Daklinza Product Monograph

SUMMARY PRODUCT INFORMATION

For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

INDICATIONS AND CLINICAL USE

DAKLINZA (daclatasvir) is indicated in combination with other agents for the treatment of chronic hepatitis C (CHC) in adult patients with hepatitis C virus (HCV) genotypes 1, 2, or 3 including patients with compensated or decompensated cirrhosis (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION).

The following points should be considered when initiating treatment with DAKLINZA:

• Treatment with DAKLINZA should be initiated and monitored by a physician experienced in the treatment of CHC.
• DAKLINZA must not be administered as monotherapy (see DOSAGE AND ADMINISTRATION).
• Treatment regimen and duration are dependent on both viral genotype and patient population (see DOSAGE AND ADMINISTRATION).
• The sustained virologic response (SVR) rates are reduced in HCV genotype 3 and genotype 1a infected patients with cirrhosis receiving DAKLINZA with sofosbuvir for 12 weeks (see CLINICAL TRIALS, DOSAGE AND ADMINISTRATION).

Geriatrics (≥ 65 years of age)

Similar safety and effectiveness of DAKLINZA were observed in patients <65 and ≥65 years of age.

Pediatrics (< 18 years of age)

Safety and effectiveness of DAKLINZA in pediatric patients have not been established.

Patients with Compensated and Decompensated Cirrhosis, and Post-Liver Transplantation

DAKLINZA efficacy has been established in combination with sofosbuvir in adults with chronic HCV infection including those with compensated (Child-Pugh Class A) or decompensated cirrhosis (Child-Pugh Class B and C), and those with HCV recurrence after liver transplantation.

However, limited data support the use of DAKLINZA in patients with decompensated liver disease (Child-Pugh Class B and C) (see CLINICAL TRIALS).

Patients Co-infected with HIV-1

DAKLINZA efficacy has been established in combination with sofosbuvir in adults with chronic HCV infection including those coinfected with human immunodeficiency virus (HIV-1).

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION and PACKAGING section of the Product Monograph.

Since DAKLINZA is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen. Refer to the corresponding Product Monograph for a list of contraindications.

DAKLINZA is contraindicated in combination with drugs that strongly induce CYP3A4 and P-glycoprotein transporter (P-gp) and thus may lead to lower exposure and loss of efficacy of DAKLINZA. Contraindicated drugs include, but are not limited to carbamazepine, dexamethasone, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine and St. John’s wort (Hypericum perforatum) (see DRUG INTERACTIONS; Drug-Drug interactions and ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics).

WARNINGS AND PRECAUTIONS

General

The efficacy of DAKLINZA as part of a retreatment regimen in patients with prior exposure to a nonstructural protein 5A (NS5A) replication complex inhibitor has not been established.

Warnings and Precautions for other agents in the regimen also apply when coadministered with DAKLINZA.

Potential for Hepatitis B Virus Reactivation

Cases of HBV reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death have been reported in HCV/HBV co-infected patients who were undergoing, or completed treatment with DAA. To decrease the risk of HBV reactivation in patients co-infected with HBV, HBV screening should be performed in all patients prior to initiation of HCV treatment. Patients with positive HBV serology (HBsAg positive) and patients with serologic evidence of resolved HBV infection (i.e. HBsAg negative and anti-HBc positive) should be monitored and treated according to current clinical practice guidelines to manage potential HBV reactivation (see WARNING AND PRECAUTIONS, Monitoring and Laboratory Tests).

Potential for dysglycemia in patients with diabetes

Diabetic patients may experience dysglycemia, including symptomatic hypoglycemia, during or after treatment with direct-acting antiviral (DAA) agents. This may be due to changes in blood glucose control resulting from improved liver function following DAA treatment. Close monitoring of blood glucose is recommended during treatment with DAKLINZA.

Genotype Specific Activity

Limited data is available to support treatment of genotypes 2, 4 and 6 infection with DAKLINZA and sofosbuvir. There is no clinical data to support treatment of genotype 5.

Carcinogenesis and Mutagenesis

No evidence of carcinogenicity was observed in studies of daclatasvir in mice and rats, and no evidence of mutagenic or clastogenic activity was observed in vitro or in vivo (see NON-CLINICAL TOXICOLOGY).

Drug Interactions

See CONTRAINDICATIONS in the Product Monograph for drugs that are contraindicated for use with DAKLINZA. Contraindications for other agents in the regimen also apply when coadministered with DAKLINZA.

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another HCV direct-acting antiviral DAA), including DAKLINZA. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered 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 effect is unknown.

Amiodarone should not be coadministered with DAKLINZA and sofosbuvir unless no other alternative antiarrhythmic treatments are possible (i.e. contraindicated or not tolerated). For patients with no alternative treatment option, close monitoring is recommended. Patients should be continuously monitored in an inpatient setting for the first 48 hours of coadministration, after which outpatient monitoring or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, patients who have discontinued amiodarone just before starting DAKLINZA and sofosbuvir should also undergo cardiac monitoring as described above.

All patients receiving DAKLINZA and sofosbuvir in combination with amiodarone should be warned of the symptoms of bradycardia and heart block and advised to seek medical advice urgently should they experience them. Symptoms of bradycardia may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems. Refer to the amiodarone and sofosbuvir Product Monographs (See DRUG INTERACTIONS; Drug-Drug Interactions, Table 6 and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Gastrointestinal

DAKLINZA contains lactose. This medicine is not recommended for patients with rare hereditary problems of galactose intolerance (severe lactase deficiency or glucose-galactose malabsorption).

Hepatic

DAKLINZA can be administered to patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics).

Of more than 3500 patients in 19 clinical trials of DAKLINZA combination therapy, more than 600 patients had cirrhosis, including 60 patients with advanced cirrhosis or decompensated liver disease. No overall differences in safety were observed between patients with cirrhosis and patients without cirrhosis (see CLINICAL TRIALS).

In a clinical trial of DAKLINZA and sofosbuvir for 12 weeks in patients with HCV genotype 3 infection, patients with cirrhosis had lower SVR rates than those without cirrhosis, and in a clinical trial of DAKLINZA, sofosbuvir, and ribavirin for 12 weeks in patients with Child Pugh A, B, or C cirrhosis, patients with decompensated (Child-Pugh C) liver disease had lower SVR rates than those whose disease was classified Child-Pugh A or B.

Renal

DAKLINZA can be administered to patients with any degree of renal impairment (see ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics).

Sexual Function/Reproduction

There are no data on the effect of daclatasvir on human fertility. No effects on fertility were observed in animal studies (see NON-CLINICAL TOXICOLOGY).

Special Populations

Pregnant Women

Daclatasvir has not been studied in pregnant women.

The potential risk for humans is unknown. Patients should be advised to notify their health care provider immediately in the event of pregnancy. DAKLINZA should not be used during pregnancy or in women of childbearing potential not using contraception. Use of effective contraception should be continued for 5 weeks after completion of DAKLINZA therapy.

Studies of daclatasvir in animals have shown both maternal and embryofetal developmental toxicity at AUC levels 4.7-fold (rat) and 72-fold (rabbit) above the recommended human dose (RHD) (see NON-CLINICAL TOXICOLOGY, Reproductive Toxicology).

Use with Ribavirin

Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately before initiation of therapy.

When DAKLINZA is used in combination with sofosbuvir and ribavirin, women of childbearing potential and their male partners must use 2 forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer also to the corresponding Product Monograph for ribavirin.

Nursing Women

It is not known whether daclatasvir and its metabolites are present in human milk. Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7- to 2-fold maternal plasma levels. A risk to the newborn/infant cannot be excluded, therefore mothers should be instructed not to breastfeed if they are taking DAKLINZA.

Pediatrics (<18 years of age)

Safety and effectiveness of DAKLINZA in pediatric patients younger than 18 years of age have not been studied.

Geriatrics (≥ 65 years of age)

Of more than 2000 patients in 12 clinical studies of DAKLINZA combination therapy, 310 were 65 years and older and 20 were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. No dose adjustment of DAKLINZA is required for elderly patients.

Liver Transplant Patients

The safety and efficacy of DAKLINZA in combination with sofosbuvir and ribavirin in the treatment of chronic HCV infection in patients who are pre-, peri- or post-liver transplant were established in a clinical trial (see CLINICAL TRIALS).

HCV/HIV-1 Co-infection

The safety and efficacy of DAKLINZA have been established in HCV patients co-infected with HIV-1 (Human Immunodeficiency Virus) (see CLINICAL TRIALS).

HCV/HBV Co-infection

The safety and efficacy of DAKLINZA have not been studied in HCV patients co-infected with HBV (hepatitis B virus). HBV reactivation has been reported during treatment and post-treatment with DAAs in patients co-infected with HBV (see WARNINGS AND PRECAUTIONS, Potential for Hepatitis B Virus Reactivation).

Monitoring and Laboratory Tests

If DAKLINZA and sofosbuvir are administered with amiodarone, close monitoring for bradycardia is recommended. Refer to the amiodarone and sofosbuvir Product Monographs (see WARNINGS AND PRECAUTIONS, Drug Interactions).

If DAKLINZA is administered with ribavirin, it is recommended that standard hematological and biochemical laboratory tests be performed in all patients prior to initiating combination therapy. Hematological and biochemical tests of renal and hepatic function should be performed at 2 weeks and 4 weeks after initiation of therapy, and periodically during therapy. More intensive laboratory monitoring and ribavirin dosage adjustment may be required in patients with decompensated cirrhosis or HCV post-transplant recurrence (see DOSAGE AND ADMINISTRATION, Table 10).

Consider screening for the presence of NS5A polymorphisms at amino acid positions M28T, 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 DOSAGE AND ADMINISTRATION and MICROBIOLOGY).

Clearance of HCV may lead to increased replication of HBV in patients who are co-infected with HCV and HBV; co-infected patients should be monitored for clinical and laboratory signs (e.g. HBsAg, anti-HBc, HBV DNA, serum aminotransferase levels, bilirubin) for hepatitis flare or HBV reactivation during and at post-treatment follow-up as clinically appropriate (see WARNINGS AND PRECAUTIONS, Potential for Hepatitis B Virus Reactivation).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The overall safety assessment of DAKLINZA is based on data from more than 3531 patients with chronic HCV infection who received DAKLINZA 60 mg once daily in combination with other HCV therapy.

The safety of DAKLINZA 60 mg once daily in combination with sofosbuvir (with or without ribavirin) was assessed in four open-label randomized clinical trials: Study AI444040, ALLY-3 (AI444218), ALLY-2 (AI444216) and ALLY-1 (AI444215) in 679 patients with chronic HCV genotype 1, 2, 3, 4 or 6 infection, including patients with HIV-1 coinfection, patients with compensated or decompensated cirrhosis, and patients with HCV recurrence after liver transplant. Patients were treated for 8, 12 or 24 weeks.

When DAKLINZA and sofosbuvir is administered with ribavirin, refer to the prescribing information of ribavirin regarding ribavirin associated adverse reactions.

Serious symptomatic bradycardia is reported with DAKLINZA and sofosbuvir combination coadministered with amiodarone (see WARNINGS AND PRECAUTIONS).

The most common adverse reactions (any severity, frequency of 10% or greater) were fatigue (19%), headache (15%), and nausea (11%). Most adverse reactions experienced were mild to moderate in severity. Five percent of patients experienced an SAE. Four patients discontinued DAKLINZA for adverse events, only one of which was considered related to study therapy.

Clinical Trial Adverse Drug Reactions

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. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The safety experience for DAKLINZA in combination with sofosbuvir (DCV+SOF), with or without ribavirin, is presented below.

DAKLINZA in Combination with Sofosbuvir +/- Ribavirin (AI444040)

In the AI444040 trial the most common adverse reactions (any severity, frequency of 10% or greater) were fatigue (29%), headache (19%) and nausea (14%). All adverse reactions experienced were mild to moderate in severity. Seven percent of patients experienced an SAE. One percent of patients discontinued for adverse events.

DAKLINZA in Combination with Sofosbuvir (ALLY-2 and ALLY-3)

In the ALLY-2 trial the most common adverse reaction (frequency of 10% or greater) was fatigue (14%). Most adverse reactions were mild to moderate in severity. Two percent of patients experienced an SAE; all SAEs were considered unrelated to treatment. There were no discontinuations for adverse events in this trial.

In the ALLY-3 trial the most common adverse reactions (frequency of 10% or greater) were headache and fatigue. All adverse reactions were mild to moderate in severity. One patient experienced a serious adverse event (SAE) that was considered unrelated to study therapy, and no patients 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 1.

DAKLINZA in Combination with Sofosbuvir and Ribavirin (ALLY-1)

In the ALLY-1 trial the most common adverse reactions (frequency of 10% or greater) among the 113 patients were headache, anemia, fatigue, and nausea. Most adverse reactions were mild to moderate in severity and were similar in patients with and without cirrhosis. Fifteen (13%) patients experienced an SAE; all SAEs were considered unrelated to treatment. Of the 15 (13%) patients who discontinued study drug for adverse events, 13 (12%) patients discontinued ribavirin only and 2 (2%) patients discontinued all study drugs.

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 2.

DAKLINZA in Combination with Sofosbuvir With or Without Ribavirin (AI444040, ALLY-1, 2 and 3)

Adverse reactions of at least moderate severity (Grades 2-4) and considered at least possibly related to treatment and occurring at a frequency of 3% or greater in a clinical trial of DAKLINZA in combination with sofosbuvir (with or without ribavirin) are presented in Table 3.

a Events of at least moderate severity (Grades 2-4) with at least a possible relationship to study drug (investigator attribution) and occurring in at least 3% of the 203 patients treated with DAKLINZA and sofosbuvir with ribavirin or the 476 patients treated with DAKLINZA and sofosbuvir without ribavirin in studies AI444040, ALLY-3, ALLY-2 and ALLY-1.

Less Common Clinical Trial Adverse Drug Reactions

Adverse reactions of at least moderate severity (Grades 2-4) reported in clinical studies of DAKLINZA administered in combination with sofosbuvir, with or without ribavirin, for the treatment of HCV infection at a frequency of <3% are listed below by body system.

General Disorders and Administration Site Conditions: malaise, non-cardiac chest pain.

Gastrointestinal Disorders: diarrhea, nausea, gastroesophageal reflux disease, abdominal pain upper, dry mouth.

Nervous System Disorders: dizziness, migraine, amnesia, cognitive disorder, disturbance in attention, dysgeusia, syncope.

Psychiatric Disorders: insomnia, anxiety, depression, irritability, nightmare, thinking abnormal.

Skin and Subcutaneous Tissue Disorders: rash, erythema, pruritus.

Investigations: blood creatinine increased, creatinine renal clearance decreased.

Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, fibromyalgia, joint swelling, muscle spasms, myalgia, pain in extremity.

Metabolism and Nutrition Disorders: decreased appetite, gout.

Renal and Urinary Disorders: renal failure.

Cardiac Disorders: diastolic dysfunction.

Respiratory, Thoracic, and Mediastinal Disorders: cough.

Vascular disorders: hypertension.

Abnormal Clinical Chemistry Findings

Selected Grade 2-4 laboratory elevations observed in HCV-infected patients treated with DAKLINZA combination therapy and occurring at a frequency of 3% or greater from phase 2 and 3 clinical trial data are presented in Table 4 by regimen.

ULN= Upper Limit of Normal

a Laboratory results were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0.

b In the ALLY-2 trial, Grade 3-4 increases in total bilirubin were observed only in patients receiving concomitant atazanavir.

Post-Market Adverse Drug Reactions

Because postmarketing adverse 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.

The following additional adverse reactions were identified during post approval use of DAKLINZA:

Cardiac Disorders

Cardiac arrhythmias including severe bradycardia and heart block have been observed in patients receiving amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral, including DAKLINZA (see WARNINGS AND PRECAUTIONS, Cardiovascular and DRUG INTERACTIONS).

DRUG INTERACTIONS

Overview

Refer to the corresponding Product Monographs of other drugs in the regimen for drug interaction information. The most conservative recommendation among all the components of the regimen should be followed.

The concomitant use of DAKLINZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of DAKLINZA and possible development of resistance, dosage adjustments of concomitant medications, or clinically significant adverse reactions from greater exposures of concomitant drugs.

Drugs contraindicated with DAKLINZA due to loss of efficacy and possible development of resistance are summarized in Table 5. Clinical guidance for preventing or managing other possible and known significant drug interactions is presented in Table 6. 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.

Drug-Drug Interactions

Potential for Other Drugs to Affect DAKLINZA

Daclatasvir is a substrate of CYP3A4, P-gp, and organic cation transporter (OCT) 1. Moderate or strong inducers of CYP3A4 or P-gp may decrease the plasma levels and therapeutic effect of daclatasvir; strong inducers of CYP3A4 are contraindicated with DAKLINZA and dose increases to 90 mg once daily (three 30 mg tablets or one 60 mg and one 30 mg tablet) are recommended with moderate inducers (see CONTRAINDICATIONS and Table 5, Table 6 and Table 8). Strong inhibitors of CYP3A4 (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, ritonavir) may result in significant changes in the plasma exposure of daclatasvir and dose reductions to 30 mg once daily (using the 30 mg tablet; DAKLINZA tablets should not be broken) are recommended (see Table 6 and Table 8). P-gp may play roles in both limiting the oral absorption of daclatasvir and mediating daclatasvir excretion, and OCT 1 may play a role in mediating liver uptake of daclatasvir. Coadministration of medicines that inhibit P-gp or OCT1 activity is likely to have a limited effect on daclatasvir exposure. A drug interaction study with cyclosporine, which is a strong P-gp inhibitor and a weak CYP3A inhibitor resulted in a 40% increase in daclatasvir AUC suggesting that inhibition of P-gp alone with no or minimal inhibition of CYP3A is not expected to significantly increase daclatasvir exposure.

Potential for DAKLINZA to Affect Other Drugs

In vitro, daclatasvir inhibited efflux transporters (P-gp, breast cancer resistance protein [BCRP]), hepatic uptake transporters (OATP 1B1, 1B3 and 2B1), organic anion transporters (OAT1, OAT3), and OCT1 and OCT2. In vivo, daclatasvir has been shown to be a weak-to-moderate inhibitor of P-gp, and a weak inhibitor of OATP1B1, OATP1B3, and BCRP. Administration of DAKLINZA may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP (eg, digoxin, rosuvastatin), which could increase or prolong their therapeutic effect and adverse reactions (see Table 6 and Table 7). Caution should be used if the medicinal product has a narrow therapeutic range (eg, digoxin, Table 6). Daclatasvir is not expected to have a clinical effect on the pharmacokinetics of substrates of OATP2B1, OAT1, OAT3, or OCT2. Daclatasvir, in vitro, did not inhibit (IC₅₀ >40 µM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Daclatasvir did not have a clinically meaningful effect on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate.

Drugs Contraindicated with DAKLINZA

DAKLINZA is contraindicated in combination with drugs that strongly induce CYP3A4 and P-gp (see Table 5), and thus, may lead to lower exposure and loss of efficacy of DAKLINZA (see CONTRAINDICATIONS).

a This table is not a comprehensive list of all drugs that strongly induce CYP3A4.

b Not marketed in Canada.

Established and Potentially Significant Drug Interactions

Table 6 provides clinical recommendations for established or potentially significant drug interactions between DAKLINZA and other drugs (see Table 7 and Table 8 for pharmacokinetic data from drug-drug interaction studies).

a This table is not all inclusive.

b The direction of the arrow (↑ = increase, ↓ = decrease) indicates the direction of the change in pharmacokinetic parameters.

c These interactions have been studied (see Table 7 and Table 8).

d Refer to section Drugs without Significant Interactions with DAKLINZA, for other protease inhibitors where no dose adjustment is required

Assessment of Drug Interactions

Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of daclatasvir on the C_max, AUC, and C_min of the coadministered drug are summarized in Table 7. The effects of the coadministered drug on the C_max, AUC, and C_min of daclatasvir are summarized in Table 8. All studies were conducted in healthy adults unless otherwise noted.

a Study conducted in patients with chronic HCV infection.

b GS-331007 is the major circulating metabolite of the prodrug sofosbuvir.

c Evaluated in opioid-dependent adults on stable methadone maintenance therapy.

NA = not available.

a Daclatasvir pharmacokinetic results are dose-normalized to 60 mg dose.

b Study conducted in patients with chronic HCV infection.

c Comparison for daclatasvir was to a historical reference (data from 3 studies of daclatasvir 60 mg once daily with peginterferon alfa and ribavirin).

d Evaluated in opioid-dependent adults on stable methadone maintenance therapy.

e Compared to historical data.

NA = not available.

Drugs without Significant Interactions with DAKLINZA

Based on the results of drug interaction studies and expected interaction potential, no dose adjustment is recommended when DAKLINZA is given with buprenorphine + naloxone, cyclosporine, escitalopram, ethinyl estradiol + norgestimate, darunavir + ritonavir, dolutegravir, famotidine, lopinavir + ritonavir, methadone, midazolam (parenteral), omeprazole, peginterferon alfa, raltegravir, rilpivirine, ribavirin, simeprevir, sofosbuvir, tacrolimus, tenofovir disoproxil fumarate or tenofovir.

Drug-Food Interactions

DAKLINZA may be taken with or without food (See DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics).

Drug-Herb Interactions

Coadministration of St. John’s wort (Hypericum perforatum), a strong inducer of CYP3A4 and P-gp, may decrease DAKLINZA plasma concentrations, which may result in loss of therapeutic effect.

St. John’s wort is contraindicated with DAKLINZA (See CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions of DAKLINZA with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

DAKLINZA must be administered in combination with other drugs for the treatment of HCV (see Table 9 and CLINICAL TRIALS).

Treatment regimen and duration are dependent on both viral genotype and patient population.

NS5A Resistance Testing in HCV Genotype 1a-Infected Patients with Cirrhosis

Consider screening for the presence of NS5A polymorphisms at amino acid positions M28T, 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).

Recommended Dose

The recommended dose of DAKLINZA is 60 mg, taken orally, once daily with or without food.

For co-infected patients (HCV-HIV-1) follow the dosage recommendation of DAKLINZA with certain antiretroviral agents (see DRUG INTERACTIONS).

For specific dose recommendations for sofosbuvir, refer to the corresponding Product Monograph.

For patients with Child-Pugh A, B or C cirrhosis or recurrence of HCV infection after liver transplant, the recommended initial dose of ribavirin is 600 mg daily with food, modified based on hemoglobin and creatinine clearance measurements (see Dose Modification and Interruption, Table 10).

The recommended regimens and treatment duration of the combination therapies are provided in Table 9.

a Daclatasvir dose is required to be adjusted based on the antiretroviral regimen (see DRUG INTERACTIONS, Table 6).

b Excludes patients with previous exposure to NS5A inhibitors.

c The treatment regimen and duration recommendations for GT-2 (Child-Pugh Class A, B or C) are based on a limited number of patients . No GT-2 post-liver transplant patients were enrolled in the clinical studies (see CLINICAL TRIALS, Table 17).

d For GT-1 patients with compensated cirrhosis (Child-Pugh Class A), DAKLINZA + sofosbuvir without ribavirin may be considered.

e Lower SVR12 rates have been reported with decompensated cirrhotic patients (Child-Pugh Class C) treated for 12 weeks with DAKLINZA + sofosbuvir + ribavirin. Consider extending treatment duration to 24 weeks with or without ribavirin. Ribavirin may be added based on clinical assessment of individual patient (see Dose Modification and Interruption and CLINICAL TRIALS).

Dose Modification and Interruption

Daklinza

Once therapy is started, dose modification of DAKLINZA is not recommended. Treatment interruption should be avoided; however, if treatment interruption of any agent in the regimen is necessary because of adverse reactions, DAKLINZA must not be given as monotherapy or with ribavirin alone.

Ribavirin

If tolerated, the ribavirin dose can be titrated up to 1000 mg/day. If the starting dose is not well-tolerated, the dose should be reduced as clinically indicated, based on haemoglobin and creatinine measurements (see Table 10).

Discontinuation of therapy is recommended for patients experiencing confirmed virologic breakthrough (greater than 1 log₁₀ IU/mL increase in HCV RNA from nadir).

Special Populations

Pediatrics (<18 years of age)

DAKLINZA has not been studied in pediatric patients <18 years of age.

Geriatrics (≥65 years of age)

No dose adjustment of DAKLINZA is required for elderly patients.

Renal Impairment

No dose adjustment of DAKLINZA is required for patients with any degree of renal impairment.

Refer to the Product Monograph for SOVALDI for information on use of those products in patients with renal impairment.

Hepatic Impairment

No dose adjustment of DAKLINZA is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment.

Missed Dose

Patients should be instructed that if they miss a dose of DAKLINZA, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

For instructions for missed doses of other agents in the regimen, refer to the corresponding Product Monographs.

OVERDOSAGE

There is limited clinical experience with overdose of DAKLINZA. In phase 1 clinical trials, healthy subjects who received up to 100 mg for up to 14 days or single doses up to 200 mg had no unexpected adverse events.

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%) and has a molecular weight greater than 500 g⋅mol^-1, dialysis is unlikely to significantly reduce plasma concentrations of the drug.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Daclatasvir, a direct-acting antiviral agent (DAA) against the hepatitis C virus, is a highly selective inhibitor of the NS5A replication complex (see MICROBIOLOGY).

Pharmacodynamics

Effect on the Electrocardiogram

The effect of daclatasvir 60 mg tablet and 180 mg tablet on the QTc interval was evaluated in a randomized, partially blinded, placebo-controlled, positive-controlled, 4-period, 4-treatment, single-dose, crossover study in 56 healthy subjects. Subjects were randomized to receive daclatasvir (60 mg or 180 mg) or matching placebo under blinded conditions; moxifloxacin 400 mg, the positive control, was administered as an open-label treatment. Daclatasvir plasma exposures after a single 180 mg dose, as measured by Cmax, AUC(0-T), AUC(INF), were approximately 2.5, 2.9, and 3.0 times the exposures after a single 60 mg dose. These exposures are expected to bracket the highest plasma concentrations expected clinically. Neither 60 mg nor 180 mg of daclatasvir resulted in clinically relevant ΔQTcF prolongations. At every time point (1 to >22 hours), the upper bound of the two-sided 90% confidence interval for ΔΔQTcF (daclatasvir minus placebo) was less than 5 msec. The concentration-response analysis of QTcF revealed no apparent trend of ΔΔQTcF with increased plasma concentration. Daclatasvir 60 mg and 180 mg had no effect on heart rate, QRS or PR intervals.

Pharmacokinetics

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in patients with chronic HCV (see Table 11).

^a Daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin.

Overall, exposure to daclatasvir in patients infected with HCV and in healthy subjects was similar at the 60 mg dose. Daclatasvir exposures are comparable when co-administered with either peginterferon alfa/ribavirin or sofosbuvir.

Absorption

Daclatasvir is rapidly absorbed with a maximum concentration appearing 1-2 hours after ingestion of the tablet formulation. In normal healthy volunteers, daclatasvir Cmax and AUCINF are proportional to dose in the 20 mg to 60 mg dose range. In both healthy subjects and patients with HCV at doses ranging from 1 to 100 mg once daily for 14 days, steady state was achieved in approximately 4 days of once-daily dosing with a mean T-HALF of 12 to 15 hours and a median Tmax of 1 to 2 hours.

In Caco-2 cells, daclatasvir exhibited an efflux ratio of > 24 suggesting that daclatasvir is likely to be a substrate of the efflux transporter P-gp. Daclatasvir is not a substrate of breast cancer resistance protein (BCRP). Despite being a P-gp substrate, daclatasvir was well absorbed with an absolute bioavailability of 67% observed in humans, suggesting that intestinal efflux is not a substantial barrier for daclatasvir absorption in vivo.

Effect of Food on Oral Absorption

In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat meal (approximately 1000 kcal, approximately 50% from fat) decreased daclatasvir C_max and AUC by 28% and 23%, respectively, compared with administration under fasting conditions. Administration of a daclatasvir 60 mg tablet after a light meal (approximately 275 kcal, approximately 15% from fat) did not reduce daclatasvir exposure. The change in exposure when daclatasvir is coadministered with a high fat meal is not considered clinically significant and is not expected to alter the efficacy of daclatasvir based on an exposure-response analysis (see DOSAGE AND ADMINISTRATION).

Distribution

At steady state, protein binding of daclatasvir in HCV-infected patients was approximately 99% and independent of dose at the dose range studied (1-100 mg). In patients who received daclatasvir 60 mg tablet orally followed by 100 μg [¹³C,¹⁵N]-daclatasvir intravenous dose, estimated volume of distribution at steady state (Vss) was 47.1 L (6.22 L/kg).

In vitro studies indicate that daclatasvir is actively and passively transported into hepatocytes, with active transport being the major contributor. The active transport is mediated by OCT1 and other unidentified uptake transporters, but not by OAT2, sodium-taurocholate cotransporting polypeptide (NTCP), or OATPs. In vitro, daclatasvir inhibited efflux transporters (P-gp, BCRP), hepatic uptake transporters (OATP 1B1, 1B3 and 2B1), organic anion transporter (OAT) 1 and OAT3, and organic cation transporter (OCT)1 and OCT2.

Metabolism

Following a single oral dose (60 mg) administration of ¹⁴C-DCV in healthy adult subjects (n = 6), the systemic exposure of the parent drug or unmodified daclatasvir was 94.3%. Minimal metabolites were present in plasma (< 5%). Overall, 8 metabolites (7 products of oxidation and 1 product of hydration) were formed in humans. Daclatasvir was the predominant radioactive component in human plasma, accounting for 97% to 100% of the plasma radioactivity. BMS-805215 was the only metabolite detected in human plasma, accounting for trace amounts to 2% of the plasma radioactivity. BMS-805215 is an active metabolite, but it is more than 100-fold less potent than daclatasvir. In vitro studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 the major CYP isoform responsible for the metabolism of daclatasvir and in the formation of BMS-805215.

Excretion

Following a single-dose of oral ¹⁴C-daclatasvir in healthy subjects, approximately 88% of total radioactivity was recovered in the feces, primarily as parent drug (approximately 53% of the dose), and some as the predominant metabolite in humans, BMS-805215 (approximately 15% of the dose); approximately 6.6% was recovered in urine predominantly as parent drug. These data indicate that the liver is the major clearance organ for daclatasvir in humans. In vitro studies indicate that daclatasvir is actively and passively transporter into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters.

Following multiple-dose administration of daclatasvir, the terminal elimination half-life of daclatasvir ranged from 9 to 15 hours in healthy subjects and 10 to 15 hours in HCV-infected patients. In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg [¹³C,¹⁵N]-daclatasvir intravenous dose, the total clearance was 4.24 L/h.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of DAKLINZA in pediatric patients has not been evaluated.

Geriatrics

Population pharmacokinetic analysis of data from clinical trials indicated that age had no apparent effect on the pharmacokinetics of daclatasvir (see WARNINGS AND PRECAUTIONS, Special Populations).

Gender

Based on population pharmacokinetic analysis of data from clinical trials, AUC values at steady state in male and female HCV-infected patients were 9940 ng.h/mL and 13243 ng.h/mL, respectively. Overall, the difference between male and female patients are minor and not considered clinically meaningful.

Race

Based on population pharmacokinetic analysis of data from clinical trials, AUC values at steady state in white, black, and Asian HCV-infected patients were 11097 ng.h/mL, 12104 ng.h/mL, and 10951 ng.h/mL, respectively. Overall, the differences between these groups are minor and not considered clinically meaningful.

Hepatic Insufficiency

The pharmacokinetics of daclatasvir 30 mg single dose was investigated in an open-label, parallel-group study of 18 non-HCV infected subjects with mild ( Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment and compared to 12 matched control subjects with normal hepatic function. For total daclatasvir, the C_max decreased by 46%, 45%, and 55% and AUC_INF decreased by 43%, 38%, and 36%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to normal subjects. The exposure for free (unbound) daclatasvir was 14% to 43% lower for C_max and 2% to 40% lower for AUC_INF in hepatically impaired subjects; hepatic impairment did not have a clinically significant effect on the free drug concentration of daclatasvir. There was no clear association between daclatasvir exposures and Child-Pugh scores. Patients with any degree of hepatic impairment may receive the recommended 60 mg dose of DAKLINZA.

Renal Insufficiency

The pharmacokinetics of daclatasvir was studied with a single 60 mg dose of daclatasvir in non-HCV infected subjects with normal renal function (creatinine clearance [CLcr] ≥ 90 mL/min, defined by the Cockcroft-Gault CLcr formula), with mild (≥ 60 to <90 mL/min), moderate (≥ 30 to <60 mL/min), or severe (CLcr < 30 mL/min) renal impairment not on hemodialysis, and in patients with end-stage renal disease (ESRD) on hemodialysis. Compared to non-HCV-infected subjects with normal renal function, the AUC of daclatasvir was estimated to be 26.4%, 59.8%, and 79.6% higher in subjects with CLcr values of 60, 30, and 15 mL/min, respectively. Daclatasvir unbound AUC was estimated to be 18.0%, 39.2%, and 51.2% higher for subjects with CLcr values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function. Subjects with end-stage renal disease requiring hemodialysis had a 26.9% increase in daclatasvir AUC and a 20.1% increase in unbound AUC compared to subjects with normal renal function. No dosage adjustment of DAKLINZA is necessary for patients with any degree of renal impairment.

Population pharmacokinetic analysis of data from HCV-infected patients indicated that mild to moderate renal impairment had no clinically meaningful effect on the pharmacokinetics of daclatasvir. Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis.

STORAGE AND STABILITY

Store at room temperature (15° to 30°C) and store in the original container.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

DAKLINZA tablets are available for oral administration in strengths 30 mg and 60 mg daclatasvir containing the following non-medicinal ingredients for the tablet core: anhydrous lactose, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, Opadry Green and silicon dioxide. The Opadry green contains the following inactive ingredients: FD & C blue #2 / indigo carmine aluminum lake, hypromellose, iron oxide (yellow), polyethylene glycol 400 and titanium dioxide.

DAKLINZA 30 mg daclatasvir (equivalent to 33 mg daclatasvir dihydrochloride) tablets are green, biconvex, pentagonal, and debossed with “BMS” on one side and “213” on the other side.

DAKLINZA 60 mg daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride) tablets are light green, biconvex, pentagonal, and debossed with “BMS” on one side and “215” on the other side.

DAKLINZA tablets, 30 mg and 60 mg are supplied in HDPE bottles containing 28 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: daclatasvir dihydrochloride

Chemical name: carbamic acid, N,N′-[[1,1′-biphenyl]-4,4′-diylbis[1H- imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1- methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C′-dimethyl ester, hydrochloride (1:2).

Molecular formula: C₄₀H₅₀N₈O₆•2HCl

Molecular mass: 811.80 g⋅mol^-1 (HCl salt), 738.88 g⋅mol^-1 (free base)

Structural formula:

Physicochemical properties:

Appearance: Daclatasvir drug substance is a white to yellow powder.

Solubility: Daclatasvir has poor solubility in water and ethanol at neutral pH. The solubility is strongly pH-dependent and the solubility is high at low pH values.

CLINICAL TRIALS

The efficacy and safety of DAKLINZA in combination with sofosbuvir, with or without ribavirin were evaluated in a phase 2 study (AI444040) and three phase 3 clinical trials: ALLY-1 (AI444215) in patients with Child-Pugh A, B or C cirrhosis or recurrence of chronic HCV infection after liver transplant, ALLY-2 (AI444216) in patients with HCV/HIV-1 coinfection and ALLY-3 (AI444218) in patients with chronic HCV genotype 3 infection and compensated liver disease (see Table 12 for details of the study design). In these studies, sustained virologic response (SVR, virologic cure) was defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12.

a For patients with HCV genotype 1 infection, the dose of ribavirin in AI444040 for patients less than 75 kg was 1000 mg/day (400 mg in the morning and 600 mg in the evening) and for patients weighing 75 kg or more, 600 mg twice daily. For patients with HCV genotype 2 or 3 infection, the dose of ribavirin was 400 mg/day twice daily. Ribavirin was to be taken with a meal.

^b The recommended initial dose of ribavirin was 600 mg daily with food, modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose could be titrated up to 1000 mg/day (see DOSAGE AND ADMINISTRATION, Table 10).

^c Includes 1 patient with HCV genotype 6. Due to this small sample size, data for patients with HCV genotype 6 infection are not further presented.

DAKLINZA in Combination with Sofosbuvir for the Treatment of Patients Infected with HCV Genotypes 1, 2, or 3 (Study AI444040)

The demographic and other baseline characteristics of the population are summarized in Table 13.

a All treatment-naive patients with HCV genotype 1 infection in AI444040 were without cirrhosis, and were randomized to a treatment duration of 12 (n=82) or 24 (n=44) weeks.

b RNA values were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL.

c a validated non-invasive diagnostic assay for liver fibrosis status.

Conversion of the FibroTest score to the corresponding METAVIR score suggests that 15% of all patients (22% of patients with prior PI failure, 14% of patients with genotype 2 or 3) had F3/F4 or F4 liver fibrosis.

Study Results

Treatment Outcomes in AI444040 Using Daclatasvir-Sofosbuvir +/- RBV

SVR and outcomes in patients without SVR in AI444040 are shown by patient population in Table 14.

a All treatment-naive patients with HCV genotype 1 infection in AI444040 were without cirrhosis, and were randomized to a treatment duration of 12 (n=82) or 24 (n=44) weeks. For treatment-naive and treatment-experienced HCV genotype 1 infected patients with cirrhosis, 24 weeks of treatment with DCV+SOF is recommended (see Table 9).

b SVR12: Sustained virologic response with HCV RNA <LLOQ at follow-up Week 12. Missing post-treatment Week 12 HCV RNA was imputed using the using the NVCB approach, ie, using the next and closest available HCV RNA measurement after the follow-up Week 12 HCV RNA visit window.

c In study AI444040, 31 patients received a 7-day lead-in with sofosbuvir monotherapy. When these patients are excluded, SVR rates for treatment-naive patients are 99% (110/111) in patients with HCV genotype 1, 94% (16/17) in patients with HCV genotype 2, and 100% (11/11) in patients with HCV genotype 3.

d SVR12 rates were not influenced by the inclusion of ribavirin in the regimen.

e Week 4: HCV RNA <LLOQ at treatment Week 4.

f EOTR: HCV RNA undetectable at End of Treatment.

g Virologic breakthrough was defined as confirmed increase in viral load of at least 1 log₁₀ IU/mL from nadir or any confirmed HCV RNA ≥LLOQ if previously declined to <LLOQ during treatment. Relapse was defined as HCV RNA ≥LLOQ during follow-up after HCV RNA undetectable at end of treatment.

h No deaths were observed in study AI444040.

SVR12 was achieved by 99% of patients with HCV genotype 1, 96% of those with genotype 2, and 89% of those with genotype 3. Response was rapid (more than 97% of patients had HCV RNA <LLOQ at Week 4) Treatment-naive patients with HCV genotype 1 who received 12 weeks of treatment had a similar response (SVR12=99%) as those treated for 24 weeks (SVR12=100%). While the addition of ribavirin to the regimen did not result in an increase in efficacy, the frequencies of adverse reactions commonly associated with ribavirin therapy (rash, cough, anemia, dyspnea, insomnia, and anxiety) were higher for patients in this study who received ribavirin than for patients who did not.

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups. The response rates for these subgroups are summarized in Table 15.

a Modified Intent to Treat analysis. Patients with missing follow-up Week 12 data were considered nonresponders at this timepoint.

Response was not influenced by HCV subtype (1a/1b), IL28B genotype, presence or absence of baseline NS5A polymorphisms, or use of ribavirin.

Outcomes in Study AI444040 are expected to be applicable to a broader patient population because patients who failed peginterferon alfa and ribavirin, with or without telaprevir or boceprevir, are treatment naive to DAKLINZA and sofosbuvir, and would be expected to achieve similar SVR rates as treatment-naive patients treated with DAKLINZA and sofosbuvir. These patient populations include:

• HCV genotype 1 patients who failed prior treatment with peginterferon alfa and ribavirin: Among the 167 HCV genotype 1 patients in the study, 17 fit the profile associated with difficult-to-treat patients who typically fail treatment with peginterferon alfa and ribavirin (METAVIR F3/F4 fibrosis, IL28B non-CC, and HCV RNA >800,000 IU/mL); all 17 patients achieved SVR with DAKLINZA and sofosbuvir. Among the 41 HCV genotype 1 patients who failed prior treatment with telaprevir or boceprevir in combination with peginterferon alfa and ribavirin, all 41 achieved SVR with DAKLINZA and sofosbuvir +/- ribavirin.
• HCV genotype 2 or 3 patients who failed peginterferon alfa and ribavirin: Among 44 treatment-naive patients with HCV genotype 2 or 3 who received DAKLINZA and sofosbuvir +/- ribavirin, 41 (93%) achieved SVR.

Outcomes in Study AI444040 with a regimen given for 24 weeks are also expected to be applicable to a duration of 12 weeks for most patients. Of 82 treatment-naive patients with HCV genotype 1 who received 12 weeks of treatment, 99% achieved SVR with DAKLINZA and sofosbuvir +/- ribavirin. It is expected that similar outcomes would be applicable in patients with HCV genotype 1 infection who failed prior treatment with peginterferon alfa and ribavirin with or without telaprevir or boceprevir, since they are treatment naive to DAKLINZA and sofosbuvir. While 12 weeks of treatment is also expected to result in a similar response as 24 weeks of treatment in patients with HCV genotype 2 and genotype 3 infection, longer treatment (24 weeks) should be considered for treatment-experienced HCV genotype 3-infected patients with cirrhosis.

DAKLINZA in Combination with Sofosbuvir and Ribavirin for Patients with Child-Pugh A, B or C Cirrhosis or with HCV Recurrence after Liver Transplant (ALLY-1) and DAKLINZA in Combination with Sofosbuvir +/- Ribavirin for Patients with HCV/HIV-1 coinfection (ALLY-2) and Genotype 3 (ALLY-3)

The demographic and other baseline characteristics of the populations included in ALLY-1, 2 and 3 are summarized in Table 16.

Table 16: Demographic and Other Baseline Characteristics of HCV Genotypes 1, 2, 3 and 4 Infected Patients Treated with DAKLINZA in ALLY-1, 2 and 3

a Concomitant HIV-1 therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of patients, NNRTI-based (efavirenz, nevirapine, or rilpivirine) regimens for 26% of patients, integrase–based regimens (raltegravir or dolutegravir) for 26%, and nucleoside only (abacavir + emtricitabine + zidovudine) regimens for 1%. Two patients were not receiving treatment for HIV-1.

b RNA values were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL.

Treatment Outcomes in ALLY-1, 2 and 3

ALLY-1; Study Results in Patients with Compensated (Child-Pugh A) and Decompensated (Child-Pugh B, C) Cirrhosis and Post-Liver Transplant.

The SVR12 rates and outcomes in patients without SVR12 in ALLY-1 are reported for patients infected with different genotypes and different levels of cirrhosis in Table 17. SVR12 rates were comparable regardless of age, race, gender, IL28B allele status or baseline HCV RNA level. In the cirrhosis cohort, 4 patients with hepatocellular carcinoma underwent liver transplantation after 1 to 71 days of treatment; 3 of the 4 patients received 12 weeks of post-liver transplant treatment extension and 1 patient, treated for 23 days before transplantation, did not receive treatment extension. All 4 patients achieved SVR12.

a Among patients with HCV genotype 1 infection and advanced cirrhosis, SVR12 was 91% (10/11) for Child-Pugh A, 92% (22/24) for Child-Pugh B, and 50% (5/10) for Child-Pugh C.

b One patient had detectable HCV RNA at end of treatment.

c Relapse rates are calculated with a denominator of patients with HCV RNA not detected at the end of treatment.

ALLY-2; Study Results in HCV-HIV-1 Co-infected Patients

The SVR12 rates and outcomes in patients without SVR12 in ALLY-2 are reported for patients with HCV/HIV-1 coinfection in Table 18. SVR12 rates were high regardless of combination antiretroviral therapy (CART). Among HCV treatment-naive patients, 98% (46/47) of those receiving a PI-based regimen, 100% (28/28) of those receiving an NNRTI-based regimen, 92% (23/25) of those receiving an integrase inhibitor-based regimen, and the 1 patient not receiving concomitant antiretroviral therapy achieved SVR. Among HCV treatment-experienced patients, 96% (22/23) of those receiving a PI-based regimen, 100% (12/12) of those receiving an NNRTI regimen, 100% (14/14) of those receiving an integrase inhibitor-based regimen achieved SVR as did the 2 patients receiving nucleoside analogs only and the 1 patient not on concomitant antiretroviral therapy.

SVR12 rates were comparable regardless of age, race, gender, IL28B allele status, or baseline HCV RNA level.

a Prior treatment was interferon-based for 49 patients, and 3 patients received sofosbuvir and ribavirin.

b Cirrhosis status was indeterminate for 5 patients.

c One patient had detectable HCV RNA at end of treatment.

d Relapse rates are calculated with a denominator of patients with HCV RNA not detected at the end of treatment.

The SVR12 rates in ALLY-2 are shown by patient population and HCV genotype in Table 19. 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, see MICROBIOLOGY.

^a Cirrhosis was present in 22/127 patients with HCV genotype 1, 1/13 patients with genotype 2, 1/10 patients with genotype 3, and no patients with genotype 4.

ALLY-3; Study Results in GT-3 Patients

The SVR12 and outcomes in patients without SVR12 for GT-3 patients in ALLY-3 are shown by patient population in Table 20. SVR12 rates in ALLY-3 were higher (93%; 111/119) in patients with F0 to F3 baseline fibrosis score by FibroTest compared with patients with F4 baseline fibrosis score (70% 21/30). SVR12 rates were higher in Treatment Naive patients than in Treatment Experienced patients. SVR12 rates were comparable regardless of age, race, gender, IL28B allele status, or baseline HCV RNA level

a Cirrhosis status was missing or inconclusive for 11 patients.

b One patient had detectable HCV RNA at end of treatment.

c Relapse rates are calculated with a denominator of patients with HCV RNA not detected at the end of treatment.

Long-term Follow-up

In an ongoing follow-up study to assess durability of response up to 3 years after treatment with DAKLINZA in phase 2 and 3 studies, no relapses occurred among 28 patients who achieved

SVR12 with DAKLINZA and sofosbuvir (± ribavirin) with a median duration of post-SVR12 follow-up of approximately 14.5 months.

MICROBIOLOGY

Mechanism of Action

Daclatasvir is an inhibitor of NS5A, a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir inhibits both viral RNA replication and virion assembly. In vitro and computer modeling data indicate that daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Antiviral Activity

In Vitro

Daclatasvir is a pan-genotypic inhibitor of full-length and chimeric replicons encoding NS5A sequences from clinical isolates representing HCV genotypes 1-6. Daclatasvir had median EC₅₀ values of 0.008 nM (range, 0.002-0.03 nM, n=35), 0.002 nM (range, 0.0007-0.006 nM, n=30), 0.008 nM (range, 0.005-0.02 nM, n=5), 0.2 nM (range, 0.006-3.2 nM, n=17), and 0.003 nM (range, 0.001-0.007 nM, n=4) against hybrid replicons containing genotypes 1a, 1b, 2, 3, and 4 patient-derived NS5A sequences, respectively, without detectable daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93. Daclatasvir activity was reduced against genotypes 1a, 1b, 2, 3, and 4 patient-derived replicons with resistance-associated polymorphisms at positions 28, 30, 31, or 93, with median EC₅₀ values of 76 nM (range, 4.6-2409 nM, n=5), 0.05 nM (range, 0.002-10 nM, n=12), 17.5 nM (range, 0.3-60 nM, n=16), 1835 nM (range, 1.3->5000 nM, n=8), and 0.035 nM (range, 0.007-158 nM, n=10).

The median EC₅₀ values of daclatasvir for genotype 5 patient-derived NS5A hybrid replicons was 0.004 nM (range, 0.003-0.019 nM, n=3) while the EC₅₀ value against a single HCV genotype 6 derived replicon was 0.054 nM.

Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV NS3 protease inhibitors, HCV NS5B nucleoside analog inhibitors, and HCV NS5B non-nucleoside inhibitors in cell culture combination antiviral activity studies using the cell-based HCV replicon system.

In Vivo

In HCV genotype 1a-infected treatment-naive patients, a single 60 mg dose of daclatasvir resulted in a 3.2 log₁₀ IU/mL mean reduction in viral load measured after 24 hours.

Resistance

See the Product Monograph for the cell culture and clinical resistance profile for sofosbuvir.

In Cell Culture

Substitutions conferring daclatasvir resistance in HCV genotypes 1-6 were selected in the cell-based replicon system and observed in the N-terminal 100 amino acid region of NS5A.

In stable genotype 1a replicon cell lines, M28T, Q30H, Q30R, L31V, and Y93C substitutions were identified and exhibited ≥500-fold reduced susceptibility to daclatasvir. For genotype 1b, the L31M/Y93H and L31V/Y93H combinations exhibited >8000-fold reduced susceptibility to daclatasvir.

In stable genotype 2a replicon cell lines, F28S, C92R, and Y93H substitutions exhibited ≥470-fold reduced susceptibility to daclatasvir, whereas for genotype 3a, Y93H exhibited 2738-fold reduced susceptibility to daclatasvir.

In stable genotype 4a replicon cell lines, R30G/S or L30H/R or Y93H/R identified in genotype 4a replicons exhibited ≥143-fold reduced susceptibility to daclatasvir. For genotype 5a, the L31F/K56R and L31V/K56R combinations exhibited >6000-fold reduced susceptibility to daclatasvir. For genotype 6a, L31M, P32L, P32S, and T58N exhibited ≥382-fold reduced susceptibility to daclatasvir.

In Clinical Studies

The resistance profile of DAKLINZA has been evaluated in a phase 2 clinical trial with sofosbuvir. Results for baseline NS5A polymorphisms and treatment-emergent substitutions are provided below.

Effect of Baseline HCV Polymorphisms on Treatment Response

In a pooled analysis of 605 available baseline NS5A sequences from patients who received daclatasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks, baseline NS5A polymorphisms at amino acid positions associated with daclatasvir resistance (28, 30, 31 or 93) were detected in 19% (116/605) of patients (32/295 genotype 1a, 15/75 genotype 1b, 33/36 genotype 2, 31/192 genotype 3, 4/6 genotype 4, and 1/1 genotype 6) with available baseline NS5A sequence. These NS5A polymorphisms included M28T/V, Q30E/H/L/R, L31M or Y93C/H/L/N/S in patients with genotype 1a; R30K/M/Q, L31M or Y93H in patients with genotype 1b; F28L or L31M in patients with genotype 2; M28V, A30E/K/S/T/V, L31M or Y93H in patients with genotype 3; L28M or L30R in patients with genotype 4; and F28M/V and R30S in patients with genotype 6.

Overall SVR12 rates for patients with or without baseline NS5A polymorphisms at 28, 30, 31 or 93 were 88% (102/116) and 96% (469/489), respectively (see Table 21). In patients without cirrhosis, the SVR12 rates in patients with and without baseline NS5A polymorphisms were high: 95% (83/87) and 99% (350/353), respectively. In patients with cirrhosis, SVR12 rates with and without baseline NS5A polymorphisms were 52% (11/21) and 85% (77/91), respectively. Specific baseline NS5A polymorphisms in the 10 patients with cirrhosis who failed were: M28T (n = 1), L31M (n = 2, both Child-Pugh B) and Y93N (n = 1) in patients with genotype 1a; A30K (n = 1), Y93H (n = 3) and A30T (n = 1) in patients with genotype 3; and L31M (n = 1, Child-Pugh C) in a patient with genotype 2. All of the described genotype 1a, genotype 2, and genotype 3 NS5A substitutions confer a greater than 100-fold reduction in daclatasvir activity in vitro, except for A30T which was only detected at baseline and not at failure. For the 14 patients with cirrhosis who failed without noted baseline NS5A polymorphisms, 6 patients had Child-Pugh C liver disease.

The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any patient in Phase 2 or 3 studies by population-based sequencing.

a Two patients with cirrhosis (1 genotype 3, 1 genotype 4) each with Child-Pugh C cirrhosis who received daclatasvir and sofosbuvir with ribavirin were classified as nonvirologic failures due to data not being available for the integrated analysis although they achieved SVR12; both patients had noted baseline NS5A polymorphisms (genotype 3: A30K; genotype 4: L28M) and are not included in this analysis.

b For 53 post-liver transplant patients treated with daclatasvir and sofosbuvir ± ribavirin for 12 weeks, the presence of baseline NS5A polymorphisms (at 28, 30, 31 or 93) did not appear to impact response rates since all patients (n = 8) with these polymorphisms achieved SVR12. The overall total row in the table includes this patient population, but they are not included in the rows for patients with and without cirrhosis, as cirrhosis status was not determined.

^c Patients with cirrhosis were only treated for 12 weeks

Resistance Substitutions in Patients Not Achieving SVR

In a pooled analysis of 679 patients who received daclatasvir/sofosbuvir with or without ribavirin in Phase 2 and 3 studies for 8, 12, or 24 weeks, 44 patients (19 with genotype 1a, 2 with genotype 1b, 2 with genotype 2, and 21 with genotype 3) qualified for resistance analysis due to virologic failure or early study discontinuation and having HCV RNA greater than 1000 IU/mL. Post-baseline NS5A and NS5B sequencing (assay cut-off of 20%) were available for 44/44 and 39/44 patients, respectively.

NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from 37/44 patients (13/19 with genotype 1a, 1/2 with genotype 1b, 2/2 with genotype 2, and 21/21 with genotype 3) not achieving SVR. Treatment-emergent NS5A RAVs are shown in Table 22.

a Treatment-emergent NS5A RAVs were observed in studies AI444215, AI444216 and AI44218.

b Six patients (2 GT-1a, 2 GT-1b, 1 GT-2, and 1 GT-3) without NS5A sequence post-baseline either died or were lost to follow-up after achieving SVR4 [N=2], were lost to follow-up during the treatment phase [N=1], were incarcerated during treatment [N=2], or achieved SVR12 but had HCV RNA < LLOQ TD on treatment [N=1].

c X represents a deletion of the designated amino acid. NS5A-P32X reduced daclatasvir susceptibility by >1,000,000-fold resistance when tested in-vitro.

NA= not applicable

Thirteen (68%) of the 19 patients with HCV genotype 1a who qualified for resistance testing harbored one or more NS5A RAVs at positions M28, Q30, L31, H58 or Y93 of which 11 were treatment-emergent (Table 22). Five of the patients with genotype 1a also had Child-Pugh C liver disease. Two patients had the same NS5A RAVs at baseline and post-baseline (M28T or Y93N). Substitutions at Q30 were most frequently observed (Q30E/H/K/R; 10/19 [52.6%]). Of the 2 patients with genotype 1b who qualified for resistance testing, a deletion at NS5A-P32 was observed in 1 patient.

The 2 patients with genotype 2 who qualified for resistance testing had the same NS5A RAVs at baseline and post-baseline (L31M).

Of the 21 patients with genotype 3 who qualified for resistance testing, 21 (100%) patients harbored one or more NS5A RAVs at positions 30, 31, 62 or 93. Substitutions at Y93 were most frequently observed (17/21 [81%]) and were observed at baseline in 6 patients and only post-baseline in 11 patients. Among the 7 patients who had no NS5A RAVs at failure, all received daclatasvir/sofosbuvir for 8 weeks.

All of the described genotype 1a Q30 substitutions, genotype 1b P32 deletion, genotype 2 L31M, and genotype 3 Y93H conferred reduced susceptibility to daclatasvir in vitro (fold-change in EC50 values of 900 or greater).

Persistence of Resistance-Associated Substitutions

Limited data on the persistence of emergent drug-resistant substitutions are available for the DAKLINZA plus sofosbuvir regimens in patients infected with HCV genotypes 1, 2 and 3. In a separate long-term follow-up study of patients predominately infected with HCV genotype 1 treated with DAKLINZA-based regimens in phase 2 and 3 clinical trials, viral populations with treatment-emergent NS5A resistance-associated substitutions persisted at detectable levels for more than 1 year in most patients.

Cross Resistance

Daclatasvir was fully active against sofosbuvir resistance-associated substitutions while daclatasvir-resistant substitutions remained fully sensitive to sofosbuvir.

Cytotoxicity

Daclatasvir showed no cytotoxicity in multiple cell lines derived from liver, lymphoid or endothelial tissue. The CC50 values ranged from 11 to 38 µM in HuH7 and from 17 to 90 µM in HuH7, Vero, MDBK, MRC5, and MT2 cell lines.

NON-CLINICAL TOXICOLOGY

Acute Toxicity

Daclatasvir has a very low potential for acute toxicity. Single doses ≤ 150 mg/kg in dogs and monkeys, and ≤ 1000 mg/kg in mice and rats produced no mortality and were well tolerated.

Chronic Toxicity

In repeat-dose toxicity studies in dogs, Daclatasvir was not tolerated at a dose of 100 mg/kg/day (AUC 158 μg•h/mL, 10.5× RHD AUC), which was associated with mortality due to bone marrow and hepatic toxicity. In contrast, with the exception of a single monkey (150 mg/kg/day; AUC 80.3 μg•h/mL, 5.3× RHD AUC) euthanized with signs of hepatic and bone marrow toxicity, monkeys tolerated Daclatasvir dosed for ≤ 9 months (≤ 300 mg/kg/day; AUC ≤ 41.2 μg•h/mL, 2.7× RHD AUC). The findings for the 1 decedent monkey were not consistent with findings in other monkeys dosed for ≤ 9 months (see study description below), and based on the overall weight of evidence from completed monkey and clinical studies, are unlikely to be related to daclatasvir although a relationship cannot be discounted.

In repeat-dose toxicity studies in rats (≤ 6 months) and monkeys (≤ 9 months), the main target organs included the liver (monkeys) and adrenal gland (rats and monkeys). In monkeys dosed for 9 months, the most robust monkey study (i.e., longest duration and greatest number of monkeys assessed), hepatic effects at 30 mg/kg/day (AUC 11.6 μg•h/mL, 0.8× RHD AUC) included minimal Kupffer-cell hypertrophy/hyperplasia. At 150 mg/kg/day (AUC 38.8 μg•h/mL, 2.7× RHD AUC), additional hepatic findings included minimal to slight mononuclear cell infiltrates, increases in liver-associated serum biomarkers (ALT, AST, CRP), and slight bile duct hyperplasia. All these changes were reversible following a 2-month recovery period, with the exception of minimal to slight Kupffer cell hypertrophy/hyperplasia, which was not considered adverse. Adrenal effects in rats included reversible adrenal cortical hypertrophy associated with increased urine corticosterone levels at 100 mg/kg/day (AUC 107 μg•h/mL, 7.1× RHD AUC). Adrenal gland changes in monkeys were characterized as reversible minimal to marked decreases in cytoplasmic vacuolation in the cortical zona fasciculata, and in males, increases in adrenal-gland weight at ≥ 30 mg/kg/day (AUC ≥ 11.6 μg•h/mL, ≥ 0.8× RHD AUC), and at a dose of 300 mg/kg/day (AUC 41.2 μg•h/mL, 2.7× RHD AUC) slight cortical hyperplasia in the zona reticularis.

Overall, with repeat dosing across species and study durations ≤ 9 months, no observed effect level (NOEL) or no observable adverse effect level (NOAEL) doses and AUC values were generally consistent indicating little potential for cumulative or new toxicities to emerge with long-term administration.

Juvenile Toxicology

In juvenile rats administered daclatasvir for 10 weeks, there were no new toxicities relative to those observed in adult rats. The highest dose tested was associated with adrenal gland hypertrophy at AUC values 7.8-fold the RHD AUC. The AUC value at the no observed adverse effect level (NOAEL) for juvenile toxicity was 3.1-fold the RHD AUC.

Carcinogenesis and Mutagenesis

Daclatasvir was not carcinogenic in mice at AUC values 8.7-fold the RHD AUC or in rats at 4.7-fold the RHD AUC. No evidence of mutagenic or clastogenic activity was observed in in vitro mutagenesis (Ames) tests, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats.

Impairment of Fertility

Daclatasvir had no effects on fertility in male or female rats at any dose tested. The highest AUC value in unaffected females was 18-fold the RHD AUC. In male rats, effects on reproductive endpoints were limited to reduced prostate/seminal vesicle weights, and minimally increased dysmorphic sperm at 200 mg/kg/day; however, neither finding adversely affected fertility or the number of viable conceptuses sired. The AUC associated with this dose in males is 19-fold the RHD AUC.

Reproductive Toxicology

Daclatasvir was not a selective developmental toxicant when administered to pregnant rats or rabbits during organogenesis. Neither maternal nor developmental toxicities were observed at maternal daclatasvir doses associated with AUC values 4.6-fold (rat) and 16-fold (rabbit) the RHD AUC. At higher doses, concomitant maternal and developmental toxicities were noted in both species; AUC values associated with these doses were 25-fold (rat) and 72-fold (rabbit) RHD AUC values.

Maternal toxicity included mortality, adverse clinical signs, and decreases in body weight and food consumption. Developmental toxicity consisted of increases in embryofetal lethality, reduced fetal body weights, and increased incidence of fetal malformations of the ribs and variations, notably affecting the developing head and skull. In a study of prenatal and postnatal development in rats, there was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day, associated with AUC values 2.6-fold the RHD AUC. At the highest dose (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. The AUC value associated with this dose is 4.7-fold the RHD AUC.

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