the perfect Daklinza Generic Name: daclatasvir Dosage Form: tablet Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings User Reviews Drug Images Support Group Q & A Pricing & Coupons WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Daklinza. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated [ see Warnings and Precautions (5.1) ]. Indications and Usage for Daklinza Daklinza is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection [ see Dosage and Administration (2) and Clinical Studies (14) ]. Limitations of Use: Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks [ see Clinical Studies (14.2) ]. Slideshow Hep C and Harvoni: 11 Facts About Your Treatment Daklinza Dosage and Administration Testing Prior to the Initiation of Therapy Testing for HBV infection: Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with Daklinza [ see Warnings and Precautions (5.1) ]. NS5A Resistance Testing in HCV Genotype 1a-Infected Patients with Cirrhosis: 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 sofosbuvir with or without ribavirin [ see Microbiology (12.4), Table 11 ]. Recommended Dosage The recommended dosage of Daklinza is 60 mg, taken orally, once daily, with or without food [ see Clinical Pharmacology (12.3) ]. Table 1 provides the recommended Daklinza-containing treatment regimens and duration based on HCV genotype and patient population. The optimal duration of Daklinza and sofosbuvir with or without ribavirin has not been established for HCV genotype 3 patients with cirrhosis or for HCV genotype 1 patients with Child-Pugh C cirrhosis [ see Clinical Studies (14.2 , 14.4) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [ see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. For specific dosage recommendations for sofosbuvir, refer to the prescribing information. For HCV genotype 1 or 3 patients with Child-Pugh B or C cirrhosis or post-transplantation patients, the starting dose of ribavirin is 600 mg once daily, increasing up to 1000 mg daily as tolerated. The starting dose and on-treatment dose of ribavirin can be decreased based on hemoglobin and creatinine clearance. For HCV genotype 3 patients with compensated cirrhosis (Child-Pugh A), the recommended dosing of ribavirin is based on weight (1000 mg for patients weighing less than 75 kg and 1200 mg for those weighing at least 75 kg administered orally in two divided doses with food). Table 1: Recommended Treatment Regimen and Duration for Daklinza in Patients with Genotype 1 or 3 HCV Patient Population Treatment and Duration Genotype 1 Without cirrhosis Daklinza + sofosbuvir for 12 weeks Compensated (Child-Pugh A) cirrhosis Decompensated (Child-Pugh B or C) cirrhosis Daklinza + sofosbuvir + ribavirin for 12 weeks Post-transplant Genotype 3 Without cirrhosis Daklinza + sofosbuvir for 12 weeks Compensated (Child-Pugh A) or decompensated (Child-Pugh B or C) cirrhosis Daklinza + sofosbuvir + ribavirin for 12 weeks Post-transplant Dosage Modification Due to Drug Interactions Refer to the drug interactions and contraindications sections for other drugs before coadministration with Daklinza. Table 2: Recommended Daklinza Dosage Modification with CYP3A Inhibitors and Inducers Concomitant Drugs Daklinza Dosage Strong CYP3A inhibitors and certain HIV antiviral agents [ see Drug Interactions (7.3) ] 30 mg once daily Moderate CYP3A inducers and nevirapine [ see Drug Interactions (7.3) ] 90 mg once daily Strong CYP3A inducers [ see Contraindications (4) ] Contraindicated Dosage reduction of Daklinza for adverse reactions is not recommended. Discontinuation of Therapy If sofosbuvir is permanently discontinued in a patient receiving Daklinza with sofosbuvir, then Daklinza should also be discontinued. Dosage Forms and Strengths Tablets: 60 mg: 60 mg of daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride), light green, biconvex, pentagonal, and debossed with BMS on one side and 215 on the other side. 30 mg: 30 mg of daclatasvir (equivalent to 33 mg daclatasvir dihydrochloride), green, biconvex, pentagonal, and debossed with BMS on one side and 213 on the other side. 90 mg: 90 mg of daclatasvir (equivalent to 99 mg daclatasvir dihydrochloride), light green, biconvex, round, and embossed with BMS on one side and 011 on the other side. Contraindications When Daklinza is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen. Refer to the respective prescribing information for a list of contraindications. Daklinza is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daklinza. Contraindicated drugs include, but are not limited to those listed in Table 3 [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Table 3: Drugs that are Contraindicated with Daklinza Drug Class Drugs Within Class that are Contraindicated with Daklinza a Clinical Comments a This table is not a comprehensive list of all drugs that strongly induce CYP3A. Anticonvulsants phenytoin, carbamazepine May lead to loss of virologic response to Daklinza Antimycobacterial agents rifampin Herbal products St. John s wort ( Hypericum perforatum ) Warnings and Precautions 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Daklinza. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Daklinza and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of Daklinza and other drugs may result in known or potentially significant drug interactions, some of which may lead to [ see Contraindications (4) and Drug Interactions (7) ]: loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments of concomitant medications or Daklinza, possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daklinza. See Table 3 for drugs contraindicated with Daklinza due to loss of efficacy and possible development of resistance [ see Contraindications (4) ]. See Table 7 for steps to prevent or manage other possible and known significant drug interactions [ see Drug Interactions (7) ]. Consider the potential for drug interactions before and during Daklinza therapy, review concomitant medications during Daklinza therapy, and monitor for the adverse reactions associated with the concomitant drugs. Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options and who will be coadministered Daklinza and sofosbuvir: Counsel patients about the risk of serious symptomatic bradycardia. Cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking sofosbuvir in combination with Daklinza who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with Daklinza should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems [ see Adverse Reactions (6.2) and Drug Interactions (7.3), Table 7 ]. Risks Associated with Ribavirin Combination Treatment If Daklinza and sofosbuvir are administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin. Adverse Reactions If Daklinza and sofosbuvir are administered with ribavirin, refer to the prescribing information for ribavirin regarding ribavirin-associated adverse reactions. The following serious adverse reaction is described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone [ see Warnings and Precautions (5.3) ]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of Daklinza in combination with other anti-HCV drugs in clinical trials. Six hundred seventy-nine subjects have received a Daklinza and sofosbuvir-based regimen. Safety experience from three clinical trials of Daklinza and sofosbuvir with or without ribavirin is presented. Daklinza and Sofosbuvir In the ALLY-3 trial, 152 treatment-naive and treatment-experienced subjects with HCV genotype 3 infection were treated with Daklinza 60 mg once daily in combination with sofosbuvir for 12 weeks. The most common adverse reactions (frequency of 10% or greater) were headache and fatigue. All adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with Daklinza 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks. The most common adverse reaction (frequency of 10% or greater) was fatigue. The majority of adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4. Table 4: Adverse Reactions (All Severity) Reported at 5% Frequency, Daklinza + Sofosbuvir, Studies ALLY-3 and ALLY-2 Adverse Reaction ALLY-3: HCV Genotype 3 n=152 ALLY-2: HCV/HIV-1 Coinfection n=153 Headache 14% 8% Fatigue 14% 15% Nausea 8% 9% Diarrhea 5% 7% Daklinza, Sofosbuvir, and Ribavirin In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with Daklinza 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks. The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue, and nausea. The majority of adverse reactions were mild to moderate in severity. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs. During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5. Table 5: Adverse Reactions (All Severity) Reported at 5% Frequency in Either Treatment Cohort, Daklinza + Sofosbuvir + Ribavirin, Study ALLY-1 Adverse Reaction Child-Pugh A, B, or C Cirrhosis n=60 Recurrence after Liver Transplantation n=53 Headache 12% 30% Anemia 20% 19% Fatigue 15% 17% Nausea 15% 6% Rash 8% 2% Diarrhea 3% 6% Insomnia 3% 6% Dizziness 0 6% Somnolence 5% 0 Laboratory Abnormalities Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of Daklinza in combination with sofosbuvir with or without ribavirin are presented in Table 6. Table 6: Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of Daklinza + Sofosbuvir Ribavirin, Studies ALLY-3, ALLY-2, and ALLY-1 Parameter Percent with Abnormality ALLY-3: HCV Genotype 3 Daklinza + Sofosbuvir n=152 ALLY-2: HCV/HIV-1 Coinfection Daklinza + Sofosbuvir n=153 ALLY-1: Child-Pugh A, B, or C with Cirrhosis and Post-transplant Daklinza + Sofosbuvir + Ribavirin n=113 a In the ALLY-2 trial, Grade 3 and 4 increases in total bilirubin were observed only in subjects receiving concomitant atazanavir. Hemoglobin ( 8.9 g/dL) 0 0 6% Alanine aminotransferase (ALT) increased ( 5.1 ULN) 0 0 2% Aspartate aminotransferase (AST) increased ( 5.1 ULN) 0 0 3% Total bilirubin increased ( 2.6 ULN) 0 5% a 8% Lipase increased ( 3.1 ULN) 2% 4% 4% Postmarketing Experience The following adverse reactions have been identified during postapproval use of Daklinza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen [ see Warnings and Precautions (5.3) and Drug Interactions (7.3) ]. Drug Interactions Potential for Other Drugs to Affect Daklinza Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of daclatasvir [ see Dosage and Administration (2.3) , Contraindications (4) , and Table 7 ]. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of daclatasvir [ see Dosage and Administration (2.3) and Table 7 ]. Potential for Daklinza to Affect Other Drugs Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daklinza may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reactions ( see Table 7 ). Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with Daklinza. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up. Established and Potentially Significant Drug Interactions Refer to the prescribing information for other agents in the regimen for drug interaction information. The most conservative recommendation should be followed. Please also refer to Section 4 (Contraindications) and Section 12.3 (Pharmacokinetics) for complete information on all drug interactions. Table 7 provides clinical recommendations for established or potentially significant drug interactions between Daklinza and other drugs [ see Contraindications (4) ]. Clinically relevant increase in concentration is indicated as and clinically relevant decrease as for drug interaction data [ see Clinical Pharmacology (12.3) ]. Table 7: Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment a The direction of the arrow ( = increase, = decrease) indicates the direction of the change in pharmacokinetic parameters. b These interactions have been studied [ see Clinical Pharmacology (12.3) , Tables 9 and 10 ]. HIV antiviral agents Protease inhibitors: Atazanavir with ritonavir b Indinavir Nelfinavir Saquinavir Daclatasvir Decrease Daklinza dose to 30 mg once daily. Other antiretrovirals: Cobicistat-containing antiretroviral regimens Examples: atazanavir/cobicistat, elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate Daclatasvir Decrease Daklinza dose to 30 mg once daily except with darunavir combined with cobicistat. Non-nucleoside reverse transcriptase inhibitors (NNRTI): Efavirenz b Etravirine Nevirapine Daclatasvir Increase Daklinza dose to 90 mg once daily. Strong CYP3A inhibitors (see also HIV antiviral agents) Examples: clarithromycin, itraconazole, ketoconazole, b nefazodone, posaconazole, telithromycin, voriconazole Daclatasvir Decrease Daklinza dose to 30 mg once daily when coadministered with strong inhibitors of CYP3A. Moderate CYP3A inducers (see also HIV antiviral agents) Examples: bosentan, dexamethasone, modafinil, nafcillin, rifapentine Daclatasvir Increase Daklinza dose to 90 mg once daily when coadministered with moderate inducers of CYP3A. Anticoagulants Dabigatran etexilate mesylate Dabigatran Use of Daklinza with dabigatran etexilate is not recommended in specific renal impairment groups, depending on the indication. Please see the dabigatran prescribing information for specific recommendations. Cardiovascular agents Antiarrhythmic: Amiodarone Amiodarone: effects unknown Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring is recommended. [ See Warnings and Precautions (5.3) and Adverse Reactions (6.2) . ] Antiarrhythmic: Digoxin b Digoxin Patients already receiving daclatasvir initiating digoxin : Initiate treatment using the lowest appropriate digoxin dosage. Monitor digoxin concentrations; adjust digoxin doses if necessary and continue monitoring. Patients already receiving digoxin prior to initiating daclatasvir : Measure serum digoxin concentrations before initiating daclatasvir. Reduce digoxin concentrations by decreasing digoxin dosage by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring. Lipid-lowering agents HMG-CoA reductase inhibitors: Atorvastatin Fluvastatin Pitavastatin Pravastatin Rosuvastatin b Simvastatin Atorvastatin Fluvastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin Monitor for HMG-CoA reductase inhibitor-associated adverse events such as myopathy. Narcotic Analgesic/Treatment of Opioid Dependence buprenorphine buprenorphine/naloxone buprenorphine norbuprenorphine For buprenorphine or buprenorphine/naloxone, no adjustment is needed, but clinical monitoring for buprenorphine-associated adverse events is recommended. Drugs without Clinically Significant Interactions with Daklinza Please see Section 12.3 (Pharmacokinetics) for information regarding anticipated interactions that are not clinically relevant. Based on the results of drug interaction trials [ see Clinical Pharmacology (12.3) ], no clinically relevant changes in exposure were observed for cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, ethinyl estradiol/norgestimate, lopinavir (with ritonavir), methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir. No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, famotidine, lopinavir (with ritonavir), omeprazole, sofosbuvir, tacrolimus, or tenofovir. No dosage adjustment for daclatasvir is necessary with darunavir/cobicistat or moderate CYP3A inhibitors, including atazanavir (unboosted), fosamprenavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, or verapamil. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary No adequate human data are available to determine whether or not Daklinza poses a risk to pregnancy outcomes. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of daclatasvir during organogenesis at doses that produced exposures up to 6 and 22 times, respectively, the recommended human dose (RHD) of 60 mg of Daklinza. However, embryofetal toxicity was observed in rats and rabbits at maternally toxic doses that produced exposures of 33 and 98 times the human exposure, respectively, at the RHD of 60 mg of Daklinza [ see Data ]. In rat pre- and postnatal developmental studies, no developmental toxicity was observed at maternal systemic exposure (AUC) to daclatasvir approximately 3.6 times higher than the RHD of Daklinza. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. If Daklinza and sofosbuvir are administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy. Data Animal Data Daclatasvir was administered orally to pregnant rats at doses of 0, 50, 200, or 1000 mg/kg/day on gestation days 6 to 15. Maternal toxicity (mortality, adverse clinical signs, body-weight losses, and reduced food consumption) was noted at doses of 200 and 1000 mg/kg/day. In the offspring, malformations of the fetal brain, skull, eyes, ears, nose, lip, palate, or limbs were observed at doses of 200 and 1000 mg/kg. The dose of 1000 mg/kg was associated with profound embryolethality and lower fetal body weight. No malformations were noted at 50 mg/kg/day. Systemic exposure (AUC) at 50 mg/kg/day in pregnant females was 6 times higher than exposures at the RHD. In rabbits, daclatasvir was initially administered at doses of 0, 40, 200, or 750 mg/kg/day during the gestation days 7 to 19. Daclatasvir dosing was modified due to vehicle toxicity during the study to doses of 20, 99, and 370 mg/kg/day, respectively. Maternal toxicity was noted at doses of 200/99 and 750/370 mg/kg/day with adverse clinical signs and severe reductions in body weight and food consumption. Mortality and euthanasia occurred in multiple dams at 750/370 mg/kg/day. At 200/99 mg/kg/day, fetal effects included increased embryofetal lethality, reduced fetal body weights, and increased incidences of fetal malformations of the ribs as well as head and skull. No malformations were noted in rabbits at 40/20 mg/kg/day. Systemic exposures (AUC) at 40/20 mg/kg/day were 22 times higher than exposures at the RHD. In a pre- and postnatal developmental study, daclatasvir was administered orally at 0, 25, 50, or 100 mg/kg/day from gestation day 6 to lactation day 20. At 100 mg/kg/day, maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the perinatal and neonatal periods and reductions in birth weight that persisted into adulthood. There was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day. Systemic exposures (AUC) at this dose were 3.6 times higher than the RHD. Lactation Risk Summary It is not known whether Daklinza is present in human milk, affects human milk production, or has effects on the breastfed infant. Daclatasvir was present in the milk of lactating rats ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for Daklinza and any potential adverse effects on the breastfed child from Daklinza or from the underlying maternal condition. If Daklinza is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. Data Milk concentrations of daclatasvir were evaluated on lactation day 10 as part of the rat pre- and postnatal development study ( see Data in 8.1 ). Daclatasvir was present in rat milk with concentrations 1.7 to 2 times maternal plasma levels. Females and Males of Reproductive Potential If Daklinza and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. Pediatric Use Safety and effectiveness of Daklinza in pediatric patients younger than 18 years of age have not been established. Geriatric Use Of 1184 subjects treated with the recommended dose of Daklinza in ten clinical trials, 7% of subjects were 65 years of age or older. Safety was similar across older and younger subjects and there were no safety findings unique to subjects 65 years and older. SVR12 rates were comparable among older and younger subjects. No dosage adjustment of Daklinza is required for elderly patients [ see Clinical Pharmacology (12.3) ]. Renal Impairment No dosage adjustment of Daklinza is required for patients with any degree of renal impairment [ see Clinical Pharmacology (12.3) ]. Refer also to the sofosbuvir and ribavirin prescribing information for information regarding use in patients with renal impairment. Hepatic Impairment Based on a hepatic impairment study in non HCV-infected subjects, no dosage adjustment of Daklinza is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment [ see Clinical Pharmacology (12.3) ]. Overdosage There is no known antidote for overdose of Daklinza. Treatment of overdose with Daklinza should consist of general supportive measures, including monitoring of vital signs and observation of the patient s clinical status. Because daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug. Daklinza Description Daklinza (daclatasvir) is an inhibitor of HCV nonstructural protein 5A (NS5A). The chemical name for drug substance daclatasvir dihydrochloride is carbamic acid, N , N -[[1,1 -biphenyl]-4,4 -diylbis[1 H -imidazole-5,2-diyl-(2 S )-2,1-pyrrolidinediyl[(1 S )-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C , C -dimethyl ester, hydrochloride (1:2). Its molecular formula is C 40 H 50 N 8 O 6 2HCl, and its molecular weight is 738.88 (free base). Daclatasvir dihydrochloride has the following structural formula: Daclatasvir dihydrochloride drug substance is white to yellow. Daclatasvir is freely soluble in water (>700 mg/mL). Daklinza 60 mg tablets contain 60 mg daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daklinza 30 mg tablets contain 30 mg daclatasvir (equivalent to 33 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous lactose (58 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daklinza 90 mg tablets contain 90 mg daclatasvir (equivalent to 99 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous lactose (173 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Opadry green contains hypromellose, titanium dioxide, polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide. Daklinza - Clinical Pharmacology Mechanism of Action Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus [ see Microbiology (12.4) ]. Pharmacodynamics Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, daclatasvir did not prolong the QT interval to any clinically relevant extent. Pharmacokinetics The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in C max , AUC, and C min up to 60 mg once daily. Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Population pharmacokinetic estimates for daclatasvir 60 mg once daily in chronic HCV-infected subjects are shown in Table 8. Table 8: Population Pharmacokinetic Estimates for Daclatasvir in Chronic HCV-Infected Subjects Receiving Daclatasvir 60 mg Once Daily and Sofosbuvir 400 mg Once Daily Parameters Daclatasvir 60 mg once daily (n=152) AUC 0-24h (ng h/mL) Mean standard deviation 10973 5288 Median (range) 9680 (3807-41243) C 24h (ng/mL) Mean standard deviation 182 137 Median (range) 148 (21-1050) Absorption and Bioavailability In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%. Effect of Food on Oral Absorption In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir C max and AUC (0-inf) by 28% and 23%, respectively, compared with fasted conditions. A food effect was not observed with administration of a daclatasvir 60 mg t to explode
numerous Daklinza this type of
EmoticonEmoticon