On February 5, 2016, FDA approved changes to the DAKLINZA(daclatasvir) label to expand the indication to include HCV genotype 1 infection and expand dosage recommendations to the following populations and to revise dosage recommendations for HCV genotype 3 subjects with compensated (Child-Pugh A) cirrhosis:
HCV genotype 1 and 3 subjects co-infected with HIV-1
- HCV genotype 1 and 3 post-transplant subjects
- HCV genotype 1 subjects with compensated (Child-Pugh A) cirrhosis and decompensated (Child-Pugh B or C) cirrhosis
- HCV genotype 3 subjects with decompensated (Child-Pugh B or C) cirrhosis
Additionally, drug-drug interaction data regarding DAKLINZA coadministration with buprenorphine/naloxone, darunavir/ritonavir, dolutegravir, or lopinavir/ritonavir were included in the label.
The major revisions are summarized below.
INDICATIONS AND USAGE
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
DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of Therapy
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
2.2 Recommended Dosage
The recommended dosage of DAKLINZA is 60 mg, taken orally, once daily, with or without food [.
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.
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1
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 1200mg 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) for a complete list) | 30 mg once daily (one 30 mg tablet) |
Moderate CYP3A inducers and nevirapine (see Drug Interactions (7.3) for a complete list) | 90 mg once daily (three 30 mg tablets, or one 60 mg and one 30 mg tablet) |
Strong CYP3A inducers (see Contraindications (4) for a complete list) | Contraindicated |
6.1 Clinical Trials Experience
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-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 ³5% Frequency, DAKLINZA + Sofosbuvir, Studies ALLY-3 and ALLY-2 | ||
Adverse Reaction | nALLY-3: HCV Genotype 3 n=152 | ALLY-2: HCV/HIV-1 Coinfection n=153 |
|---|---|---|
Headache | 21 (14% | 8% |
Fatigue | 21 (14% | 15% |
Nausea | 12 (8% | 9% |
Diarrhea | 7 (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 ³5% 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
Lipase Elevations: 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 | |
Hemoglobin (£8.9 g/dL) | 0 | 0 | 6% | |
Alanine aminotransferase (ALT) increased (³5.1 ´ ULN) | 0 | 0 | 2% | |
Aspartate aminotransferase (AST) increased (³5.1 ´ ULN) | 0 | 0 | 3% | |
Total bilirubin increased (>2.6 ´ ULN) | 0 | 5%a | 8% | |
Lipase increased (³3.1 ´ ULN) | 2% | 4% | 4% | |
a In the ALLY-2 trial, Grade 3 and 4 increases in total bilirubin were observed only in subjects receiving concomitant atazanavir.
7 DRUG INTERACTIONS
Table 7: Established and Other Potentially Significant Drug Interactions | |||
Concomitant Drug Class: Drug Name | Effect on Concentrationa | Clinical Comment | |
|---|---|---|---|
HIV antiviral agents |
|
| |
Protease inhibitors: Atazanavir with ritonavirb Indinavir Nelfinavir Saquinavir | ↑ Daclatasvir | Decrease DAKLINZA dose to 30 mg once daily. | |
Other antiretrovirals: Cobicistat-containing antiretroviral regimens Examples: atazanavir/cobicistat, elvitegravir/cobicistat/ | ↑ Daclatasvir | Decrease DAKLINZA dose to 30 mg once daily except with darunavir combined with cobicistat. | |
Non-nucleoside reverse transcriptase inhibitors (NNRTI): Efavirenzb Etravirine Nevirapine | ↓ Daclatasvir | Increase DAKLINZA dose to 90 mg once daily. | |
Strong CYP3A inhibitors (see also HIV antiviral agents) |
|
| |
Examples: clarithromycin, itraconazole, ketoconazole,bnefazodone, posaconazole, telithromycin, voriconazole | ↑ Daclatasvir | Decrease DAKLINZA dose to 30 mg once daily when coadministered with strong inhibitors of CYP3A. | |
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. | |
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].
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
No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids. No clinically relevant interaction is anticipated for daclatasvir with concomitant use of rilpivirine.
CLINICAL STUDIES
Clinical Trials in HCV/HIV Coinfected Subjects (ALLY-2)
ALLY-2 was an open-label trial that included 153 subjects with chronic hepatitis C and HIV coinfection who received DAKLINZA and sofosbuvir for 12 weeks. Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects were HCV treatment-naive (n=101) or HCV treatment-experienced (n=52). Prior exposure to NS5A inhibitors was prohibited. The dose of DAKLINZA was 60 mg once daily (dose-adjusted for concomitant antiretroviral use) and the dose of sofosbuvir was 400 mg once daily [see Drug Interactions (7.3)].
The 153 treated subjects had a median age of 53 years (range, 24-71); 88% of subjects were male; 63% were white, 33% were black, and 1% were Asian. Sixty-eight percent of subjects had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most subjects (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 16% of the subjects had compensated cirrhosis, and 73% had IL28B rs12979860 non-CC genotype. Concomitant HIV therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of subjects, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine) for 26%, integrase-based regimens (raltegravir or dolutegravir) for 26%, and nucleoside-only regimens (abacavir + emtricitabine + zidovudine) for 1%. Two patients were not receiving treatment for HIV.
SVR and outcomes in subjects with HCV genotype 1 without SVR12 in ALLY-2 are shown by patient population in Table 14. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations for these genotypes; therefore, these results are not presented in Table 14. SVR12 rates were comparable regardless of antiretroviral therapy, HCV treatment history, age, race, gender, IL28B allele status, HCV genotype 1 subtype, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms, seeMicrobiology (12.4).
No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. There was no change in absolute CD4+ T-cell counts at the end of 12 weeks of treatment.
Table 14: ALLY-2: SVR12 in Subjects with Genotype 1 and 3 HCV/HIV Coinfection Treated with DAKLINZA in Combination with Sofosbuvir for 12 Weeks | |
Treatment Outcomes | Total n=137 |
|---|---|
SVR12 Genotype 1 | 97% (123/127) |
No cirrhosisa | 98% (103/105) |
With cirrhosis | 91% (20/22) |
Genotype 3b | 100% (10/10) |
Outcomes for genotype 1 subjects without SVR12 |
|
On-treatment virologic failurec | 0.8% (1/127) |
Relapsed | 1.6% (2/126) |
Missing post-treatment data | 0.8% (1/126) |
a Includes 5 subjects with inconclusive cirrhosis status.
b One subject with cirrhosis.
c One subject had detectable HCV RNA at end of treatment.
d Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at the end of treatment.
Clinical Trials in Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Recurrence after Liver Transplantation (ALLY-1)
ALLY-1 was an open-label trial of DAKLINZA, sofosbuvir, and ribavirin that included 113 subjects with chronic HCV infection and Child-Pugh A, B, or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53). Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects could be HCV treatment-naive or treatment-experienced, although prior exposure to NS5A inhibitors was prohibited. Subjects received DAKLINZA 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post treatment. Subjects received an initial ribavirin dose of 600 mg or less daily with food; the initial and on-treatment dosing of ribavirin was modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose was titrated up to 1000 mg per day. A high proportion of reductions in ribavirin dosing occurred in the trial. By week 6, approximately half of the subjects received 400 mg per day or less of ribavirin. In total, 16 subjects (15%) completed less than 12 weeks and 11 subjects (10%) completed less than 6 weeks of ribavirin therapy, respectively. For the cohort of patients with cirrhosis (Child-Pugh A, B, or C), the median time to discontinuation of ribavirin was 43 days (range, 8-82, n=9). For the post-transplant cohort, the median time to discontinuation of ribavirin was 20 days (range, 3-57, n=7).
The 113 treated subjects in ALLY-1 had a median age of 59 years (range, 19-82); 67% of the subjects were male; 96% were white, 4% were black, and 1% Asian. Most subjects (59%) were treatment-experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL. Fifty-eight percent of subjects had HCV genotype 1a, 19% had HCV genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6, 77% had IL28B rs12979860 non-CC genotype. Among the 60 subjects in the cirrhosis cohort, 20% were Child-Pugh A, 53% were Child-Pugh B, and 27% were Child-Pugh C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD) score of 15 or greater. Most (55%) of the 53 subjects in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSUREÒ results).
SVR12 and outcomes in subjects without SVR12 in ALLY-1 are shown for subjects with HCV genotype 1 by patient population in Table 15. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations; therefore, these results are not presented in Table 15.
SVR12 rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. For SVR12 outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology (12.4). No HCV genotype 1 or genotype 3 subjects with Child-Pugh C cirrhosis had baseline resistance-associated NS5A amino acid polymorphisms. SVR12 rates were comparable between genotype 3 (5/6 with Child-Pugh B or C cirrhosis and 10/11 post-liver transplant) and genotype 1 subjects with or without decompensated cirrhosis.
Table 15: ALLY-1: SVR12 in Genotype 1 Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Genotype 1 Recurrence after Liver Transplantation Treated with DAKLINZA in Combination with Sofosbuvir and Ribavirin for 12 Weeks | ||
Treatment Outcomes | Child-Pugh A, B, or C Cirrhosis n=45 | Post-Liver Transplant n=41 |
|---|---|---|
SVR12 |
|
|
Genotype 1 | 82% (37/45) | 95% (39/41) |
Child-Pugh A | 91% (10/11) | - |
Child-Pugh B | 92% (22/24) | - |
Child-Pugh C | 50% (5/10) | - |
Genotype 1a | 76% (26/34) | 97% (30/31) |
Genotype 1b | 100% (11/11) | 90% (9/10) |
Outcomes for subjects without SVR12 |
|
|
On-treatment virologic failure | 2% (1/45)a | 0 |
Relapseb | 16% (7/44) | 5% (2/41) |
a One subject had detectable HCV RNA at end of treatment.
b Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at end of treatment.
Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response
Genotype 1a NS5A polymorphisms: In HCV genotype 1a-infected subjects with cirrhosis, the presence of an NS5A amino acid polymorphism at position M28, Q30, L31, or Y93 (defined as any change from reference identified by population-based nucleotide sequencing) was associated with reduced efficacy of DAKLINZA and sofosbuvir with or without ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials (see Table below). Due to the limited sample size, insufficient data are available to determine the impact of specific NS5A polymorphisms at these positions on SVR12 rates in subjects with cirrhosis. Six of 54 subjects (11%) with cirrhosis had one of the following specific NS5A polymorphisms at baseline: M28V/T (n=2), Q30R (n=1), L31M (n=2), or Y93N (n=1); 2 subjects with M28V or Q30R achieved SVR12 while 4 subjects with M28T, L31M, or Y93N did not achieve SVR. Eleven of 112 subjects (10%) without cirrhosis had one or more of the following specific NS5A polymorphisms at baseline: M28T/V (n=3), Q30H/L/R (n=5), L31M (n=1), and Y93C/H/S (n=4); all noncirrhotic subjects with these baseline NS5A polymorphisms achieved SVR12. Based on an analysis of 1026 HCV genotype 1a NS5A amino acid sequences from pooled clinical trials, the prevalence of polymorphisms at these positions was 11% overall, and 11% in the U.S.
Genotype 1b NS5A polymorphisms: In a pooled analysis of 43 subjects infected with HCV genotype 1b with available baseline nucleotide sequence data in ALLY-1 and -2, virus from 21% (n=9) of subjects receiving DAKLINZA and sofosbuvir with or without ribavirin had one of the following baseline NS5A amino acid polymorphisms: R30K/M/Q (n=4), L31M (n=2), or Y93H (n=3). All 9 subjects with NS5A polymorphisms achieved SVR12, including 5 who were noncirrhotic and 4 who were in the post-transplant period.
Genotype 3 NS5A polymorphisms: In the ALLY-3 trial in which HCV genotype 3-infected subjects received DAKLINZA and sofosbuvir for 12 weeks, the presence of an NS5A Y93H polymorphism was associated with a reduced SVR12 rate (see Table below). In a pooled analysis of 175 subjects infected with HCV genotype 3 with available baseline nucleotide sequence data in the ALLY-1, -2, and -3 trials, virus from 7% (13/175) of subjects had the NS5A Y93H polymorphism, and all 13 of these subjects were in the ALLY-3 trial. Phylogenetic analysis of NS5A sequences indicated that all genotype 3 subjects with available data in the ALLY-1, -2, and -3 trials (n=175) were infected with HCV subtype 3a.
Impact of NS5A Amino Acid Polymorphisms on SVR12 Rates in Subjects with HCV Genotype 1a or Genotype 3 Infection in Phase 3 Trials of DAKLINZA + Sofosbuvir ± Ribavirin | ||
NS5A Polymorphisms | SVR12 Rates after 12 Weeks of Treatment with DAKLINZA + Sofosbuvir ± Ribavirina | |
| With NS5A Polymorphism(s) % (n/N) | Without NS5A Polymorphism(s) % (n/N)b |
|---|---|---|
HCV genotype 1a-infected subjects: M28,c Q30,cL31,c or Y93c | 76% (13/17) | 95% (142/149) |
Without cirrhosisd | 100% (11/11) | 99% (100/101) |
With cirrhosis (Child-Pugh A, B, or C) | 33% (2/6) | 88% (42/48) |
HCV genotype 3-infected subjects: Y93H | 54% (7/13) | 92% (149/162) |
Without cirrhosisd | 67% (6/9) | 98% (125/128) |
With cirrhosis (Child-Pugh A, B, or C) | 25% (1/4) | 71% (24/34) |
a HCV genotype 1a-infected subjects received DAKLINZA + sofosbuvir ± ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials. HCV genotype 3-infected subjects received DAKLINZA + sofosbuvir for 12 weeks in the ALLY-3 trial; no data on the impact of Y93H are available for HCV genotype 3-infected subjects treated with DAKLINZA + sofosbuvir ± ribavirin in ALLY-1 and ALLY-2 trials.
b None of the 11 subjects with Child-Pugh C cirrhosis had an indicated NS5A polymorphism; 5 achieved SVR (genotype 1a: 4/9; genotype 3a: 1/2).
c Any change from genotype 1a reference.
d Includes subjects who were post-transplant with undefined cirrhosis status.
Daklinza is a product of Bristol-Myers Squibb. The complete labeling will be posted at Drugs@FDA, and DailyMed.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
