (CKD-EPI)) shwed a difference between treatment grups f 1.0 ml/min/ m2/year that was als statistically significant (p< ). POSITION STATEMENT: Cmparative Effectiveness The FDA has deemed the drug(s) r bilgical prduct(s) in this cverage plicy t be apprpriate fr self-administratin r administratin by a caregiver (i.e., nt a healthcare prfessinal). Therefre, cverage (i.e., administratin) in a prvider-administered setting such as an utpatient hspital, ambulatry surgical suite, physician ffice, r emergency facility is nt cnsidered medically necessary. Initiatin f Jynarque (tlvaptan) meets the definitin f medical necessity when ALL f the fllwing criteria are met ( 1 t 7 ) 1. Member has a diagnsis f autsmal dminant plycystic kidney disease (ADPKD) as cnfirmed by EITHER f the fllwing ( a r b ):

4 a. Psitive family histry f ADPKD AND presence f multiple kidney cysts as seen n apprpriate imagining studies (i.e., ultrasngraphy, CT, r MRI) dcumentatin frm the medical recrd nting the family histry and imaging results must be submitted b. Genetic testing shwing a pathgenic mutatin in the PKD1 r PKD2 gene labratry dcumentatin f the genetic test results must be submitted 2. The member is at high risk fr rapid prgressin t end-stage renal disease (ESRD) as determined by their treating nephrlgist 3. Member has a baseline (within the past 6 mnths) estimated glmerular filtratin rate (egfr) f greater than r equal t 25 ml/min/1.73m 2 labratry dcumentatin f egfr must be submitted 4. Treatment with Jynarque (tlvaptan) is prescriber by, r in cnsultatin with, a nephrlgist 5. Member is 18 years f age r lder 6. The member des nt have any f the fllwing FDA-labeled cntraindicatins t Jynarque (tlvaptan) treatment ( a t g ): a. A histry, signs r symptms f significant liver impairment r injury (des nt apply t uncmplicated plycystic liver disease) b. Taking strng CYP 3A inhibitrs (e.g., clarithrmycin, ketcnazle, ritnavir, vricnazle ) c. Uncrrected abnrmal bld sdium cncentratins d. Unable t sense r respnd t thirst e. Hypvlemia f. Hypersensitivity (e.g., anaphylaxis, rash) t tlvaptan r any cmpnent f the prduct g. Uncrrected urinary utflw bstructin 7. BOTH f the fllwing dsage limits ( a and b ): a. The initial dsage des nt exceed 45 mg (AM dse)-15 mg (PM dse) per day b. After titratin the maximum dsage des nt exceed 90 mg (AM dse)-30 mg (PM dse) per day must be achieved using the fewest number f tablets and blister cards pssible Apprval duratin: 6 mnths Cntinuatin f Jynarque (tlvaptan) meets the definitin f medical necessity when ALL f the fllwing criteria are met ( 1 t 3 ): 1. An authrizatin r reauthrizatin fr Jynarque (tlvaptan) has been previusly apprved by Flrida Blue r anther health plan in the past 2 years fr the treatment f autsmal dminant plycystic kidney disease, OR the member has previusly met ALL indicatin-specific initiatin criteria 2. Member has nt prgressed t end-stage renal disease (ESRD) that requires dialysis 3. The dsage f Jynarque (tlvaptan) des nt exceed 90 mg (AM dse)-30 mg (PM dse) per day must be achieved using the fewest number f tablets and blister cards pssible Apprval duratin: 1 year

5 DOSAGE/ADMINISTRATION: THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE. FDA-apprved T slw kidney functin decline in adults at risk f rapidly prgressing autsmal dminant plycystic kidney disease (ADPKD) The initial dsage is 60 mg rally per day as 45 mg taken n waking and 15 mg taken 8 hurs later. Titrate t 60 mg plus 30 mg then t 90 mg plus 30 mg per day if tlerated with at least weekly intervals between titratins. Patients may dwn-titrate based n tlerability. Encurage patients t drink enugh water t avid thirst r dehydratin. Dse Adjustments Drug Interactins: In patients taking cncmitant mderate CYP 3A inhibitrs (e.g., flucnazle), reduce the dse f as fllws: 90 mg and 30 mg reduce t 45 mg and 15 mg 60 mg and 30 mg reduce t 30 mg and 15 mg 45 mg and 15 mg reduce t 15 mg and 15 mg Cnsider further reductins if patients cannt tlerate the reduced dse. Interrupt Jynarque temprarily fr shrt term therapy with mderate CYP 3A inhibitrs if the recmmended reduced dses are nt available. Use is cntraindicated in patients taking strng CYP 3A inhibitrs Adverse Reactins: At the nset f signs r symptms cnsistent with hepatic injury r if ALT, AST, r bilirubin increase t >2 times ULN, immediately discntinue Jynarque, btain repeat tests as sn as pssible (within 48 t 72 hrs), and cntinue testing as apprpriate. If labratry abnrmalities stabilize r reslve, Jynarque may be reinitiated with increased frequency f mnitring as lng as ALT and AST remain belw 3x ULN. D nt restart in patients wh experience signs r symptms cnsistent with hepatic injury r whse ALT r AST ever exceeds 3x ULN during treatment with tlvaptan, unless there is anther explanatin fr liver injury and the injury has reslved. In patients with a stable, lw baseline AST r ALT, an increase abve 2x baseline, even if less than 2x ULN may indicate early liver injury. Such elevatins may warrant treatment suspensin and prmpt (48- t 72 hrs) re-evaluatin f liver test trends prir t reinitiating therapy with mre frequent mnitring. Hepatic impairment: Because f the risk f serius liver injury, use is cntraindicated in patients with a histry, signs r symptms f significant liver impairment r injury. This cntraindicatin des nt apply t uncmplicated plycystic liver disease which was present in 60% and 66% f patients in TEMPO 3:4 and REPRISE clinical trials, respectively. Renal impairment: Efficacy studies included patients with nrmal and reduced renal functin. TEMPO 3:4 required patients t have an estimated creatinine clearance 60 ml/min, while REPRISE included patients with egfrckd-epi 25 t 65 ml/min/1.73m 2. Data is nt available fr ADPKD patients with lwer renal functin. Drug Availability

6 Mrning and Afternn Dses 7-Day Blister Card (Cntaining 14 Tablets) NCD 28-Day Cartn (4 Blister Cards Cntaining a Ttal f 56 Tablets) 45 mg and 15 mg mg and 30 mg mg and 30 mg PRECAUTIONS: Bxed Warning WARNING: RISK OF SERIOUS LIVER INJURY Jynarque (tlvaptan) can cause serius and ptentially fatal liver injury. Acute liver failure requiring liver transplantatin has been reprted. Measure ALT, AST and bilirubin befre initiating treatment, at 2 weeks and 4 weeks after initiatin, then mnthly fr the first 18 mnths and every 3 mnths thereafter. Prmpt actin in respnse t labratry abnrmalities, signs, r symptms indicative f hepatic injury can mitigate, but nt eliminate, the risk f serius hepattxicity. Because f the risks f serius liver injury, Jynarque is available nly thrugh a restricted distributin prgram under a Risk Evaluatin and Mitigatin Strategy (REMS) called the JYNARQUE REMS Prgram. Cntraindicatins Patient with a histry, signs r symptms f significant liver impairment r injury. This cntraindicatin des nt apply t uncmplicated plycystic liver disease. Patients taking strng CYP 3A inhibitrs Patients with uncrrected abnrmal bld sdium cncentratins Patients unable t sense r respnd t thirst Patients with hypvlemia Patients with hypersensitivity (e.g., anaphylaxis, rash) t tlvaptan r any cmpnent f the prduct Patients with uncrrected urinary utflw bstructin Patients with anuria Precautins/Warnings Serius Liver Injury Jynarque can cause serius and ptentially fatal liver injury. Acute liver failure requiring liver transplantatin has been reprted in the pst-marketing ADPKD experience. Discntinuatin in respnse t labratry abnrmalities r signs r symptms f liver injury (such as fatigue, anrexia, nausea, right upper abdminal discmfrt, vmiting, fever, rash, pruritus, icterus,

7 dark urine r jaundice) can reduce the risk f severe hepattxicity. T reduce the risk f significant r irreversible liver injury, assess ALT, AST and bilirubin prir t initiatin f Jynarque, at 2 weeks and 4 weeks after initiatin, then mnthly fr 18 mnths and every 3 mnths thereafter. Jynarque REMS Prgram - Jynarque is available nly thrugh a restricted distributin prgram under a Risk Evaluatin and Mitigatin Strategy (REMS) called the JYNARQUE REMS Prgram, because f the risks f liver injury. Ntable requirements include the fllwing: Prescribers must be certified by enrlling in the REMS prgram Prescribers must infrm patients receiving Jynarque abut the risk f hepattxicity assciated with its use and hw t recgnize the signs and symptms f hepattxicity and the apprpriate actins t take if it ccurs Patients must enrll in the REMS prgram and cmply with nging mnitring requirements Pharmacies must be certified by enrlling in the REMS prgram and must nly dispense t patients wh are authrized t receive Jynarque. Further infrmatin, including a list f qualified pharmacies/distributrs, is available at r by telephne at Hypernatremia, Dehydratin and Hypvlemia - Jynarque increases free water clearance and, as a result, may cause dehydratin, hypvlemia and hypernatremia. Therefre, ensure abnrmalities in sdium cncentratins are crrected prir t initiatin f therapy. Instruct patients t drink water when thirsty, and thrughut the day and night if awake. Mnitr fr weight lss, tachycardia and hyptensin because they may signal dehydratin. In the tw duble-blind, placeb-cntrlled trials f patients with ADPKD, hypernatremia (defined as any serum sdium cncentratin >150 meq/l) was bserved in 4.0% vs. 0.6% and 1.4% vs. 0% f tlvaptan-treated vs. placeb-treated patients, respectively. The rate f dehydratin and hypvlemia in the tw studies was 2.1% vs. 0.7% and 2.3% vs. 0.4% fr tlvaptan-treated versus placeb-treated patients, respectively. If serum sdium increases abve nrmal range r the patient becmes hypvlemic r dehydrated and fluid intake cannt be increased, then suspend treatment until serum sdium, hydratin status and vlume status is within the nrmal range. C-Administratin with Inhibitrs f CYP 3A - Cncmitant use f Jynarque with drugs that are mderate r strng CYP 3A inhibitrs (e.g., ketcnazle, itracnazle, lpinavir/ritnavir, indinavir/ritnavir, ritnavir, and cnivaptan) increases tlvaptan expsure. Use with strng CYP 3A inhibitrs is cntraindicated; dse reductin f Jynarque is recmmended fr patients while taking mderate CYP 3A inhibitrs. Other Drug Interactins - The xbutyric acid metablite f tlvaptan is an inhibitr f OATP1B1/B3 and OAT3 in vitr. Patients wh take Jynarque shuld avid cncmitant use with OATP1B1/B3 and OAT3 substrates (e.g., statins, bsentan, glyburide, nateglinide, repaglinide, methtrexate, fursemide), as the plasma cncentratins f these substrates may be increased. Tlvaptan is an inhibitr f BCRP. Patients wh take Jynarque shuld avid cncmitant use with BCRP substrates (e.g., rsuvastatin). As a V2-receptr antagnist, tlvaptan will interfere with the V2-agnist activity f desmpressin. Avid cncmitant use f Jynarque with a V2-agnist Pregnancy - Available data with Jynarque use in pregnant wmen are insufficient t determine if there is a drug assciated risk f adverse develpmental utcmes.. At maternally nn-txic dses, tlvaptan did nt cause any develpmental txicity in rats r in rabbits. Hwever, effects n embryfetal develpment ccurred in bth species at maternally txic dses. Advise pregnant wmen f the ptential risk t the fetus. BILLING/CODING INFORMATION: The fllwing cdes may be used t describe:

8 HCPCS Cding J8499 Prescriptin drug, ral, nn-chemtherapeutic, Nt Otherwise Specified ICD-10 Diagnses Cdes That Supprt Medical Necessity Q61.2 Plycystic kidney, adult type REIMBURSEMENT INFORMATION: Refer t sectin entitled POSITION STATEMENT. PROGRAM EXCEPTIONS: Federal Emplyee Prgram (FEP): Fllw FEP guidelines. State Accunt Organizatin (SAO): Fllw SAO guidelines. Medicare Part D: BCBSF has delegated t Prime Therapeutics authrity t make cverage determinatins fr the Medicare Part D services referenced in this guideline. Medicare Advantage: N Natinal Cverage Determinatin (NCD) and/r Lcal Cverage Determinatin (LCD) were fund at the time f guideline creatin. DEFINITIONS: Nne RELATED GUIDELINES: Nne OTHER: PROPKD Scring Algrithm and Risk Categries Variable Categry Pints Bilgical sex Hypertensin befre 35 years f age Female 0 Male 1 N 0 Yes 2 At least ne urlgical cmplicatin* N 0

9 befre 35 years f age Yes 2 PKD2 0 Mutatin type PKD1/Nn- Truncating 2 PKD1/Truncating 4 Risk Categries: Lw-risk: 0 t 3 pints Intermediate-risk: 4 t 6 pints High-risk: 7 t 9 pints *Qualifying cmplicatins include hematuria, cyst infectin, and cyst-related flank pain REFERENCES: 1. Blignan D, Palmer SC, Rusp M, et al. Interventins fr preventing the prgressin f autsmal dminant plycystic kidney disease. Cchrane Database Syst Rev Jul 14;(7):CD Chapman AB, Devuyst O, Eckardt KU, et al. Autsmal-dminant plycystic kidney disease (ADPKD): executive summary frm a Kidney Disease: Imprving Glbal Outcmes (KDIGO) Cntrversies Cnference. Kidney Int Jul;88(1): Epub 2015 Mar Clinical Pharmaclgy [database nline]. Tampa, FL: Gld Standard, Inc.; Available at: Accessed 7/16/ Crnec-Le Gall E, Audrézet MP, Russeau A, et al. The PROPKD Scre: A New Algrithm t Predict Renal Survival in Autsmal Dminant Plycystic Kidney Disease. J Am Sc Nephrl Mar;27(3): Epub 2015 Jul Crnec-Le Gall E, Blais JD, Irazabal MV, et al. Can we further enrich autsmal dminant plycystic kidney disease clinical trials fr rapidly prgressive patients? Applicatin f the PROPKD scre in the TEMPO trial. Nephrl Dial Transplant Jul 19. [Epub ahead f print] 6. Edwards ME, Chebib FT, Irazabal MV, et al. Lng-Term Administratin f Tlvaptan in Autsmal Dminant Plycystic Kidney Disease. Clin J Am Sc Nephrl Jul 19. pii: CJN [Epub ahead f print] 7. Harris T, Sandfrd R, de Cninck B, et al. Eurpean ADPKD Frum multidisciplinary psitin statement n autsmal dminant plycystic kidney disease care: Eurpean ADPKD Frum and Multispecialist Rundtable participants. Nephrl Dial Transplant Dec 22.. [Epub ahead f print]. 8. Hrie S, Mchizuki T, Mut S, et al. Evidence-based clinical practice guidelines fr plycystic kidney disease Clin Exp Nephrl Aug;20(4): Jynarque (tlvaptan) package insert. Tky, Japan: Otsuka Pharmaceutical C; April Micrmedex Healthcare Series [Internet Database]. Greenwd Village, Cl: Thmsn Healthcare. Updated peridically. Accessed 7/16/18.

10 11. Müller RU, Haas CS, and Sayer JA. Practical appraches t the management f autsmal dminant plycystic kidney disease patients in the era f tlvaptan. Clin Kidney J Feb;11(1): Epub 2017 Jul Pei Y, Obaji J, Dupuis A, et al. Unified criteria fr ultrasngraphic diagnsis f ADPKD. J Am Sc Nephrl Jan;20(1): Epub 2008 Oct Trres VE, Chapman AB, Devuyst O, et al. Multicenter, pen-label, extensin trial t evaluate the lng-term efficacy and safety f early versus delayed treatment with tlvaptan in autsmal dminant plycystic kidney disease: the TEMPO 4:4 Trial. Nephrl Dial Transplant Mar 1;33(3): Trres VE, Chapman AB, Devuyst O, et al. Tlvaptan in Later-Stage Autsmal Dminant Plycystic Kidney Disease. N Engl J Med Nv 16;377(20): Epub 2017 Nv Trres VE, Chapman AB, Devuyst O, et al. Tlvaptan in patients with autsmal dminant plycystic kidney disease. N Engl J Med Dec 20;367(25): Epub 2012 Nv Trres VE, Higashihara E, Devuyst O, et al. Effect f Tlvaptan in Autsmal Dminant Plycystic Kidney Disease by CKD Stage: Results frm the TEMPO 3:4 Trial. Clin J Am Sc Nephrl May 6;11(5): Epub 2016 Feb 23. COMMITTEE APPROVAL: This Medical Cverage Guideline (MCG) was apprved by the BCBSF Pharmacy Plicy Cmmittee n 08/08/18. GUIDELINE UPDATE INFORMATION: 09/15/18 New Medical Cverage Guideline.