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New York State Medicaid Preferred Drug Program Fax Number: (800) 268-2990Sovaldi? Combination Therapy Prior Authorization WorksheetEnrollee Informationenrollee Name: FORMTEXT ?????enrollee medicaid Id number (2 letters, 5 numbers, 1 letter): FORMTEXT ?????enrollee date of birth: FORMTEXT ?????gender: FORMCHECKBOX Female FORMCHECKBOX Male Prescriber Informationprescriber Name: FORMTEXT ?????Contact person: FORMTEXT ?????10-digit Npi number: FORMTEXT ?????office Phone Number:( FORMTEXT ??? ) FORMTEXT ??? - FORMTEXT ????office Fax number:( FORMTEXT ??? ) FORMTEXT ??? - FORMTEXT ????Are you a gastroenterologist, hepatologist, transplant physician or infectious disease specialist? FORMCHECKBOX Yes FORMCHECKBOX NoIf no, are you working in collaboration with a specialist listed above? FORMCHECKBOX Yes FORMCHECKBOX NoIf no, do you have clinical experience with the management and treatment of hepatitis c virus (HCV) infection? FORMCHECKBOX Yes FORMCHECKBOX NoClinical experience is defined as the management AND treatment of at least 10 patients with HCV infection within the past 12 months and at least 10 HCV-related CME credits in the last 12 months.Clinical CriteriaMEDICAL STATUSDiagnosis Chronic Hepatitis C Infection FORMCHECKBOX Yes FORMCHECKBOX NoHCV Genotype: FORMCHECKBOX 1a FORMCHECKBOX 1b FORMCHECKBOX 2 FORMCHECKBOX 3 FORMCHECKBOX 4Has documentation confirming genotype been submitted? FORMCHECKBOX Yes FORMCHECKBOX NoBaseline quantitative HCV RNA: FORMTEXT ????? IU/mlDate completed: FORMTEXT ?????Does the member have cirrhosis? FORMCHECKBOX Yes FORMCHECKBOX No If yes, please indicate Child-Pugh class: FORMCHECKBOX A FORMCHECKBOX B FORMCHECKBOX C OR METAVIR fibrosis score: FORMCHECKBOX 1 FORMCHECKBOX 2 FORMCHECKBOX 3 FORMCHECKBOX 4 (evaluation of liver fibrosis is recommended for all patients with HCV to assist in determining the HCV treatment strategy) Does the patient have severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) or end stage renal disease (ESRD)? FORMCHECKBOX Yes FORMCHECKBOX No(sofosbuvir is not recommended in patients with severe renal impairment or ESRD) Was screening for evidence of current or prior Hepatitis B virus (HBV) infection completed? FORMCHECKBOX Yes FORMCHECKBOX No Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-upPREGNANCYFor female patients of child bearing potential: Has a negative pregnancy test been collected within 30 days prior to initiation of therapy OR medical record submitted documenting pregnancy status? FORMCHECKBOX Yes FORMCHECKBOX NoTREATMENT HISTORYWas the current Sovaldi regimen initiated at another healthcare facility or previously covered by another health plan? FORMCHECKBOX Yes FORMCHECKBOX NoIF YES, how many weeks of previous therapy have been completed prior to the date of this request? FORMTEXT ?????Please check the box that best describes the patient’s HCV treatment status:Treatment-na?ve FORMCHECKBOX Yes FORMCHECKBOX NoTreatment-experienced FORMCHECKBOX Yes FORMCHECKBOX NoIf treatment experienced, is the patient a non-responder to:pegylated interferon + ribavirin FORMCHECKBOX Yes FORMCHECKBOX Nosofosbuvir + ribavirin FORMCHECKBOX Yes FORMCHECKBOX Nopegylated interferon + ribavirin + HCV protease inhibitor (telaprevir, boceprevir or simeprevir) FORMCHECKBOX Yes FORMCHECKBOX Noother: FORMTEXT ?????TREATMENT READINESSPlease indicate which of the following scales/assessment tools was used to evaluate the readiness of the patient (only one is required): FORMCHECKBOX SAMHSA-HRSA Center for Integrated Health Solutions – Drug & Alcohol Screening Tools – Available at: checked, please provide the name of SAMSHA-HRSA drug and alcohol screening tool used (required): FORMTEXT ????? FORMCHECKBOX Psychosocial Readiness Evaluation and Preparation for Hepatitis C Treatment (PREP-C) – Available at: Has the patient demonstrated treatment readiness, including the ability to adhere to the prescribed treatment regimen? FORMCHECKBOX Yes FORMCHECKBOX NoCONTINUATION OF THERAPY REQUESTS **This portion is not required for initial therapy requests Week 4 (±2 weeks) HCV RNA Level: FORMTEXT ?????Date Taken: FORMTEXT ?????Week 12 HCV RNA Level: FORMTEXT ?????Date Taken: FORMTEXT ?????Has documentation confirming HCV RNA levels at the appropriate week been submitted? FORMCHECKBOX Yes FORMCHECKBOX NoHas the patient completed all HCV evaluation appointments and procedures and demonstratedcompliance to their treatment regimen? FORMCHECKBOX Yes FORMCHECKBOX NoCURRENT TREATMENT REGIMENPlease indicate the Sovaldi combination treatment regimen that is being prescribed:HCV GenotypeSpecific Patient Population (if applicable)Treatment RegimenTreatment DurationSovaldi + ribavirin (RBV) ± peginterferon alfa Accepted Regimens* FORMCHECKBOX 1,4interferon eligibleSovaldi + RBV + peginterferon alfa12 weeks FORMCHECKBOX 1interferon ineligibleSovaldi + RBV24 weeks FORMCHECKBOX 2--Sovaldi + RBV^12 weeks FORMCHECKBOX 2with cirrhosisSovaldi + RBV16 weeks FORMCHECKBOX 3--Sovaldi + RBV^24 weeks FORMCHECKBOX 3--Sovaldi + RBV + peginterferon alfa12 weeks FORMCHECKBOX 1,2,3,4with hepatocellular carcinoma awaiting liver transplantSovaldi +RBV48 weeks or until time of liver transplantation, whichever comes firstSovaldi + Olysio Accepted Regimens? FORMCHECKBOX 1without cirrhosis, without HIV co-infectionSovaldi + Olysio12 weeks FORMCHECKBOX 1with cirrhosis, without HIV-1 co-infectionSovaldi + Olysio24 weeksSovaldi + Daklinza Accepted Regimens FORMCHECKBOX 1**without cirrhosis or with compensated (Child-Pugh A) cirrhosisSovaldi + Daklinza12 weeks FORMCHECKBOX 1**with decompensated (Child-Pugh B-C) cirrhosis or post-transplantSovaldi + Daklinza + RBV12 weeks FORMCHECKBOX 3without cirrhosis Sovaldi + Daklinza12 weeks FORMCHECKBOX 3with compensated (Child-Pugh A) or decompensated (Child-Pugh B-C) cirrhosis or post-transplantSovaldi + Daklinza + RBV12 weeks*For patients with HCV/HIV-1 co-infection, follow the dosage recommendations above.^Recommended treatment regimen and duration for pediatric patients who are ≥ 12 years of age or weigh ≥ 35kg. **Consider screening for the presence of NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis who are infected with HCV genotype 1a prior to the initiation of treatment with Daklinza and Sovaldi with or without RBV.?Consider screening for the presence of NS 3Q80K polymorphism in patients who are infected with HCV genotype 1a prior to initiation of treatment with Olysio and Sovaldi. Please provide dosing information for the treatment regimen selected above: FORMCHECKBOX Sovaldi STRENGTH: 400 mg DIRECTIONS: 1 tablet daily with or without food QUANTITY: FORMTEXT ????? REFILLS: FORMTEXT ????? FORMCHECKBOX Daklinza STRENGTH: 60 mg DIRECTIONS: 1 tablet daily with or without food QUANTITY: FORMTEXT ????? REFILLS: FORMTEXT ????? FORMCHECKBOX Pegasys FORMCHECKBOX Pegintron DOSAGE FORM: FORMTEXT ????? DIRECTIONS: FORMTEXT ????? QUANTITY: FORMTEXT ????? REFILLS: FORMTEXT ????? FORMCHECKBOX Ribavirin FORMCHECKBOX Other Ribavirin Product FORMTEXT ?????STRENGTH: FORMTEXT ????? DIRECTIONS: FORMTEXT ????? QUANTITY: FORMTEXT ????? REFILLS: FORMTEXT ????? FORMCHECKBOX OlysioSTRENGTH: 150 mg DIRECTIONS: 1 capsule daily with or without food QUANTITY: FORMTEXT ????? REFILLS: FORMTEXT ?????Please answer the following questions if requesting a non-preferred ribavirin product as part of treatment: Patient has experienced a treatment failure with a preferred drug. FORMCHECKBOX Yes FORMCHECKBOX NoPatient has experienced an adverse drug reaction with a preferred drug. FORMCHECKBOX Yes FORMCHECKBOX NoThere is a documented history of successful therapeutic control with a nonpreferred drug and transition to a preferred drug is medically contraindicated. FORMCHECKBOX Yes FORMCHECKBOX No FORMCHECKBOX Other (Please specify the clinical reason the patient is unable to use a preferred agent in the same drug class. If necessary, fax additional pages): FORMTEXT ?????Please provide any additional information that should be considered in the space below: FORMTEXT ?????I attest that this is medically necessary for this patient and that all of the information on this form is accurate to the best of my knowledge. I attest that documentation of the above diagnosis and medical necessity is available for review if requested by New York Medicaid. FORMTEXT ?????Prescriber’s signaturedateSofosbuvir (Sovaldi?)Sofosbuvir is an oral treatment option for adult patients with chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, or 4 infection, with compensated cirrhosis (Child-Pugh A) or without cirrhosis in combination with pegylated interferon and/or ribavirin (RBV).1 It is also approved by the Food and Drug Administration (FDA) for pediatric patients ≥12 years of age or ≥35 kg, with GT 2 or 3 infection with compensated cirrhosis (Child-Pugh A) or without cirrhosis in combination with RBV. Sofosbuvir is indicted for the treatment of HCV for both adult and pediatric patients with HCV/human immunodeficiency virus (HIV)-1 co-infection, adult patients with hepatocellular carcinoma awaiting liver transplant and adult patients who are pegylated interferon ineligible. Sofosbuvir must be given as a component of an antiviral treatment regimen. It is not indicated for monotherapy.Approved by the FDA in December 2013, sofosbuvir was the first direct-acting antiviral (DAA) agent in the nucleoside/nucleotide polymerase inhibitor class.1 A nucleotide analog, sofosbuvir interferes with the HCV life cycle by inhibiting HCV NS5B ribonucleic acid (RNA)-dependent RNA polymerase to prevent replication of the HCV virus. Sofosbuvir is indicated for use in combination with pegylated interferon and ribavirin (PR) for HCV genotypes 1 and 4 in adult patients and in combination with RBV for GT 2 and 3 for both adult and pediatric patients ≥12 years of age or ≥35 kg. The combination of sofosbuvir and simeprevir (Olysio?) is also FDA-approved for the treatment of HCV GT 1 infection in treatment-na?ve or experienced adult patients without cirrhosis or with compensated cirrhosis (Child-Pugh A).2 Advantages of sofosbuvirSofosbuvir is taken orally once daily with or without food as a component of an antiviral treatment regimen.1 The product is FDA-approved for both adult and pediatric patients ≥12 years of age or ≥35 kg with HCV who are treatment na?ve or experienced with or without compensated (Child-Pugh A) cirrhosis. The treatment regimen and duration is dependent on both the HCV GT and patient characteristics. Published clinical trials have demonstrated the efficacy of sofosbuvir in combination with PR for adult patients with GT 1 or 4 and in combination with RBV alone for both adult and pediatric patients with GT 2 or 3. Recommended treatment regimens are identical for patients with HCV mono-infection or HCV/HIV-1 co-infection. The primary endpoint was defined as HCV RNA less than the lower level of quantification (<25 IU/mL) at 12-weeks post treatment (SVR12).Published phase III trials:TrialSubjectsTreatment armsOverall SVR12 rate SVR12 rate by genotype1234NEUTRINOPEVuZE5vdGU+PENpdGU+PFJlY051bT4xPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNl
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ADDIN EN.CITE.DATA 1,4201 adults with prior breakthrough, relapse, or null response with interferon SOF + RBV x 12 weeksSOF + RBV x 16 weeks50%71%--82%89%30%62%--NR=not reported; PR=peginterferon + ribavirin; RBV=ribavirin; SOF=sofosbuvir; SVR12=12-weeks post treatment Cautions1Prior to initiating therapy with any HCV DAA agent, all patients should be tested for evidence of current or prior hepatitis B virus (HBV) infection by measuring the hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment with a DAA agent and during post-treatment follow-up. Coadministration of amiodarone with sofosbuvir in combination with another DAA is not recommended due to risk of severe symptomatic bradycardia. Sofosbuvir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug transporters. Do not coadminister sofosbuvir with potent P-gp inducers due to risk of reduced sofosbuvir concentrations and treatment failure.Sofosbuvir should not be used as monotherapy and only as a component of an antiviral regimen dependent on the patient’s genotype and other conditions (see table below). Sofosbuvir dose must not be reduced nor should treatment be interrupted. For patients with severe renal impairment or with end stage renal disease, no dosage recommendations are available. Where does sofosbuvir fit into therapy and how should it be used? In January 2014, The American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society – USA, launched for the purpose of disseminating expert opinion on management of chronic HCV. The guidelines continue to evolve as newer HCV DAA agents become available and treatment evidence emerges. Patient-specific factors must be taken into consideration when deciding to initiate therapy and baseline genotype must be established to guide treatment regimen and duration as outlined below. Sofosbuvir is dosed 400 mg once daily with or without food as part of an antiviral regimen. The goal of treatment is undetectable HCV RNA at SVR12.Sofosbuvir treatment regimen and duration recommendations ADDIN EN.CITE <EndNote><Cite><RecNum>1</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="59v0rz5ad02p5yevxzy5zrzppsr5wr0x9exa">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>Sovaldi (sofosbuvir) product information. Foster City, CA: Gilead Sciences, Inc; December 2013</title></titles><dates></dates><urls></urls></record></Cite></EndNote>1Genotype Patient PopulationAdult Regimen and DurationPediatric Regimen and Duration*GT 1Treatment na?ve or experienced without cirrhosisSOF + simeprevir for 12 weeksNot indicatedTreatment na?ve or experienced with compensated cirrhosis (Child-Pugh A)SOF + simeprevir for 24 weeksNot indicatedGT 1 or 4Treatment-na?ve without cirrhosis or with compensated cirrhosis (Child-Pugh A)SOF + PR for 12 weeksNot indicatedGT 2SOF + RBV for 12 weeksSOF + RBV for 12 weeksGT 3SOF + RBV for 24 weeksSOF + RBV for 24 weeksGT=genotype; PR=pegylated interferon and ribavirin; RBV=ribavirin; SOF=sofosbuvir*Recommended treatment regimen and duration for pediatric patients who are ≥12 years of age or weighing ≥35 kgFor adult patients with HCV awaiting liver transplantation, the recommended treatment is SOF + RBV for up to 48 weeks or until transplant, whichever occurs first. For adult patients with GT 1 who are interferon ineligible, the recommended regimen is SOF+RBV for 24 weeks. References: 1. Sovaldi? product information. Gilead Sciences, 2017. 2. Olysio? product information. Janssen Therapeutics, 2017. 3. Lawitz et al. NEJM 2013;368(20):1878-87. 4. Jacobson et al. NEJM 2013;368(20):1867-77.Sofosbuvir Initiation and MonitoringOnce patient readiness for chronic hepatitis C virus (HCV) treatment has been determined, the algorithm below outlines key decision points for initiating and monitoring combination therapy including sofosbuvir. Prior to initiating HCV DAA therapy, test for the evidence of HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.Note: Ribavirin (RBV) is contraindicated in pregnancy; therefore, all female patients of childbearing age (or female partners of male patients) should be sure they are not pregnant prior to beginning treatment and should use 2 methods of non-hormonal birth control throughout treatment. Also note, HCV RNA testing should be conducted using a sensitive assay. left5818505GT= genotype00GT= genotype11525254016375003373445503745546247054191000GT 1 interferon eligible or genotype 2 or 4: treatment is completeGT 1 interferon eligible or genotype 2 or 4: treatment is complete280352512668250018008605581650057990005052098008235951312545Yes0Yes-2571742447925Initiate sofosbuvir 400 mg once daily with weight based ribavirin for both pediatric and adult patient 00Initiate sofosbuvir 400 mg once daily with weight based ribavirin for both pediatric and adult patient 26479492447925Initiate sofosbuvir 400 mg once daily with peginterferon alpha and weight based ribavirin for adult patients only00Initiate sofosbuvir 400 mg once daily with peginterferon alpha and weight based ribavirin for adult patients only11661905038751Has the patient been diagnosed with HCV GT 1, 2, 3 or 4 and received quantitative HCV RNA testing?GT 1 interferon eligible or genotype 4Continue sofosbuvir 400 mg once daily as a component of antiviral therapy to the end of treatment week 12 Repeat quantitative HCV RNA. Is HCV RNA ≤ 25 IU/ ml?GT 1 interferon ineligible or GT 3: continue regimen for an additional 12 weeks for total treatment duration of 24 weeksObtain HCV RNA 12 weeks after the end of treatment to determine sustained virological response (SVR12) NoNoYesHepatocellular carcinoma: continue regimen for up to an additional 36 weeks or until liver transplantation, whichever occurs first, for total treatment duration of 48 weeksEvaluate patient adherence and consider discontinuing therapy If therapy is discontinued no further HCV RNA testing is requiredSeek alternative treatment options or conduct testing prior to treatmentDoes the patient have hepatocellular carcinoma and awaiting liver transplantation?Has the patient been diagnosed with HCV GT 1, 2, 3 or 4 and received quantitative HCV RNA testing?GT 1 interferon eligible or genotype 4Continue sofosbuvir 400 mg once daily as a component of antiviral therapy to the end of treatment week 12 Repeat quantitative HCV RNA. Is HCV RNA ≤ 25 IU/ ml?GT 1 interferon ineligible or GT 3: continue regimen for an additional 12 weeks for total treatment duration of 24 weeksObtain HCV RNA 12 weeks after the end of treatment to determine sustained virological response (SVR12) NoNoYesHepatocellular carcinoma: continue regimen for up to an additional 36 weeks or until liver transplantation, whichever occurs first, for total treatment duration of 48 weeksEvaluate patient adherence and consider discontinuing therapy If therapy is discontinued no further HCV RNA testing is requiredSeek alternative treatment options or conduct testing prior to treatmentDoes the patient have hepatocellular carcinoma and awaiting liver transplantation?116619040293033388395404233320857053766161003705860283773900115951028409900010204701842237GT 1 interferon ineligible or GT 2 or 3 00GT 1 interferon ineligible or GT 2 or 3 36807511532123001918812153138900187642515208250028264071263800No0No1907061519243Yes0YesDaclatasvir (Daklinza?)Daclatasvir (Daklinza?), a direct-acting antiviral (DAA) agent, is an inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A inhibitor) that received Food and Drug Administration (FDA) approval in July 2015. Daclatasvir is indicated for use with sofosbuvir (Sovaldi?), with or without ribavirin, for the treatment of HCV genotype (GT) 1 or 3 infection in adult patients.1 The product label was expanded in February 2016 to include treatment recommendations for the following HCV GT 1 and GT 3 infected populations: patients co-infected with human immunodeficiency virus (HIV)-1, liver transplant recipients (post-transplantation), and patients with compensated (Child-Pugh A) or decompensated (Child-Pugh B or C) cirrhosis. NS5A resistance-associated polymorphism testing is recommended for patients with GT 1a and cirrhosis. Daclatasvir is a substrate of cytochrome P450 3A (CYP3A) and is primarily metabolized by CYP3A.1 Additionally, daclatasvir is an inhibitor of P-glycoprotein (P-gp), organic anion transport polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). The metabolism of daclatasvir may alter the plasma concentrations of other drugs and, conversely, other drugs may alter the concentration of daclatasvir, when administered concurrently. The recommended dosage of daclatasvir is 60 mg once daily, administered by mouth with or without food.1 Daclatasvir must be used in combination with sofosbuvir 400 mg once daily, with or without ribavirin, for 12 weeks. The daclatasvir dose should be reduced to 30 mg once daily when given in combination with drugs that strongly inhibit CYP3A and certain HIV antiviral agents (e.g., certain protease inhibitors and cobicistat-containing regimens). Conversely, when used in combination with drugs that moderately induce CYP3A and nevirapine, efavirenz and etravirine (non-nucleoside reverse transcriptase inhibitors [NNRTIs]), the daclatasvir dose should be increased to 90 mg once daily. Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A (e.g., phenytoin, carbamazepine, rifampin, and St. John’s wort). Daclatasvir is commercially available in 30 mg and 60 mg tablets. Advantages of daclatasvirDaclatasvir with sofosbuvir, with or without RBV, is an oral regimen given daily for 12 weeks with or without food.1 No dosage adjustments are needed for patients with renal impairment. Additionally, no dose adjustments are needed for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment. The safety and efficacy of the combination of daclatasvir and sofosbuvir, with or without RBV, were evaluated in 3 Phase 3 open-label trials (ALLY-1, -2, and -3).1-3 Both ALLY-1 and ALLY-3 were 12-week studies.1,2 ALLY-2 had 2 treatment durations: 8 and 12 weeks.3 The primary endpoint of the studies was defined as HCV RNA less than the lower level of quantification (<25 IU/mL) at 12 weeks post-treatment (SVR12). Phase 3 open-label trialsTrialPopulationStudy Arm (study size [n])SVR (study size [n])ALLY-11Compensated/decompensated cirrhosis or post-liver transplantdaclatasvir/sofosbuvir/ribavirin(n = 113)Advanced cirrhosis (n = 60) = 83%Post-transplant (n = 53) = 94%ALLY-23GT 1, 2, 3, or 4, TN and TE,HIV co-infected daclatasvir/ sofosbuvir(n = 203)12 weeks:TN (n = 101) = 96.4%TE (n = 52) = 97.7%8 weeks:TN (n = 50) = 75.6%TE = not studiedALLY-32GT 3, TN and TE, with/without cirrhosisdaclatasvir/ sofosbuvir(n = 152)TN (n = 101) = 90%Without cirrhosis = 97%With cirrhosis = 58%TE (n = 51) = 86%Without cirrhosis = 94%With cirrhosis = 69%GT = genotype; SVR = sustained virological response; TN = treatment-na?ve; TE = treatment experiencedCautions1Prior to initiating therapy with any HCV direct acting antiviral (DAA) agent, all patients should be tested for evidence of current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment with a DAA agent and during post-treatment follow-up. In HCV GT 1a infected patients with cirrhosis, NS5A polymorphisms at amino acid positions M28, Q30, L31 or Y93, resulted in reduced efficacy of daclatasvir with sofosbuvir, with or without RBV. It is estimated that the prevalence of polymorphisms at the aforementioned positions is 11% in the United States. Since data from the daclatasvir clinical trials were insufficient (ALLY-1 and ALLY-2), the impact of NS5A polymorphisms at amino acid positions M28, Q30, L31 or Y93 was difficult to assess and was not reported in the product labeling. Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A, as the effectiveness of daclatasvir is reduced. The daclatasvir dose should be increased when given in combination with drugs that moderately induce CY3A and nevirapine, efavirenz and etravirine and reduced when given in combination with drugs that inhibit CYP3A and certain HIV antiviral agents. Co-administration of amiodarone with daclatasvir and sofosbuvir may result in bradycardia and is not recommended. If the combination cannot be avoided then cardiac monitoring is recommended. For patients utilizing daclatasvir concurrently with dabigatran, the patient’s renal function should be monitored. Dabigatran dose adjustments may be required. Daclatasvir can increase the therapeutic concentration of digoxin. For patients initiating digoxin therapy, start with the lowest digoxin dose and for patients already receiving digoxin, reduce digoxin dose by 30% to 50% or modify the dosing frequency. Digoxin blood levels should be monitored. Concurrent administration of daclatasvir and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) can result in an increase in the therapeutic levels of statins. Patients should be monitored for statin-associated adverse events.Daclatasvir can increase the therapeutic concentrations of buprenorphine and its metabolite, norbuprenorphine; no adjustment to the buprenorphine or buprenorphine/naloxone dose is required. Patients should be monitored for adverse events. SVR12 can be reduced in HCV genotype 3 infected patients with cirrhosis. Currently there are no daclatasvir data in pregnant women and the benefits and risks should be evaluated before prescribing to a pregnant woman. In animal studies (i.e., rats and rabbits) embryofetal toxicity was observed at maternally toxic doses that produced exposures 33 and 98 times the human exposure, respectively. When given in combination with RBV, the combination is contraindicated in pregnant women due to teratogenicity of RBV.Where does daclatasvir fit into therapy?In January 2014, The American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society – USA, launched for the purpose of disseminating expert opinion on management of chronic hepatitis C as newer HCV DAA agents become available and treatment evidence emerges. There are no comparative efficacy data available to date for the HCV DAA agents, but it is likely that guidelines for optimal regimens will continue to evolve and will need to integrate patient-specific as well as economic factors. Many patient-specific factors must be taken into consideration when deciding to initiate therapy and baseline host and viral factors will affect relapse rates and treatment duration. The goal of treatment is undetectable HCV RNA 12 weeks post-treatment (SVR12). Daclatasvir in combination with sofosbuvir, with or without RBV, for 12 weeks is an option for patients with HCV GT 1 or 3 infections including those co-infected with HIV, patients status-post liver transplantation, and patients with cirrhosis (compensated or decompensated). References: 1. Daklinza? prescribing information. Bristol-Myers Squibb, 2016. 2. Nelson, D et al. Hepatology. 2015; 61(4): 1127-1135. 3. Wyles, PJ et al. NEJM. 2015; 373(8): 714-725. Daclatasvir Initiation and MonitoringOnce patient readiness for chronic HCV treatment has been determined, the algorithm below outlines key decision points for initiating and monitoring daclatasvir. Prior to initiating HCV DAA therapy, test for evidence of HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.3905250114300Seek alternative treatment options or conduct testing prior to treatment 00Seek alternative treatment options or conduct testing prior to treatment 438150-1905Has the patient been diagnosed with HCV genotype 1 or 3 and received quantitative HCV RNA testing? 00Has the patient been diagnosed with HCV genotype 1 or 3 and received quantitative HCV RNA testing? 332422520955NO00NO3162300603250019519901652270YES00YES1905000175895YES00YES178117411874500178117415855950017811743023870003324225642620NO00NO31337251042670003905250123190Complete a medication profile review prior to initiating treatment.Dose adjustments are required for drugs that moderately induce CYP3A and nevirapine, and drugs that are strong inhibitors of CYP3A.**Drugs that strongly induce CYP3A are contraindicated.00Complete a medication profile review prior to initiating treatment.Dose adjustments are required for drugs that moderately induce CYP3A and nevirapine, and drugs that are strong inhibitors of CYP3A.**Drugs that strongly induce CYP3A are contraindicated.428625142240Has review of the patient’s medication record been completed? 00Has review of the patient’s medication record been completed? 41910036195Start the combination daclatasvir and sofosbuvir, with or without RBV, and administer for 12 weeks.00Start the combination daclatasvir and sofosbuvir, with or without RBV, and administer for 12 weeks.438150260350Obtain HCV RNA level 12 weeks after completion of therapy to determine SRV12. 00Obtain HCV RNA level 12 weeks after completion of therapy to determine SRV12. -114300111760CYP3A = cytochrome P450 3A; NNRTIs = non-nucleoside reverse transcriptase inhibitors; RBV = ribavirin; SVR = sustained virological response*SVR rates are reduced in HCV genotype 3 infected patients with cirrhosis.**Refer to the daclatasvir product label for a list of drugs that are strong or moderate inducers of CYP3A, drugs that are strong inhibitors of CYP3A, and other drugs that require dose adjustment and/or monitoring.00CYP3A = cytochrome P450 3A; NNRTIs = non-nucleoside reverse transcriptase inhibitors; RBV = ribavirin; SVR = sustained virological response*SVR rates are reduced in HCV genotype 3 infected patients with cirrhosis.**Refer to the daclatasvir product label for a list of drugs that are strong or moderate inducers of CYP3A, drugs that are strong inhibitors of CYP3A, and other drugs that require dose adjustment and/or monitoring.Simeprevir (Olysio?)Approved by the Food and Drug Administration (FDA) in November 2013, simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor intended for use in combination with peginterferon alfa and ribavirin (PR) for genotype (GT) 1- or 4-infected patients or in combination with sofosbuvir in HCV GT 1-infected patients.1Advantages of simeprevirSimeprevir is taken once daily with food in combination with PR or sofosbuvir (Sovaldi?).1 Simeprevir is a direct acting antiviral (DAA) agent that inhibits HCV NS3/4A, preventing the cleavage of viral polyproteins during HCV replication. Use of simeprevir in combination with PR or sofosbuvir has been shown to increase rates of sustained virologic response (SVR) in both treatment-na?ve and treatment-experienced patients with or without cirrhosis. In phase III trials, the primary endpoint was defined as undetectable HCV RNA (<25 IU/mL) at 12 weeks post treatment (SVR12).Phase III Trials: TrialSubjectsTreatment Arm*Overall SVR rate (%)Genotype 1a SVR rate (%)Genotype 1b SVR rate (%)QUEST 1 and 22 (pooled analysis)785Treatment-na?veSMV12 + PR24/4880%75%85%PR48 (control)50%47%53%PROMISE2393Treatment-experiencedSMV12 + PR24/4879%70%86%PR48 (control)37%28%43%*By weeks on each component; PR = peginterferon alfa and ribavirin; SMV = simeprevirThe combination of simeprevir and sofosbuvir in HCV-infected patients (COSMOS) trial, a phase 2, randomized, open-label trial, demonstrated the safety and efficacy of this treatment regimen when administered for 12 or 24 weeks.3CautionsPrior to initiating therapy with any HCV direct acting antiviral (DAA) agent, all patients should be tested for evidence of current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment with a DAA agent and during post-treatment follow-up. Simeprevir efficacy in combination with PR is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism. Screening for NS3 Q80K polymorphism is strongly recommended prior to initiation of therapy; alternative therapy should be considered in patients with the polymorphism due to reduced efficacy observed in clinical trials. Simeprevir should not be used as monotherapy. Additionally, the dose must not be reduced nor should treatment be interrupted.Simeprevir should not be used if a patient has previously failed therapy that included simeprevir or another HCV NS3/4A protease inhibitor (e.g., boceprevir or telaprevir).Simeprevir is not recommended for patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Hepatic laboratory testing before and during therapy is recommended. Therapy should be discontinued if an elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation. Higher rates of rash (including photosensitivity), pruritus, and nausea occurred in simeprevir-treated patients vs. patients receiving PR alone. If a severe rash develops, simeprevir should be discontinued and not restarted.Simeprevir is metabolized by cytochrome P450 (CYP) 3A; co-administration with a moderate or strong inducer or inhibitor of CYP3A is not recommended. Simeprevir inhibits organic anion transporting polypeptide (OATP) 1B1/3 and P-glycoprotein (P-gp) transporters; therefore, co-administration of drugs that are substrates for OATP1B1/3 and P-gp transporters may result in increased plasma concentration of those drugs.Symptomatic bradycardia can occur when simeprevir is co-administered with sofosbuvir and amiodarone. The combination is not recommended, but if the combination cannot be avoided cardiac monitoring is recommended. Where does simeprevir fit into therapy and how should it be used?In January 2014, the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society – USA, launched for the purpose of disseminating expert opinion on management of HCV as newer HCV DAA agents become available and treatment evidence emerges. There are no comparative efficacy data available to date among the HCV DAA agents, but it is likely that guidelines for optimal regimens will continue to evolve. Patient-specific factors and economic factors must be taken into consideration when deciding to initiate therapy. The goal of treatment is undetectable HCV RNA at SVR12.Olysio? treatment regimen and duration recommendations:Simeprevir and sofosbuvir for mono-infected patients with HCV GT 1 infection1GT 1 TN and TE*Treatment regimen and durationWithout cirrhosissimeprevir + sofosbuvir for 12 weeksWith cirrhosissimeprevir + sofosbuvir for 24 weeksGT = genotype; TN = treatment na?ve; TE = treatment experienced; *treatment experienced patients include prior relapsers, prior partial responders, and prior null responders who failed pegylated interferon-based therapySimeprevir and PR therapy in patients with HCV GT 1 or 4 infection1GT 1 or 4 infectionTreatment regimen and durationTN patients and prior relapsers*Without cirrhosis and with/without HIV co-infection OR with cirrhosis and without HIV co-infectionSimeprevir + PR for 12 weeks FOLLOWED by an additional 12 weeks of PR (for a total treatment duration of 24 weeks)With cirrhosis and with HIV co-infectionSimeprevir + PR for 12 weeks FOLLOWED by an additional 36 weeks of PR (for a total treatment duration of 48 weeks)Prior non-responders (including partial§ and null responders?)With/without cirrhosis and with/without HIV co-infectionSimeprevir + PR for 12 weeks FOLLOWED by an additional 36 weeks of PR (for a total treatment duration of 48 weeks)GT = genotype; HIV = human immunodeficiency virus; PR = peginterferon alfa + ribavirin; TN = treatment na?ve *Prior relapse = HCV RNA not detected at the end of prior peginterferon alfa therapy and HCV-RNA detected during follow-up§Prior partial responder = prior on-treatment ≥2 log10 HCV RNA reduction from baseline at week 12 and HCV RNA detected at end of pegylated interferon therapy?Null responder = prior on-treatment ≥2 log10 HCV RNA reduction from baseline at week 12 during prior pegylated interferon therapyReferences: 1. Simeprevir (Olysio?) product information. Janssen Corporation, a subsidiary of Johnson & Johnson (J&J); 2016. 2. Data on file. Janssen Corporation, subsidiary of J&J; 2013. 3. Lawitz et al. Lancet 2014; 384:1756-65.Simeprevir Initiation and MonitoringOnce patient readiness for chronic HCV treatment has been determined, the algorithms below outline key decision points for initiating and monitoring combination therapy including simeprevir. Additionally, test for evidence of HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.Note: Ribavirin is contraindicated in pregnancy; therefore, all female patients of childbearing age (or female partners of male patients) should ensure they are not pregnant prior to beginning treatment and should use 2 methods of non-hormonal birth control throughout treatment. Also note, HCV RNA testing should be conducted with a sensitive assay.Algorithm 1: Simeprevir in combination with PR for treatment-na?ve prior relapsers and prior non-responders476241729105Is the patient treatment na?ve or a prior relapser* without cirrhosis and with/without HIV co-infection OR with cirrhosis and without HIV co-infection? 0Is the patient treatment na?ve or a prior relapser* without cirrhosis and with/without HIV co-infection OR with cirrhosis and without HIV co-infection? 55816493702050001762759351536000 Has the patient been diagnosed with HCV GT 1 without NS3 Q80K polymorphism or GT 4 and received quantitative HCV RNA testing?Begin treatment with simeprevir 150 mg once daily with food in combination with PR for 12 weeks Repeat quantitative HCV RNA at the end of treatment week 4.Is HCV RNA ≤25 IU/ml?Continue PR for additional 12 weeks for total treatment duration of 24 weeksObtain HCV RNA 12 weeks after the end of treatment to determine SVR12No NoYesYesYesYesContinue PR for additional 36 weeks for total treatment duration of 48 weeksSeek alternative treatment options or conduct testing prior to treatmentIs the patient a prior non-responder** including those with/without cirrhosis and with/without HIV co-infection OR treatment na?ve or a prior relapser with cirrhosis and HIV co-infected?Has the patient been diagnosed with HCV GT 1 without NS3 Q80K polymorphism or GT 4 and received quantitative HCV RNA testing?Begin treatment with simeprevir 150 mg once daily with food in combination with PR for 12 weeks Repeat quantitative HCV RNA at the end of treatment week 4.Is HCV RNA ≤25 IU/ml?Continue PR for additional 12 weeks for total treatment duration of 24 weeksObtain HCV RNA 12 weeks after the end of treatment to determine SVR12No NoYesYesYesYesContinue PR for additional 36 weeks for total treatment duration of 48 weeksSeek alternative treatment options or conduct testing prior to treatmentIs the patient a prior non-responder** including those with/without cirrhosis and with/without HIV co-infection OR treatment na?ve or a prior relapser with cirrhosis and HIV co-infected?GT = genotype; HIV = human immunodeficiency virus; PR = peginterferon alfa + ribavirin; SVR12 = sustained virological response*Prior relapse = undetectable HCV RNA at the end of prior interferon-based therapy and detectable HCV RNA during follow-up**Non-responder includes partial (prior on- treatment ≥2 log 10 HCV RNA reduction from baseline at week 12 and HCV RNA detected at end of pegylated interferon therapy) and null responder (prior on-treatment ≥2 log 10 HCV RNA reduction from baseline at week 12 during prior pegylated interferon therapy)Algorithm 2: Simeprevir in combination with sofosbuvir for treatment-na?ve and treatment-experienced* patients mono-infected with genotype 1 5391151147955Seek alternative treatment options or conduct testing prior to treatment00Seek alternative treatment options or conduct testing prior to treatment4937125240665No00No1498600294640Has the patient been diagnosed with HCV GT 1 and is not HIVco-infected?00Has the patient been diagnosed with HCV GT 1 and is not HIVco-infected? 3352800410210Yes00Yes49841151943100032257996477000147955041275Has the patient been diagnosed with cirrhosis? 00Has the patient been diagnosed with cirrhosis? 32194498382000345757578740No00No1514475109220Yes00Yes1355724-317500135572513334004900294000346075087630Simeprevir 150 mg and sofosbuvir 400 mg once daily with food for a total of 12 weeksRepeat quantitative HCV RNA at the end of treatment week 4Is HCV RNA ≤25 IU/ ml? 00Simeprevir 150 mg and sofosbuvir 400 mg once daily with food for a total of 12 weeksRepeat quantitative HCV RNA at the end of treatment week 4Is HCV RNA ≤25 IU/ ml? 184150106680Simeprevir 150 mg and sofosbuvir 400 mg once daily with food for a total of 24 weeksRepeat quantitative HCV RNA at the end of treatment week 4 and week 12Is HCV RNA ≤25 IU/ ml? 00Simeprevir 150 mg and sofosbuvir 400 mg once daily with food for a total of 24 weeksRepeat quantitative HCV RNA at the end of treatment week 4 and week 12Is HCV RNA ≤25 IU/ ml? 442214015106650032861247835900020853401291590Is HCV≤ 25 IU/mL? 00Is HCV≤ 25 IU/mL? 328612416979900020669252040890Continue therapy 00Continue therapy 329564924314150011906252830830Obtain HCV RNA 12 weeks after the end of treatment to determine SVR1200Obtain HCV RNA 12 weeks after the end of treatment to determine SVR12768667520256500505587045212000147955077152400-2095503194685GT = genotype; SVR12 = sustained virological response*Treatment experienced patients include prior relapsers, prior partial responders, and prior null responders who failed prior peginterferon alfa therapy.00GT = genotype; SVR12 = sustained virological response*Treatment experienced patients include prior relapsers, prior partial responders, and prior null responders who failed prior peginterferon alfa therapy.48196501108710Discontinue therapy00Discontinue therapy43948351050290No00No130937044513500 ................
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