Date of approval.
Year
Month
Date
Daclatasvir Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Daclatasvir Hydrochloride Tablets
Trade name: DAKLINZATM
English name: Daclatasvir Hydrochloride Tablets
Hanyu Pinyin：Yansuan Dalatawei Pian
Ingredients
The active ingredient of this product is daclatasvir hydrochloride
Chemical Name.
Methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2-methylpropyl) carbamate dihydrochloride
Chemical structure formula.
Molecular formula: C40H50N8O6-2HCl
Molecular weight: 738.88 (free base), 811.80 (hydrochloride)
【Properties】.
This product is a light green biconvex pentagonal film-coated tablet with the word “BMS” depressed on one side and “215” depressed on the other side.
Indications
Daclatasvir Hydrochloride Tablets are used in combination with other drugs for the treatment of chronic hepatitis C virus infection in adults.
Daclatasvir Hydrochloride Tablets should not be used as monotherapy.
Specification
60mg (calculated by C40H50N8O6)
Dosage]
Recommended Dosage
The recommended dose of Dalatavir Hydrochloride Tablets is 60mg once daily, administered orally, either before or after a meal. Dalatavir Hydrochloride Tablets must be combined with other drugs (see Table 1, Table 2 and [clinical trials]). Refer to their instructions for recommended doses of other drugs in the dosing regimen.
Table 1: Recommended regimen for daltegravir hydrochloride tablets without interferon
Patient Population Treatment Regimen and Dosing Schedule Daclatasvir Hydrochloride Tablets + Asulpride Softgels for 24 Weeks for Patients with Genotype 1,2,4,5 or 6 Chronic Hepatitis Ca Non-Cirrhotic Patients Daclatasvir Hydrochloride Tablets + Sofosbuvir for 12 Weeks for Patients with Cirrhosis
Child-Pugh A or B
Daclatasvir hydrochloride tablets + sofosbuvir + ribavirin for 12 weeks
or
Daclatasvir hydrochloride tablets + sofosbuvir (without ribavirin) for 24 weeks
Child-Pugh C Dalatavir hydrochloride tablets + sofosbuvir with or without ribavirin for 24 weeksb Genotype 3 chronic hepatitis Ca non-cirrhotic patients Dalatavir hydrochloride tablets + sofosbuvir for 12 weeks Cirrhotic patients Dalatavir hydrochloride tablets + sofosbuvir with or without ribavirin for 24 weeksb Genotype 1-6 chronic hepatitis Ca non-cirrhotic patients who have relapsed after liver transplantation Patients with Child-Pugh A or B cirrhosis on daclatasvir hydrochloride tablets + sofosbuvir + ribavirin for 12 weeks
Genotype 1, 2, 4, 5 or 6
Genotype 3
Daclatasvir hydrochloride tablets + sofosbuvir + ribavirin for 12 weeks
Daclatasvir hydrochloride tablets + sofosbuvir with or without ribavirin for 24 weeks bChild-Pugh C cirrhotic patients Daclatasvir hydrochloride tablets + sofosbuvir with or without ribavirin for 24 weeks baIncluding patients co-infected with human immunodeficiency virus (HIV). For recommended doses in combination with anti-HIV drugs, see [Drug Interactions].
bAddition of ribavirin should be considered based on individual patient tolerability, see [Clinical Trials].
Table 2: Recommended regimens for interferon-containing daltegravir hydrochloride tablets
Patient population Treatment regimen and duration of dosing Patients with primary treatment of genotype 4 chronic hepatitis C non-cirrhotic or compensated cirrhosis Daclatasvir hydrochloride tablets in combination with interferon alpha + ribavirin for 24 weeks of daclatasvir hydrochloride tablets and interferon alpha + ribavirin for 24-48 weeks aa If the patient is HCV RNA non-detectable at both 4 and 12 weeks of treatment, the three drugs in the regimen should be combined If the patient obtains undetectable HCV RNA at only one of the time points of 4 and 12 weeks of treatment, daltegravir hydrochloride tablets should be discontinued at week 24, and interferon alfa and ribavirin should be continued until 48 weeks.
Ribavirin Dosing Guidance
When co-administered with Dalatavir Hydrochloride Tablets, the dose of ribavirin is adjusted according to body weight (<1,000 mg/day for patients 75 kg; 1,200 mg/day for patients ≥75 kg).
The recommended starting dose of ribavirin is 600 mg daily in patients with ChildPugh B or C cirrhosis or in patients with chronic hepatitis C relapse after liver transplantation. If well tolerated, the dose may be increased to 1000 mg daily. The starting ribavirin dose and therapeutic dose should be reduced according to hemoglobin levels and creatinine clearance (see Table 3).
Table 3: Dosing guidelines for ribavirin in combination with daltegravir hydrochloride tablets in dosing regimens for patients with Child-Pugh class B or C cirrhosis or after liver transplantation Laboratory values/clinical criteria Ribavirin dosing guidelines Hemoglobin > 12 g/dL 600 mg daily > 10-£12 g/dL 400 mg daily > 8.5 -£10 g/dL 200 mg £8.5 g/dL Discontinuation of ribavirin Creatinine clearance >50 mL/min Guideline dosage based on hemoglobin levels in this table >30 -£50 mL/min 200 mg Every other day £30 mL/min or hemodialysis Discontinuation of ribavirin Dose adjustment, suspension of dosing and discontinuation of therapy
Dose adjustment of Dalatavir Hydrochloride Tablets is not recommended and suspension of dosing should be avoided. However, if the administration of any of the drugs in the combination regimen needs to be suspended due to an adverse reaction, treatment with daclatasvir hydrochloride tablets alone or daclatasvir hydrochloride tablets alone in combination with ribavirin should not be used.
Patients are advised to discontinue therapy once there is a confirmed virologic breakthrough (HCV RNA elevation greater than 1 log10 IU/mL from nadir). There are no virologic discontinuation rules applicable to the combination regimens of daltavir hydrochloride tablets and acepromazine softgels or daltavir hydrochloride tablets and sofosbuvir. The HCV RNA thresholds (i.e., discontinuation rules) that require discontinuation for patients treated with daclatasvir hydrochloride tablets in combination with pegylated interferon a + ribavirin (PR) are shown in Table 4.
Table 4: Discontinuation rules for patients with inadequate virologic response treated with daclatasvir hydrochloride tablets, pegylated interferon a and ribavirin HCV RNA measures 4 weeks of treatment: > 1000 IU/ml discontinuation of daclatasvir hydrochloride tablets, pegylated interferon a and ribavirin 12 weeks of treatment: ≥25 IU/ml discontinuation of daclatasvir hydrochloride tablets, pegylated interferon a and ribavirin 24 weeks of treatment: ≥25 IU/ml discontinuation of pegylated interferon a and ribavirin (24 weeks of treatment with Dalatavir Hydrochloride Tablets completed) missed doses
For a missed dose of Dalatavir Hydrochloride Tablets, patients should be instructed to make up the dose as soon as possible if it is within 20 hours of the scheduled dosing time; if it is beyond 20 hours, no more doses should be made up and the next dose should be continued at the scheduled time. Refer to the instructions for other drugs in the dosing regimen for information on missed doses.
Renal Impairment
Dilatavir Hydrochloride Tablets do not require dose adjustment in patients with any degree of renal impairment (see [Pharmacokinetics]). For recommended doses of other drugs in the dosing regimen, refer to their instructions.
Hepatic impairment
No dose adjustment is required for Dalatavir Hydrochloride Tablets in patients with any degree of hepatic impairment (see [Pharmacokinetics]). For recommended doses of other drugs in the dosing regimen, refer to their instructions.
Directions for administration
Dalatavir hydrochloride tablets are administered orally, either before or after a meal. Patients should be instructed to swallow the tablets whole. Due to the poor taste of the active ingredient, it should not be chewed or crushed.
[Adverse Reactions].
Clinical studies experience with Dalatavir Hydrochloride Tablets combined with Asulavir Softgels
Clinical studies in China
The HALLMARK ASIA (AI447036) study evaluated a regimen of Dalatavir Hydrochloride Tablets 60 mg once daily in combination with Asulavir Softgels in 159 Asian patients with genotype 1b chronic hepatitis C, 127 of whom were from mainland China. The safety profile of this study (AI447036) with a 24-week treatment course of daclatasvir hydrochloride tablets in combination with asuravir softgels was consistent with the results observed in global studies. The most common (≥5%) adverse reactions are listed in Table 5. there was one non-treatment related death. Serious adverse events occurred in 5 subjects
(3.1%], and 2 (1.3%) subjects discontinued treatment due to adverse events. Most events were mild to moderate in severity. The safety profile of daltegravir hydrochloride tablets in combination with asuravir softgels was similar in patients with and without cirrhosis.
Table 5: Systematic organ classification/incidence of adverse reactions reported in the HALLMARK ASIA (AI447036) study of daltegravir hydrochloride tablets in combination with asuravir softgelsa
Adverse reactionsb
n=159 Blood and lymphatic system disorders Thrombocytopenia (5.0%) Common laboratory tests Monocyte count reduction (5.7%) Commona
Incidence categorized as very common (≥1/10) and common (≥1/100 to
<1/10).
b
Events that were potentially associated (in the judgment of the investigator) with the study drug and had an incidence of at least 5% in 159 patients treated with daclatasvir hydrochloride tablets in combination with asuravir softgels in the HALLMARK ASIA (AI447036) study.
Global Clinical Studies
The safety of daclatasvir hydrochloride tablets 60 mg once daily in combination with asuravir softgels was evaluated in 1059 patients with chronic hepatitis C in five Phase 2/3 global studies (see [Clinical Trials] Table 13). The duration of treatment in the study was 24 weeks. The most common adverse reactions (incidence ≥10%) included headache (14%) and fatigue (12%). Most adverse reactions were mild to moderate. 6% of patients experienced serious adverse events and 3% discontinued due to adverse events; the most common adverse events leading to discontinuation were elevated alanine aminotransferase (ALT) and elevated aspartate aminotransferase (AST). in HALLMARK DUAL (AI447028), patients treated initially during the initial 12-week treatment period, the placebo The incidence of adverse reactions was similar between the daclatasvir hydrochloride tablet combined with asulpride softgels treatment group. In addition, the safety profile of daclatasvir hydrochloride tablets in combination with asulpride softgels was similar in patients with and without cirrhosis.
List of Adverse Reactions
Adverse reactions reported in patients treated with daclatasvir hydrochloride tablets in combination with asuravir softgels are listed in Table 6.
Table 6: Adverse reactions reported in global clinical studies of Dalatavir Hydrochloride Tablets in combination with Asulprasvir Softgels
System organ classification/incidencea Adverse reactionsb
n=1059 Hematologic and lymphatic system disorders
Common eosinophilia (2%) Neurological disorders
Very common headache (14%) Gastrointestinal disorders
Common diarrhea (7%), nausea (8%) Skin and subcutaneous tissue disorders
Common rash (3%) Systemic disease and site of administration symptoms
Very common
Common fatigue (11%)
Fever (4%) Laboratory tests
Common
ALT elevation (8%), AST elevation (6%) Incidence was categorized as very common (≥1/10) and common (≥1/100 to <1/10).
Pooled data were obtained from the HALLMARK DUAL (AI447028), HALLMARK NIPPON (AI447026), AI447031, AI447017, and AI447011 studies. In these five studies, events that were at least potentially related to the study drug (in the judgment of the investigator) and occurred at a rate of at least 5% occurred in 1059 patients treated with daltegravir hydrochloride tablets in combination with asuravir softgels. A number of other adverse reactions with an incidence of less than 5% in clinical studies are also listed based on an assessment of the potential causality of the severity to the dosing regimen.
Daclatasvir hydrochloride tablets in combination with sofosbuvir sofosbuvir
Four open randomized clinical studies [AI444040, ALLY-3 (AI444218), ALLY-2 (AI444216), and ALLY-1 (AI444215), see [Clinical Trials] Table 13] evaluated daclatasvir hydrochloride tablets 60 mg daily in 679 patients with chronic hepatitis C of genotype 1, 2, 3, 4, or 6 once in combination with sofosbuvir (with or without ribavirin), including patients with HIV co-infection, patients with compensated or decompensated cirrhosis, and patients with chronic hepatitis C relapse after liver transplantation. Patients were treated for a period of 8, 12 or 24 weeks. The most common adverse reactions (incidence ≥10%) were fatigue (19%), headache (15%), and nausea (11%). Most adverse reactions were mild or moderate. 5% of patients experienced one serious adverse event. 4 patients discontinued daltegravir hydrochloride tablets due to adverse events, of which only 1 patient had an adverse event considered to be related to study treatment. The safety profile of daclatasvir hydrochloride tablets in combination with sofosbuvir was similar in patients with compensated cirrhosis and non-cirrhotic liver disease.
Adverse reactions reported in treatment with dalactavir hydrochloride tablets in combination with sofosbuvir (with or without ribavirin) are listed in Table 7 according to the protocol.
Table 7: Adverse reactions reported in clinical studies of daclatasvir hydrochloride tablets in combination with sofosbuvir (with or without ribavirin) by system organ/incidencea
Adverse reactionsb Dalatavir hydrochloride tablets + sofosbuvir + ribavirin n=203 Dalatavir hydrochloride tablets + sofosbuvir
n=476 Blood and lymphatic system disorders Very common anemia (17%) Psychiatric disorders Very common insomnia (6%) Insomnia (3%) Neurological disorders Very common headache (21%) Headache (12%) Respiratory, thoracic and mediastinal disorders Common cough (5%) Gastrointestinal disorders Very common nausea (13%) Nausea (10%) Common diarrhea (6%) Diarrhea (5%) General and site of administration Disease Very common fatigue (23%) Fatigue (17%)a Incidence was categorized as very common (≥1/10) as well as common (≥1/100 to <1/10).
b Pooled data from the AI444040, ALLY-3 (AI444218), ALLY-2 (AI444216), and ALLY-1 (AI444215) studies, occurring in 203 patients using daltegravir hydrochloride tablets + sofosbuvir + ribavirin and in 476 patients using daltegravir hydrochloride tablets + sofosbuvir without ribavirin with at least events that were potentially associated (in the judgment of the investigator) with the study drug and occurred at least 5% of the time. See [Clinical Trials].
Dalatavir hydrochloride tablets in combination with pegylated interferon alpha and ribavirin
The safety of treatment with Dalatavir Hydrochloride Tablets 60 mg once daily in combination with pegylated interferon alfa and ribavirin was evaluated in 1536 patients with chronic hepatitis C in ten controlled clinical studies (see [Clinical Trials] Table 13). The most common adverse reactions (incidence ≥15%) included fatigue (37%), headache (28%), pruritus (23%), anemia (22%), flu-like illness (22%), nausea (20%), insomnia (20%), neutropenia (20%), weakness (20%), rash (19%), decreased appetite (18%), dry skin (18%), hair loss ( 17%) and fever (15%).
Compared to 216 patients treated with placebo, pegylated interferon alfa and ribavirin, there were no more adverse events above 5% in the daltegravir hydrochloride tablet treatment group. The incidence of grade 3-4 adverse events was higher in patients treated with placebo, pegylated interferon alfa, and ribavirin (24%) than in patients treated with dalactavir hydrochloride tablets, pegylated interferon alfa, and ribavirin (20%). the incidence of treatment-related serious adverse events, and adverse reactions leading to discontinuation of the drug, was similar in the 2 treatment groups.
The incidence of adverse reactions in the cirrhotic subgroup of patients treated with daltegravir hydrochloride combined with pegylated interferon alfa and ribavirin was similar to that in patients treated with placebo, pegylated interferon alfa and ribavirin [92% (157/170) vs 96% (22/23)], and the incidence of grade 3-4 liver function abnormalities in the cirrhotic subgroup was low (less than 10%), indicating that dalactavir hydrochloride tablets have no adverse effect on the safety of patients with compensated cirrhosis.
Post-marketing Experience
The following events have been reported in post-marketing clinical use of Dalatavir Hydrochloride Tablets. The incidence cannot be assessed as it was spontaneously reported and the population size is unknown.
Dalatavir Hydrochloride Tablets in combination with Asulavir Softgels
Skin and subcutaneous tissue disorders: erythema multiforme.
Dalatavir Hydrochloride Tablets in combination with sofosbuvir regimen in combination with amiodarone
Cardiac disease: Arrhythmias (including severe bradycardia and heart block) have been observed in patients on amiodarone in combination with dalactavir hydrochloride tablets and sofosbuvir (see [Precautions] and [Drug Interactions] and see the instructions for amiodarone and sofosbuvir).
Laboratory results of Dalatavir Hydrochloride Tablets in combination with Asulpride Softgels, in combination with Sofosbuvir with or without Ribavirin, or in combination with pegylated interferon alpha and Ribavirin
Clinical studies in China
The specific grade 3-4 laboratory test abnormalities observed in the data from the HALLMARK ASIA (AI447036) clinical study of daltegravir hydrochloride tablets in combination with asulpride softgels for the treatment of patients with chronic hepatitis C are listed in Table 8.
Table 8: Specific grade 3-4 laboratory test abnormalities in the HALLMARK ASIA (AI447036) clinical study of Dalatavir Hydrochloride Tablets in combination with Asuravir Softgelsa Incidence of parameter abnormalities Dalatavir Hydrochloride Tablets in combination with Asuravir Softgels
n = 159 ALT elevation (³5.1 × ULN)1% AST elevation (³5.1 × ULN)2% Total bilirubin elevation (³2.6 × ULN)<1% a 13 (8.2%) subjects experienced a grade 3/4 platelet reduction during treatment. However, all of these subjects had grade 2 platelet reduction at baseline. None of these patients developed concomitant clinical symptoms and none discontinued treatment due to thrombocytopenia. The platelet count changes observed in this study were not considered clinically relevant and correlated with the baseline characteristics of the subjects.
Global Clinical Studies
Abnormalities in specific grade 3-4 laboratory tests observed in data from global phase 2 and 3 clinical studies of dalactavir hydrochloride tablets in combination with asuravir softgels in patients with chronic hepatitis C are listed in Tables 9 and 10.
Table 9: Specific grade 3-4 laboratory test abnormalities in global clinical studies of dalactavir hydrochloride tablets in combination with asulisovir soft gelatin capsules
Incidence of abnormalities Dalatavir hydrochloride tablets + Asuravir softgels Dalatavir hydrochloride tablets + Sofosbuvir with or without ribavirin Parameters n=1059an = 679b ALT elevation (≥5.1 x ULN) 5% <1% AST elevation (≥5.1 x ULN) 3% <1% Total bilirubin elevation (≥2.6 x ULN) <1% 3% Pooled data from the cHALLMARK DUAL (AI447028), HALLMARK NIPPON (AI447026), AI447031, AI447017, and AI447011 studies.
Pooled data were obtained from the AI444040, ALLY-3 (AI444218), ALLY-2 (AI444216), and ALLY-1 (AI444215) studies. 203 (30%) of 679 patients received daltegravir hydrochloride tablets in combination with sofosbuvir and ribavirin. 1% of the 679 patients had a 3/4 Grade 3/4 hemoglobin reduction was observed in 1% of 679 patients, but not in patients receiving only daclatasvir hydrochloride tablets and sofosbuvir.
Grade 3/4 total bilirubin elevations were observed only in HIV co-infected patients treated with atazanavir, in compensated or decompensated cirrhosis, and in patients treated with ribavirin after transplantation.
Table 10: Incidence of abnormalities in specific grade 3-4 laboratory abnormal parameters in clinical studies of dalactavir hydrochloride tablet regimens containing pegylated interferon alfa/ribavirin Dalactavir hydrochloride tablets combined with pegylated interferon alfa/ribavirin
n=1536 placebo combined with pegylated interferon alfa/ribavirin
n=216aALT,
elevated
(³5.1 × ULN) 2% 2% AST,
Elevated
(³5.1 × ULN) 2% 3% Total bilirubin elevation
(³2.6 × ULN) 6% 1% Data from 10 placebo-controlled clinical studies of daclatasvir hydrochloride tablets in combination with pegylated interferon alpha and ribavirin
Contraindications
For contraindications to the use of this product in combination with other drugs, please refer to the instructions for the respective drug.
This product is contraindicated in patients with prior hypersensitivity to this product or any component of the product.
Combination with CYP3A4 potent inducers is contraindicated as it may result in lower exposure dose and reduced efficacy of Dalatavir Hydrochloride Tablets. Contraindicated drugs include, but are not limited to, those listed in Table 11 (see [Drug Interactions]).
Table 11 Drugs prohibited in combination with Daclatasvir Hydrochloride Tablets
Mechanism of Interaction Clinical Review Contraindicated Drugsa Anticonvulsants
Phenytoin, carbamazepine, oxcarbazepine, phenobarbital Combination of drugs with potent induction of CYP3A4 may result in deficiency of virologic response to daltavir hydrochloride tablets Anti-branched bacillus drugs
Rifampicin, rifabutin, rifapentine Systemic use of glucocorticoids
Dexamethasone Herbal
St John’s wort This table is not a complete list of all potent CYP3A4-inducing drugs.
[Caution].
Potential hepatotoxicity of treatment regimens containing Asuravir softgels
Asuravir softgel-containing regimens can cause drug-induced liver injury (sometimes severe). See prescribing information for Asuravir Softgels for recommendations on monitoring liver function. The incidence of clinically significant ALT or AST elevations in treatment regimens of daltegravir hydrochloride tablets without asulisvir softgels is similar to that of patients in the placebo group.
Potential Risk of Hepatitis B Virus Reactivation
Cases of hepatitis B virus (HBV) reactivation, including deaths, have been reported during and after the application of direct antiviral agents for the treatment of hepatitis C. All patients should be screened for HBV prior to initiating treatment. patients with HBV/HCV co-infection are at risk for HBV reactivation and should therefore be monitored and treated according to current clinical guidelines.
Drug Interactions
See [Contraindications] for drugs that are contraindicated in combination with Dalatavir Hydrochloride Tablets due to the potential for lack of antiviral potency. See [Drug Interactions] for explicit interactions with potential drugs. Refer to the respective prescribing information for drug interactions of other drugs in the regimen. The most conservative recommendations should be followed.
Severe bradycardia and heart block have been observed in patients on amiodarone in combination with daltegravir hydrochloride tablets and sofosbuvir (with or without other heart rate-lowering drugs). Bradycardia generally occurs within hours to days and subsides after termination of HCV therapy. The mechanism responsible for the bradycardic effect has not been clearly identified.
Amiodarone and Dalatavir hydrochloride tablets should be combined with sofosbuvir when and only when other antiarrhythmic therapy is contraindicated or not tolerated. Close monitoring is recommended for patients without other alternative therapies. Continuous inpatient monitoring should be performed within 48 hours of the combination, followed by daily outpatient heart rate monitoring or self-monitoring during the first two weeks of treatment.
Due to the long half-life of amiodarone, patients who discontinue amiodarone just prior to initiation of treatment with daltegravir hydrochloride tablets with sofosbuvir should still receive cardiac monitoring as described above.
All patients on combined amiodarone, daclatasvir hydrochloride tablets and sofosbuvir should be advised to be alert for symptoms of bradycardia and heart block and advised to seek medical help as soon as they develop such symptoms.
Refer to Amiodarone and Sofosbuvir prescribing information (see [Drug Interactions] and [Adverse Reactions], Postmarketing Experience).
Retreatment with Dalatavir Hydrochloride Tablets
The effectiveness of a re-treatment regimen containing Dalatavir Hydrochloride Tablets has not been established in patients with prior exposure to NS5A inhibitors.
Liver damage/cirrhosis
Dose adjustment of Dalatavir Hydrochloride Tablets is not required in patients with hepatic impairment. No clinically meaningful effects on the pharmacokinetics of dalactavir hydrochloride have been observed in studies of subjects with non-chronic hepatitis C with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9), or severe (Child-Pugh C, score ≥10) liver impairment (see [Pharmacokinetics]).
Of the more than 3,500 patients in nineteen clinical studies of daltegravir hydrochloride tablet combination therapy, more than 600 patients had cirrhosis. No overall differences in safety or efficacy were observed between patients with and without cirrhosis (see [Clinical Trials]). The safety and efficacy of Dalatavir Hydrochloride Tablets in combination with Asulavir Softgels has not been established in patients with decompensated cirrhosis.
Organ Transplant Patients
The safety and efficacy of daclatasvir hydrochloride tablets in combination with sofosbuvir and ribavirin for the treatment of chronic hepatitis C in patients before, during, or after liver transplantation was determined in a clinical study (see [Clinical Trials]).
HCV/HBV (hepatitis B virus) co-infection
The safety and efficacy of daltegravir hydrochloride tablets in the treatment of patients with chronic hepatitis C has not been established in patients co-infected with HBV.
Effect on the ability to drive and use machines
The effect of Dalatavir Hydrochloride Tablets on the ability to drive and use machines has not been studied.
Other
Do not use if the inner package is opened or damaged.
For Pregnant and Lactating Women]
There are no data on the use of Dalatavir Hydrochloride Tablets in pregnant women. Animal studies of dalactavir hydrochloride have shown maternal and embryo-fetal developmental toxicity at levels above the recommended human dose (RHD) AUC (see animal study data for dalactavir hydrochloride below). Daclatasvir Hydrochloride tablets should not be administered during pregnancy or to women of childbearing age who are not practicing contraception. The use of effective contraception should be continued for up to 5 weeks after completion of treatment with Dalatavir Hydrochloride Tablets.
Data from animal studies of Dalatavir Hydrochloride
Administration to pregnant rats or rabbits during organogenesis showed no selective developmental toxicity of dalactavir hydrochloride. No maternal toxicity or developmental toxicity was observed at maternal area under the curve (AUC) of dalactavir hydrochloride of 4.6 times (rats) and 16 times (rabbits) the recommended human dose. At higher doses, maternal and developmental toxicity was observed in both species; the corresponding AUCs were 25 times (rat) and 72 times (rabbit) the recommended human dose. Maternal toxicity included death, adverse clinical signs, weight loss, and reduced food intake. Developmental toxicity included increased embryo-fetal lethality, reduced fetal weight, increased incidence of fetal rib deformities and mutations, and significant effects on head and cranial development. In a pre- and postnatal developmental study in rats, there was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day, corresponding to an AUC value 2.6 times the recommended human dose. At the highest dose (100 mg/kg/day), maternal toxicity, including death and obstructed labor, and developmental toxicity, including slightly reduced offspring viability in the perinatal and neonatal periods, and reduced birth weight persisted into adulthood. This dose corresponds to an AUC value of 4.7 times the recommended human dose.
In combination with other HCV drugs.
When Dalatavir Hydrochloride Tablets are combined with pegylated interferon a and ribavirin, the contraindications and warnings for pegylated interferon a and ribavirin apply equally to this combination regimen. Ribavirin can cause birth defects and/or fetal death, and additional animal studies have shown abortifacient effects of interferon. Therefore, extra care must be taken to avoid pregnancy in female patients and in female partners of male patients. A negative pregnancy test must be obtained prior to initiation of ribavirin therapy. Refer to the prescribing information for ribavirin for detailed advice on contraception.
For information on the use of other drugs in the dosing regimen for pregnant and lactating women, refer to their prescribing information.
Lactation
It is not known if daltegravir hydrochloride is secreted into human breast milk. Daclatasvir hydrochloride is secreted into the milk of lactating rats at concentrations of 1.7 to 2 times the maternal plasma level. Breastfeeding is not recommended for mothers who are using daltavir hydrochloride tablets. Also refer to the prescribing information related to other drugs in the regimen.
[Pediatric Dosage].
The safety and efficacy of Daclatasvir Hydrochloride Tablets have not been established in pediatric patients.
Geriatric Use]
There were more than 2,000 patients from twelve clinical studies of dalactavir hydrochloride tablets in combination therapy, 310 of whom were 65 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.
[Drug Interactions].
Possible Effects of Other Drugs on Dalatavir Hydrochloride Tablets
Dalatavir hydrochloride is a CYP3A4 substrate. Moderate or potent CYP3A4 inducers may reduce plasma levels and therapeutic effects of daltavir hydrochloride (see [Contraindications] and Table 12). When combined with CYP3A4 intermediate-acting inducers, the dose of dalactavir hydrochloride tablets should be increased to 90 mg daily (3 tablets of 30 mg or 1 tablet each of 60 mg and 30 mg). potent inhibitors of CYP3A4 can increase plasma levels of dalactavir hydrochloride (see Table 12). When used in combination with CYP3A4 potent inhibitors, the dose of dalactavir hydrochloride tablets should be reduced to 30 mg daily. Dalatamivir hydrochloride is also a substrate for P-glycoprotein transporter protein (P-gp) and organic cation transporter (OCT) 1, but combination with drugs that alter P-gp or OCT1 activity alone (with no concurrent effect on CYP3A) is unlikely to have a clinically meaningful effect on exposure to Dalatamivir hydrochloride.
Possible Effects of Dalatavir Hydrochloride Tablets on Other Drugs
Dalatamivir hydrochloride is an inhibitor of P-gp, organic anion transporting peptide (OATP) 1B1/1B3, and breast cancer resistance-associated protein (BCRP). Administration of daltegravir hydrochloride tablets may increase systemic exposure to P-gp, OATP 1B1/1B3, or BCRP substrate drugs and may increase or prolong treatment effects and adverse effects. Drugs with a narrow therapeutic window should be applied with caution. In vitro, daltegravir hydrochloride did not inhibit (IC50 > 40 µM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6. daltegravir hydrochloride did not have a clinically meaningful effect on the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate). In vitro, daltegravir hydrochloride is an inhibitor of renal uptake of transporter proteins, organic anion transporter (OAT) 1/3, and OCT2, but no clinically meaningful effects on the pharmacokinetics of these transporter substrates are expected.
Tabular Summary of Drug Interaction Information
Refer to the respective prescribing information for drug interaction information for other drugs in the regimen. The most conservative recommendations should be followed.
Table 12 provides information on drug interaction studies for Dalatavir Hydrochloride Tablets, including clinical recommendations for identified or potentially significant drug interactions. Clinically relevant increases in concentration are indicated as “↑”, clinically relevant decreases are indicated as “↓”, and no clinically relevant changes are indicated as “↔”. The obtained geometric mean ratios of AUC, Cmax and Cmin are also shown, with 90% confidence intervals (CI) in parentheses. Unless otherwise noted, the studies presented in Table 12 were conducted in healthy adult subjects.
Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets and Other Drugs
Drug Interactions in Different Therapeutic Areas Recommendations for Coadministration Antivirals, HCV Protease Inhibitors Asulpride* 200 mg twice daily
(Dalatavir Hydrochloride 30 mg once daily)
*Non commercially available capsule formulation. ↔ Dalatavir Hydrochloride
AUC*: 1.20 (1.11, 1.30)
Cmax*: 1.07 (0.97, 1.18)
Cmin*: 1.33 (1.22, 1.45)
↔ Asuravir
AUC**: 0.87 (0.73, 1.04)
Cmax**: 0.58 (0.45, 0.76)
Cmin**: 1.76 (1.42, 2.17)
*Results are dose normalized to 60 mg dose.
**Results are dose normalized to a 600 mg dose. No dose adjustment of Dalatavir Hydrochloride Tablets or Asuravir Softgels is required. no interactions have been studied with Boceprevir.
Due to inhibition of CYP3A4 by Boceprevir, expected.
↑
Dalatavir hydrochloride
When Dalatamivir hydrochloride tablets are combined with Boceprevir or other potent inhibitors of CYP3A4, the dose of Dalatamivir hydrochloride tablets should be reduced to 30 mg once daily. simeprevir 150 mg once daily
(Dalatamivir hydrochloride 60 mg once daily)↔ Dalatamivir hydrochloride
AUC: 1.96 (1.84, 2.10)
Cmax: 1.50 (1.39, 1.62)
Cmin: 2.68 (2.42, 2.98)
↔ Simeprevir
AUC: 1.44 (1.32, 1.56)
Cmax: 1.39 (1.27, 1.52)
Cmin: 1.49 (1.33, 1.67) No dose adjustment of dalactavir hydrochloride tablets or simeprevir was required. Table 12: Information on drug interactions of Dalatavir Hydrochloride Tablets with other drugs
Drug Interactions in Different Therapeutic Areas Recommendations for Coadministration Telaprevir, 500 mg q12h (Dalatavir hydrochloride 20 mg once daily)
Telaprevir, 750 mg q8h (daclatasvir hydrochloride 20 mg once daily) ↑ daclatasvir hydrochloride
AUC: 2.32 (2.06, 2.62)
Cmax: 1.46 (1.28, 1.66)
↔ Telaprevir
auc: 0.94 (0.84, 1.04)
Cmax: 1.01 (0.89, 1.14)
↑ Dalatavir hydrochloride
AUC：2.15 (1.87, 2.48)
Cmax: 1.22 (1.04, 1.44)
↔ Telaprevir
AUC: 0.99 (0.95, 1.03)
Cmax: 1.02 (0.95, 1.09)
Telaprevir inhibits CYP3A4. When Dalatavir Hydrochloride Tablets are used in combination with Telaprevir or other potent inhibitors of CYP3A4, the dose of Dalatavir Hydrochloride Tablets should be reduced to 30 mg once daily. PEGylated interferon and ribavirin pegylated interferon a 180 µg once weekly and ribavirin 1000 or 1200 mg/day given in two divided doses
(Dalatasvir hydrochloride 60 mg once daily)
Studies in patients with chronic hepatitis C
↔ Dalatavir hydrochloride
AUC: ↔∗
Cmax: ↔∗
Cmin: ↔∗
↔ Polyethylene glycol interferon a
Cmin: ↔∗
↔ Ribavirin.
AUC: 0.94 (0.80, 1.11)
Cmax: 0.94 (0.79, 1.11)
Cmin: 0.98 (0.82, 1.17)
*Dalactavir hydrochloride was compared with historical reference. PK Valley levels of pegylated interferon a in patients receiving triple therapy with pegylated interferon a, ribavirin and daltavir hydrochloride were similar to those receiving pegylated interferon a, ribavirin and placebo. No dose adjustment of daltavir hydrochloride tablets, pegylated interferon a, or ribavirin was required. Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets and Other Drugs
Drug interactions in different therapeutic areas Recommendations for co-administration Nucleotide analogs Polymerase inhibitors
Sofosbuvir 400 mg once daily (daclatasvir hydrochloride 60 mg once daily)
Studies in patients with chronic hepatitis C
↔ Dalatavir Hydrochloride*
AUC: 0.95 (0.82, 1.10)
Cmax: 0.88 (0.78, 0.99)
Cmin: 0.91 (0.71, 1.16)
↔ GS-331007 **
auc: 1.0 (0.95, 1.08)
Cmax: 0.8 (0.77, 0.90)
Cmin: 1.4 (1.35, 1.53)
*Dalactavir hydrochloride was compared to a historical reference (data from three studies of dalactavir hydrochloride 60 mg once daily in combination with pegylated interferon a and ribavirin).
**GS-331007 is the major circulating metabolite of the former drug sofosbuvir. No dose adjustment of Dalatavir Hydrochloride Tablets or Sofosbuvir is required. Antivirals, HIV or HBV protease inhibitors Atazanavir 300 mg/ritonavir 100 mg once daily
(Dalatasvir hydrochloride 20 mg once daily)
↑Dalactavir Hydrochloride
AUC*: 2.10 (1.95, 2.26)
Cmax*: 1.35 (1.24, 1.47)
Cmin*: 3.65 (3.25, 4.11)
Ritonavir inhibits CYP3A4
*Results were dose normalized to a 60 mg dose. When daltavir hydrochloride tablets are used in combination with atazanavir/ritonavir or other potent inhibitors of CYP3A4, the dose of daltavir hydrochloride tablets should be reduced to 30 mg once daily. Atazanavir/cobicistat interaction has not been studied.
As atazanavir/cobicistat inhibits CYP3A4, it is expected that.
↑
Dalatasvir dirinavir hydrochloride 800 mg/ritonavir 100 mg once daily
(dalactavir hydrochloride 30 mg once daily)
Dirinavir 600 mg/ritonavir 100 mg twice daily
(Dalatasvir hydrochloride 30 mg once daily)
↔ Dalatasvir hydrochloride
AUC*: 1.41 (1.32, 1.50)
Cmax*: 0.77 (0.70, 0.85)
↔ Direnavir
AUC: 0.90 (0.73, 1.11)
Cmax: 0.97 (0.80, 1.17)
Cmin: 0.98 (0.67, 1.44)
*Results were dose normalized to a 60 mg dose. No dose adjustment was required for dalactavir hydrochloride tablets, dirinavir/ritonavir, or dirinavir/cobicistat. Dirinavir/cobicistat interactions have not been studied.
Expected.
↔ Dalatasvir lopinavir hydrochloride 400 mg/ritonavir 100 mg twice daily
(daclatasvir hydrochloride 30 mg once daily) ↔ Daclatasvir hydrochloride
AUC*: 1.15 (1.07, 1.24)
Cmax*: 0.67 (0.61, 0.74)
↔ Lopinavir.
auc: 1.15 (0.77, 1.72)
Cmax: 1.22 (1.06, 1.41)
Cmin: 1.54 (0.46, 5.07)
*Results were that dose normalization to the 60 mg dose did not require adjustment of dalactavir hydrochloride tablets or lopinavir/ritonavir. Nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) Tenofovir disoproxil fumarate 300 mg once daily
(Dalatasvir hydrochloride 60 mg once daily) ↔ Dalatasvir hydrochloride
AUC: 1.10 (1.01, 1.21)
Cmax: 1.06 (0.98, 1.15)
Cmin: 1.15 (1.02, 1.30)
↔ Tenofovir
AUC: 1.10 (1.05, 1.15)
Cmax: 0.95 (0.89, 1.02)
Cmin: 1.17 (1.10, 1.24) No dose adjustment of daclatasvir hydrochloride tablets or tenofovir was required. Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets and Other Drugs
Drug interactions in different therapeutic areas Recommendations for co-administration Lamivudine
Zidovudine
Emtricitabine
Abacavir
Didanosine
Stavudine
Interactions have not been studied.
Expected.
↔ Dalatavir Hydrochloride
↔ NRTI No dose adjustment of Dalatavir Hydrochloride tablets or NRTI is required. Non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz 600 mg once daily (Dalatavir hydrochloride 60 mg once daily for 9 days/120 mg once daily for 5 days)
↓ Dalatavir Hydrochloride
AUC*: 0.68 (0.60, 0.78)
Cmax*: 0.83 (0.76, 0.92)
Cmin*: 0.41 (0.34, 0.50)
Efavirenz induces CYP3A4
*Results were dose normalized to 60 mg dose
When Dalatavir Hydrochloride Tablets are combined with efavirenz or other CYP3A4-mediated inducers, the dose of Dalatavir Hydrochloride Tablets should be increased to 90 mg once daily. Etravirine
Nevirapine
Interactions have not been studied.
Due to induction of CYP3A4 by etravirine or nevirapine, it is expected that.
↓ Daratavir Hydrochloride Rilpivirine
Interaction not studied.
Expected.
↔ Daclatasvir Hydrochloride
↔ Rilpivirine does not require dose adjustment of daltavir hydrochloride tablets or rilpivirine. Integrase inhibitor Dolutegravir 50 mg once daily
(Dalatavir hydrochloride 60 mg once daily)
↔ Daclatasvir Hydrochloride
AUC: 0.98 (0.83, 1.15)
Cmax: 1.03 (0.84, 1.25)
Cmin: 1.06 (0.88, 1.29)
↑ Dolutegravir
AUC: 1.33 (1.11, 1.59)
Cmax: 1.29 (1.07, 1.57)
Cmin: 1.45 (1.25, 1.68)
Inhibition of P-gp and BCRP by daltegravir hydrochloride does not require dose adjustment of daltegravir hydrochloride tablets or dolutegravir. Raltegravir.
Interactions have not been studied.
Expected.
↔ Dalatavir hydrochloride
↔ Raltegravir.
No dose adjustment of dalactavir hydrochloride tablets or raltegravir is required. Etigevir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate have not been studied for this fixed-dose combination tablet interaction.
Expected due to cobicistat inhibition of CYP3A4: ↑ Dalatasvir hydrochloride is not recommended in combination with cobicistat or other potent inhibitors of CYP3A4. Fusion inhibitor Enfuvirtide
Interactions have not been studied.
Expected.
↔ Dalatavir Hydrochloride
↔ Enfuvirtide does not require dose adjustment of dalactavir hydrochloride tablets or Enfuvirtide. cCR5 receptor antagonist
Maraviroc.
Interactions have not been studied.
Expected.
↔ Dalatavir hydrochloride.
↔ Maravi if no dose adjustment of Dalatavir Hydrochloride Tablets or Maraviroc is required. Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets and Other Drugs
Drug interactions in different therapeutic areas Recommendations for co-administration Acid suppressants H2-receptor antagonists
Famotidine 40 mg single dose
(Daclatasvir hydrochloride 60 mg single dose)
↔ Daclatasvir hydrochloride
AUC: 0.82 (0.70, 0.96)
Cmax: 0.56 (0.46, 0.67)
Cmin: 0.89 (0.75, 1.06)
Increase in gastric pH No dose adjustment of Dalatavir Hydrochloride Tablets is required. Proton pump inhibitor Omeprazole 40 mg once daily
(Dalatavir hydrochloride 60 mg single dose)
↔ Dalatavir hydrochloride
AUC: 0.84 (0.73, 0.96)
Cmax: 0.64 (0.54, 0.77)
Cmin: 0.92 (0.80, 1.05)
Increase in gastric pH No dose adjustment of Dalatavir Hydrochloride Tablets is required. Antimicrobial agents Clarithromycin
Telithromycin
Interactions have not been studied.
Expected due to inhibition of CYP3A4 by the antimicrobial agent.
↑ Daclatasvir Hydrochloride Tablets are not recommended in combination with potent inhibitors of CYP3A4. Erythromycin
Interactions have not been studied.
Expected due to inhibition of CYP3A4 by antimicrobial agents.
↑ Daclatasvir hydrochloride is recommended with caution when combining daclatasvir hydrochloride tablets with erythromycin due to the potential for increased daclatasvir hydrochloride concentrations. Azithromycin
Ciprofloxacin
Interactions have not been studied.
Expected.
↔ Dalatavir hydrochloride
↔ Azithromycin or ciprofloxacin
No dose adjustment of dalactavir hydrochloride tablets, azithromycin or ciprofloxacin is required. Anticoagulants
Dabigatran.
Interactions have not been studied.
Because dabigatran inhibits P-gp, it is expected that.
↑ Safety monitoring is recommended when initiating treatment with dabigatran hydrochloride tablets in patients treated with dabigatran or other enteric P-gp substrates (narrow therapeutic window). Warfarin
Interactions have not been studied.
Expected.
↔ Dalatavir hydrochloride
↔ Warfarin does not require dose adjustment of Dalatavir hydrochloride tablets or warfarin. Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets and Other Drugs
Drug interactions in different therapeutic areas Recommendations on co-administration Anticonvulsants Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Interactions have not been studied.
As anticonvulsants induce CYP3A4, it is expected that.
↓ Dalatavir hydrochloride
Combination of Dalatavir Hydrochloride Tablets with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or other potent inducers of CYP3A4 is contraindicated (see [Contraindications]). Antidepressants Selective 5-hydroxytryptamine reuptake inhibitor etapren 10 mg once daily
(Dalatasvir hydrochloride 60 mg once daily)
↔ Daclatasvir hydrochloride
AUC: 1.12 (1.01, 1.26)
Cmax: 1.14 (0.98, 1.32)
Cmin: 1.23 (1.09, 1.38)
↔ Etazaprun
AUC: 1.05 (1.02, 1.08)
Cmax: 1.00 (0.92, 1.08)
Cmin: 1.10 (1.04, 1.16) No dose adjustment of Dalatavir Hydrochloride Tablets or etapren is required. Antifungal agent Ketoconazole 400 mg once daily
(Daclatasvir hydrochloride 10 mg single dose) ↑ Daclatasvir hydrochloride
AUC: 3.00 (2.62, 3.44)
Cmax: 1.57 (1.31, 1.88)
Inhibition of CYP3A4 by ketoconazole When Dalatavir Hydrochloride Tablets are combined with ketoconazole or other potent inhibitors of CYP3A4, the dose of Dalatavir Hydrochloride Tablets should be reduced to 30 mg once daily. Itraconazole
Posaconazole
Voriconazole
Interactions have not been studied.
Due to inhibition of CYP3A4 by antifungal agents, it is expected that.
↑ Daratavir fluconazole hydrochloride
Interaction has not been studied.
Due to inhibition of CYP3A4 by antifungal agents, expected to.
↑ Dalatavir hydrochloride
Moderate increase in dalactavir hydrochloride concentration expected, but no dose adjustment of dalactavir hydrochloride tablets or fluconazole required Anti-branch bacteriophage Rifampicin 600 mg once daily
(daclatasvir hydrochloride 60 mg single dose) ↓ daclatasvir hydrochloride
AUC: 0.21 (0.19, 0.23)
Cmax: 0.44 (0.40, 0.48)
Induction of CYP3A4 by rifampicin Daclatasvir hydrochloride tablets are contraindicated in combination with rifampicin, rifabutin, rifapentine, or other potent inducers of CYP3A4 (see [Contraindications]). Rifabutin
Rifapentine has not been studied for interaction.
Due to induction of CYP3A4 by anti-branched bacteriophage agents, it is expected that.
↓ Dalatavir Hydrochloride Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets with Other Drugs
Drug interactions in different therapeutic areas Recommendations on co-administration Cardiovascular drugs Anti-arrhythmic drugs Amiodarone
Interactions have not been studied For patients without alternative antiarrhythmic drug options, close monitoring is recommended if amiodarone is combined with Dalatavir Hydrochloride Tablets + Sofosbuvir. Refer to prescribing information for amiodarone and sofosbuvir (see [Adverse Reactions]). Digoxin 0.125 mg once daily
(Dalatasvir hydrochloride 60 mg once daily)
0.25 mg single dose
(Dalatasvir hydrochloride 60 mg once daily and Asulpride 100 mg twice daily)
↑Digoxin
AUC: 1.27 (1.20, 1.34)
Cmax: 1.65 (1.52, 1.80)
Cmin: 1.18 (1.09, 1.28)
AUC: 1.29 (1.20, 1.39)
Cmax: 1.77 (1.50, 2.07)
Caution should be exercised when combining daltavir hydrochloride tablets with P-gp digoxin and other P-gp substrates with a narrow therapeutic window. The lowest dose of digoxin should be prescribed initially. Serum digoxin concentrations should be monitored, and digoxin should be administered using a dose-escalation approach to achieve the desired clinical outcome. Calcium channel blockers Diltiazem
Verapamil
Interactions have not been studied.
Because calcium channel blockers inhibit CYP3A4, it is expected that.
↑ Dalatavir Hydrochloride Because of the potential for increased concentrations of Dalatavir Hydrochloride, caution is advised when combining Dalatavir Hydrochloride Tablets with diltiazem or verapamil. Corticosteroids Systemic application of dexamethasone
Interactions have not been studied.
Due to induction of CYP3A4 by dexamethasone, it is expected that.
↓ Daclatasvir Hydrochloride Tablets are contraindicated in combination with systemic dexamethasone or other potent inducers of CYP3A4 (see [Contraindications]). Herbal Supplements St. John’s wort No interactions have been studied.
Due to the induction of CYP3A4 by St. John’s wort, it is expected that.
↓ Daclatasvir hydrochloride is contraindicated in combination with daclatasvir hydrochloride tablets and St. John’s wort or other potent CYP3A4 inducers (see [Contraindications]). Table 12: Information on drug interactions between Dalatavir Hydrochloride Tablets and other drugs
Drug interactions in different therapeutic areas Recommendations for co-administration Hormonal contraceptives Ethinylestradiol 35 μg once daily for 21 days + Norgestimate 0.180/0.215/0.250 mg once daily for 7/7/7 days
(Dalatasvir hydrochloride 60 mg once daily)
↔ Ethinylestradiol
AUC: 1.01 (0.95, 1.07)
Cmax: 1.11 (1.02, 1.20)
↔ Norethindrone
auc: 1.12 (1.06, 1.17)
Cmax: 1.06 (0.99, 1.14)
↔ Norethindrone
AUC: 1.12 (1.02, 1.23)
Cmax: 1.07 (0.99, 1.16) No clinically meaningful effect on the pharmacokinetics of oral contraceptives. Based on the known pharmacokinetic profile of the daltegravir hydrochloride clearance pathway and oral contraceptives, co-administration should have no clinically meaningful effect on daltegravir hydrochloride pharmacokinetics. Ethinylestradiol 30 μg once daily + norethindrone acetate 1.5 mg once daily (high-dose oral contraceptive)
(Dalatavir Hydrochloride 60 mg once daily and Asulisibet 100 mg twice daily)
↔ Ethinylestradiol
AUC: 0.86 (0.83, 0.89)
Cmax: 0.93 (0.86, 0.99)
↔ Ethinylestradiol
AUC: 1.02 (0.94, 1.11)
Cmax: 0.93 (0.85, 1.01)
↔ Ethinylestradiol*
auc: 1.27 (1.21, 1.33)
Cmax: 1.36 (1.28, 1.45)
↔ Ethinylestradiol*
auc: 1.43 (1.34, 1.52)
Cmax: 1.26 (1.17, 1.36)
* Comparison of ethinyl estradiol/norethindrone pharmacokinetics when high-dose oral contraceptives are combined with acepromazine and daltegravir hydrochloride with ethinyl estradiol/norethindrone pharmacokinetics when low-dose oral contraceptives (ethinyl estradiol 20 μg once daily/norethindrone 1 mg once daily) are administered alone. No clinically meaningful effects on the pharmacokinetics of high-dose oral contraceptives were observed. Based on the known pharmacokinetic profile of the daltegravir hydrochloride clearance pathway and oral contraceptives, the combination should not have a clinically meaningful effect on daltegravir hydrochloride pharmacokinetics. Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets with Other Drugs
Drug Interactions in Different Therapeutic Areas Recommendations for Co-administration Immunosuppressant Cyclosporine 400 mg single dose
(Dalatavir hydrochloride 60 mg once daily)
↔ Daclatasvir hydrochloride
AUC: 1.40 (1.29, 1.53)
Cmax: 1.04 (0.94, 1.15)
Cmin: 1.56 (1.41, 1.71)
↔ Cyclosporine
AUC: 1.03 (0.97, 1.09)
Cmax: 0.96 (0.91, 1.02) No dose adjustment of Dalatavir Hydrochloride tablets or cyclosporine, tacrolimus, rapamycin, or morte-macrolimus is required. Tacrolimus 5 mg single dose
(daclatasvir hydrochloride 60 mg once daily)
↔ Daclatasvir hydrochloride
AUC: 1.05 (1.03, 1.07)
Cmax: 1.07 (1.02, 1.12)
Cmin: 1.10 (1.03, 1.19)
↔ Tacrolimus
AUC: 1.00 (0.88, 1.13)
Cmax: 1.05 (0.90, 1.23) Rapamycin
Motilmicol esters
Interactions have not been studied.
Expected.
↔ Dalatavir hydrochloride
↔ Immunosuppressive lipid-lowering agents HMG-CoA reductase inhibitors
Rosuvastatin 10 mg single dose
(Dalatasvir hydrochloride 60 mg once daily)
↑ Rosuvastatin
AUC: 1.58 (1.44, 1.74)
Cmax: 2.04 (1.83, 2.26)
Daclatasvir hydrochloride inhibits OATP 1B1, OATP 1B3, and BCRP Caution should be exercised when combining daclatasvir hydrochloride tablets with rivastigmine, other OATP 1B1/OATP 1B3, or BCRP substrates. Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Simvastatin Interactions have not been studied.
Due to inhibition of OATP 1B1 and/or BCRP by daltegravir hydrochloride, it is expected that
↑ statin concentrations
Table 12: Drug Interaction Information for Dalatavir Hydrochloride Tablets with Other Drugs
Drug interactions in different therapeutic areas Recommendations for co-administration Narcotic analgesics Buprenorphine/naloxone, stable maintenance 8/2 mg to 24/6 mg once daily 112
(Dalatavir hydrochloride 60 mg once daily) ↔ Dalatavir hydrochloride
AUC: ↔*
Cmax: ↔*
Cmin: ↔*
↔ Buprenorphine.
AUC: 1.37 (1.24, 1.52)
Cmax: 1.30 (1.03, 1.64)
Cmin: 1.17 (1.03, 1.32)
↔ Norbuprenorphine
AUC: 1.62 (1.30, 2.02)
Cmax: 1.65 (1.38, 1.99)
Cmin: 1.46 (1.12, 1.89)
*Compared with historical data. No dose adjustment of Dalatavir Hydrochloride Tablets or Buprenorphine is required. Methadone, stable maintenance 40-120 mg once daily
(Dalatavir hydrochloride 60 mg once daily) ↔ Dalatavir hydrochloride
AUC: ↔*
Cmax: ↔*
Cmin: ↔*
↔ R-Methadone.
AUC: 1.08 (0.94, 1.24)
Cmax: 1.07 (0.97, 1.18)
Cmin: 1.08 (0.93, 1.26)
*Compared with historical data. No dose adjustment of Dalatavir Hydrochloride Tablets or Methadone is required. Sedation Benzodiazepines Midazolam 5 mg single dose
(Dalatasvir hydrochloride 60 mg once daily)
Midazolam ↔ Midazolam
AUC: 0.87 (0.83, 0.92)
Cmax: 0.95 (0.88, 1.04) No dose adjustment for midazolam, other benzodiazepines, or other CYP3A4 substrates is required. Triazolam
Alprazolam
Interactions have not been studied.
Expected.
↔ Triazolam
↔ Alprazolam.
No clinically meaningful effects on the pharmacokinetics of any of the following drugs are expected when Dalatavir Hydrochloride Tablets are combined with any of the following drugs: PDE-5 inhibitors, ACE inhibitor drugs (e.g., enalapril), angiotensin II receptor antagonist drugs (e.g., cloxacin, irbesartan, olmesartan, candesartan, valsartan), amiodarone, propyzamide, propamyphene, flecainide mexiletine, quinidine, or antacids.
Drug overdose]
Clinical experience with overdose of Dalatavir Hydrochloride Tablets is limited. no unintended adverse reactions were observed in healthy subjects administered doses up to 100 mg for 14 days or single doses up to 200 mg in phase 1 clinical studies.
There is no known antidote for drug overdose with Dalatavir Hydrochloride Tablets. Treatment of daclatasvir hydrochloride tablets overdose should include general supportive measures (including monitoring of vital signs) and observation of the patient’s clinical status. Because daltegravir hydrochloride is highly protein bound (99%) and has a molecular weight greater than 500, dialysis is unlikely to significantly reduce blood levels.
Clinical Trials]
The efficacy and safety of daclatasvir hydrochloride tablets in combination with other drugs was evaluated in a phase 2/3 study (see Table 13). HCV RNA values were measured during the clinical study using the COBAS TaqMan HCV assay (version 2.0) (using the High Purity System). The lowest lower limit of detection (LLOQ) of the assay was 25 IU/ mL for all studies described in this section, except for the HALLMARK NIPPON (AI447026) study (whose LLOQ was 15 IU/mL). There was a high degree of concordance (98-100%) between SVR24 and SVR12. On-treatment virologic failure included patients with virologic breakthrough (confirmed HCV RNA elevation from nadir >1 log10 IU/mL or confirmed undetectable HCV RNA on treatment followed by HCV RNA ³LLOQ), non-responders with detectable HCV RNA or missing HCV RNA data at the end of treatment, and non-responders due to taking non-study anti HCV drugs taken during treatment and not tested for HCV RNA were counted as non-responders. Relapse was defined as confirmation of HCV RNA during the visit among patients with non-detectable HCV RNA at the end of treatment.The relapse rate was calculated using the number of patients with non-detectable HCV RNA at the end of treatment as the denominator. Laboratory findings were graded using the AIDS for Adults and Children with Adverse Event Severity (DAIDS) scale (version 1.0).
Table 13: Clinical Studies of Dalatavir Hydrochloride Tablets with Other Drugs in Subjects with Chronic Hepatitis C
Clinical Study Patient Population Study Subgroups
(number of subjects treated) Dalatavir Hydrochloride Tablets in combination with Asulpride Softgels HALLMARK ASIA (AI447036) Interferon alpha for treatment intolerant or unfit genotype 1b chronic hepatitis C compensated liver disease (including cirrhosis) Asian subjects Dalatavir Hydrochloride Tablets + Asulpride Softgels, 24 weeks
(n = 159) HALLMARK DUAL (AI447028) Primary, non-responsive or partially responsive to interferon alfa and ribavirin therapy; or subjects with genotype 1b chronic hepatitis C compensated liver disease (including cirrhosis) intolerant or unsuitable for interferon therapy Dalatavir hydrochloride tablets + Asuravir softgels, 24 weeks (n = 643)
Placebo, 12 weeks (n = 102)
HALLMARK NIPPON (AI447026) Genotype 1b chronic hepatitis C compensated liver disease (including cirrhosis) in Japanese subjects with poor response (no or partial response) to interferon alpha/beta and ribavirin therapy, intolerance or unsuitability for interferon therapy Dalatavir hydrochloride tablets + Asuravir softgels, 24 weeks (n = 222) AI447031 Genotype Type 1b chronic hepatitis C compensated liver disease (including cirrhosis) primary Japanese subjects Dalatavir Hydrochloride Tablets + Asulpride Softgels for 24 weeks (n = 119)
Telaprevir + interferon alfa-2b + ribavirin, 24 weeks (n = 111) Dalatavir hydrochloride tablets combined with sofosbuvir and ribavirin ALLY-1 (AI444215) genotype 1, 2, 3, 4, 5, or 6 chronic hepatitis C with advanced cirrhosis or post-transplantation subjects Dalatavir hydrochloride tablets + sofosbuvir + ribavirin 12 weeks (n = 113) ALLY-2 (AI444216) gene 1, 2, 3, 4, 5, or 6 chronic hepatitis C and chronic HCV/HIV co-infection in subjects with primary and treated compensated liver disease (including cirrhosis) Dalatavir hydrochloride tablets + sofosbuvir, 12 weeks (n = 153) ALLY-3 (AI444218) gene 3 Subjects with primary or treated compensated liver disease (including cirrhosis) with type 1 HCV infection Dalatavir hydrochloride tablets + sofosbuvir, 12 weeks (n = 152) AI444040 Subjects with primary or treated chronic hepatitis C with genotype 1, 2, or 3 without cirrhosis Dalatavir hydrochloride tablets + sofosbuvir with or without ribavirin, 12 weeks (n = 82)
Dalatavir hydrochloride tablets + sofosbuvir with or without ribavirin, 24 weeks (n = 129) Dalatavir hydrochloride tablets combined with pegylated interferon alpha and ribavirin COMMAND-3 (AI444052) subjects with compensated liver disease (including cirrhosis) with primary treatment of chronic hepatitis C type 1 Dalatavir hydrochloride tablets + pegylated interferon alpha-2a + ribavirin, 24 weeks (n = 402)
telaprevir + pegylated interferon alpha-2a + ribavirin, 12 weeks (n = 200) COMMAND-4 (AI444042) subjects with compensated liver disease (including cirrhosis) with genotype 4 chronic hepatitis C primary treatment Dalatavir hydrochloride tablets + pegylated interferon alpha + ribavirin, 24 weeks (n = 82)
Placebo + pegylated interferon alfa + ribavirin, 24 weeks (n = 42) GT: genotype
Dalatavir hydrochloride tablets in combination with asuravir softgels for patients with genotype 1b chronic hepatitis C
Clinical study in China.
HALLMARK ASIA (Study AI447036) is an open study evaluating the efficacy of daclatasvir hydrochloride tablets in combination with asuravir softgels (DUAL) for 24 weeks of continuous treatment in subjects with genotype 1b chronic hepatitis C who were intolerant or unfit for treatment with interferon alpha (with or without ribavirin).
A total of 159 subjects with genotype 1b chronic hepatitis C who were intolerant/unsuitable for interferon alfa treatment were treated in this open study: 127/159 (80%) from mainland China, 15/159 (9%) from Taiwan, and 17/159 (11%) from Korea. 159 treated subjects had a median age of 56.0 years and 35% were male. 32.7% had cirrhosis at baseline.
High SVR rates were observed in subjects from all three sites (91% in China, 94.% in Korea, and 87% in Taiwan), with an overall SVR24 rate of 91% (145/159). Similar SVR24 rates were observed across subgroups based on baseline demographics or disease characteristics (including gender, age, BMI, IFN/RBV unsuitability/intolerance, IL28B genotype, and cirrhotic status), and high response rates were observed in both cirrhotic and non-cirrhotic subjects (90% vs 92%). Virologic failure was rare, with 12 subjects (8%) experiencing treatment failure and 2 subjects (1%) experiencing virologic relapse after undetectable HCV RNA at the end of treatment. Table 14 summarizes patient outcomes by country/region for SVR and those who did not achieve SVR in the HALLMARK ASIA (AI447036) study. 91% (119/131) of subjects aged 65 years and older achieved SVR and 100% (7/7) of subjects aged 70 years and older achieved SVR. the table summarizes the results based on baseline NS5A resistance-related polymorphisms summarizes the SVR rates. Epidemiological information on these polymorphisms can be found in [Pharmacological Toxicology].
Table 14: HALLMARK ASIA (Study AI447036): Treatment Outcomes in Patients with Genotype 1b Chronic Hepatitis C with Dalatavir Hydrochloride Tablets in Combination with Asulpride Softgels Treatment Outcomes Mainland China
n=127 South Korea
n=17 Taiwan
n=15 Total
n=159 SVR
All 91% (116/127) 94% (16/17) 87% (13/15) 91% (145/159) with Y93H or L31F/I/M/Va
20%(2/10) without Y93H or L31F/I/M/Va
98%(114/116) 67%(2/3)
100%(14/14)67%(4/6)
100%(9/9)42%(8/19)
99% (137/139) cirrhosis
Non-cirrhotic 91% (38/42)
92%(78/85)83%(5/6)
100% (11/11) 100% (4/4)
82% (9/11) 90% (47/52) 92% (98/107) Outcomes in patients without SVR On-treatment virologic failure 9% (11/127) 6% (1/17) 08% (12/159) Relapse 0013% (2/15) 1% (2/147)a Patients with baseline NS5A sequence data were included in the analysis.
Clinical studies conducted worldwide.
HALLMARK DUAL (Study AI447028) is a global study enrolling patients with genotype 1b chronic hepatitis C and compensated liver disease who were primary treatment, pegylated interferon alpha/ribavirin treatment non-responders or partial responders, or patients who were intolerant or unsuitable for interferon-based therapy. Patients in the primary cohort were randomized 2:1 to receive either daclatasvir hydrochloride tablets 60 mg once daily in combination with asulpride softgels 100 mg twice daily for 24 weeks or placebo for 12 weeks (placebo patients were subsequently enrolled in another study and received daclatasvir hydrochloride tablets in combination with asulpride softgels for 24 weeks). Non-responders or partial responders and patients in the intolerant/unsuitable cohort received daclatasvir hydrochloride tablets 60 mg once daily in combination with asuravir softgels 100 mg twice daily for 24 weeks. Patients were followed up for 24 weeks after discontinuation of treatment.
The HALLMARK DUAL (AI447028) effectiveness analysis included 745 patients, 643 of whom received daclatasvir hydrochloride tablets in combination with asulpride softgels. The median age of these 643 patients was 57 years (range: 20-79); 48% were male; 70% were white, 24% were Asian (mainly from Taiwan and Korea), and 5% were black. The mean baseline HCV RNA level was 6.4 log10 IU/mL; 32% of patients had cirrhosis (Child-Pugh A) and 29% were IL28B CC genotype. 102 placebo-treated patients had similar baseline characteristics to those treated with daltegravir hydrochloride tablets in combination with asuravir softgels.
SVR (primary endpoint) results and patient outcomes without SVR in HALLMARK DUAL (AI447028) are presented by patient population in Table 15. The table also summarizes the SVR rates of patients according to baseline NS5A resistance-associated polymorphisms. Information on the incidence of these polymorphisms can be found in [Pharmacology and Toxicology].
Table 15: Treatment outcomes in patients with genotype 1b chronic hepatitis C in the HALLMARK DUAL (AI447028 study) with daclatasvir hydrochloride tablets in combination with asulpride softgels
Treatment outcome primary treatment
n=203 All prior treatment failures (partial responders and non-responders)
n=205Interferon intolerance/unsuitability
n=235SVR
All 91% (184/203) 82% (169/205) 83% (194/235) Containing Y93H or L31F/I/M/Va
Without Y93H or L31F/I/M/Va
59% (10/17)
96% (162/169) 28% (7/25)
92% (151/165) 37% (11/30)
90% (172/191) Cirrhosis
Non-cirrhotic
91% (29/32)
91% (155/171) 87% (55/63)
80% (114/142) 81% (90/111)
84% (104/124) Outcome of patients without SVR
On-treatment virologic failure
Relapse
Missing data after treatment 6% (12/203)
3% (5/189)
1% (2/203) 14% (29/205)
4% (7/174)
0 12% (28/235)
6% (12/204)
<1% (1/235) Patients with available baseline NS5A sequence data were included in the analysis.
The SVR rate (82%) was the same in 84 previous partial responders and 119 previous non-responders in patients with prior treatment failure. Virologic response onset was rapid (HCV RNA <LLOQ at week 4 in 95% of patients). Virologic response did not differ between treatment populations by race, sex, age, IL28B allele, or presence of cirrhosis. Consistently high SVR rates were obtained in all populations classified by baseline viral load. 88% (117/133) of patients aged 65 years and older achieved SVR and 100% (10/10) of patients aged 75 years and older achieved SVR.
HALLMARK NIPPON (AI447026 study) is an open study enrolling patients from Japan with genotype 1b chronic hepatitis C compensated liver disease who responded poorly to interferon alpha or beta combined with ribavirin therapy (including non-responders or partial responders) or who were intolerant/unsuitable for interferon-based therapy. Patients in the poor responders and intolerant/unfit cohort were given daltegravir hydrochloride tablets 60 mg once daily in combination with asuravir softgels 100 mg twice daily for 24 weeks and followed for 24 weeks after cessation of treatment.
The 222 patients treated in the HALLMARK NIPPON (AI447026) study had a median age of 63 years (range: 24-75 years); 35% were men. The mean baseline HCV RNA level was 7 log10 IU/mL, and 10% had compensated cirrhosis (Child-Pugh A). Of the 87 patients in the poor responder cohort, 36 were previous partial responders and 48 were previous non-responders. Of the 135 patients in the interferon intolerant/unfit cohort, 35 were intolerant and 100 were unfit. The majority of patients in the poor responder cohort were non-IL28B CC genotypes, while the majority of patients in the intolerant/unfit cohort were IL28B CC genotypes.
The outcomes of patients who achieved SVR and those who did not in the HALLMARK NIPPON (AI447026) study are presented by patient population in Table 16. The table also summarizes the SVR rates of patients based on baseline NS5A resistance-associated polymorphisms. Information on the incidence of these polymorphisms can be found in [Pharmacology and Toxicology].
Table 16: Treatment Outcomes in Patients with Genotype 1b Chronic Hepatitis C in HALLMARK NIPPON (AI447026 Study) with Dalatavir Hydrochloride Tablets in Combination with Asulavir Softgels
Treatment outcome in patients with previous poor response
(partial responders and non-responders)
n=87Interferon intolerant/unsuitable
n=135SVR
All 81% (70/87) 88% (119/135) Containing Y93H or L31F/I/M/Va
Without Y93H or L31F/I/M/Va
29% (4/14)
90% (65/72) 54% (13/24)
96% (100/104) Cirrhosis
Non-cirrhotic
91% (10/11)
79% (60/76) 91% (10/11)
88% (109/124) Outcome of patients without SVR
On-treatment virologic failure
Relapse 13% (11/87)
8% (6/76) 4% (6/135)
8% (10/129) Analysis included patients with available baseline NS5A sequence data.
In the prior poor responders cohort, 78% of prior partial responders, 81% of prior non-responders achieved SVR. 94% of intolerant patients, 86% of unfit patients in the intolerant/unfit cohort achieved SVR. virologic response onset was rapid (96% of patients with HCV RNA <LLOQ at week 4). Virologic response did not differ between sex, age, baseline HCV RNA level, IL28B allele status, and presence of cirrhosis in those with poor prior response and in the interferon intolerant/unfit population. 91% (81/89) of patients aged 65 years or older and 100% (4/4) of patients aged 75 years or older achieved SVR.
The AI447031 study was a phase 3 open-controlled study in Japanese patients with genotype 1b chronic hepatitis C virus infection treated with either daclatasvir hydrochloride tablets in combination with asuravir softgels or with telaprevir + pegylated interferon a-2b/ribavirin combination for 24 weeks in primary treatment. SVR12 rates (HCV RNA < LLOQ TD or TND at 12-week post-treatment follow-up) were 89% (106/119) and 62% (69/111) in the daltavir hydrochloride tablets combined with asulpride softgels and telaprevir + pegylated interferon + ribavirin groups, respectively. SVR rates with daltegravir hydrochloride tablets in combination with asuravir softgels were influenced by the presence of baseline NS5A gene polymorphisms (see Table 17).
Also in this study, patients with chronic hepatitis C who had relapsed on a previous IFN-containing regimen received daclatasvir hydrochloride tablets in combination with asulpride softgels for 24 weeks. The SVR12 rate for those who relapsed was 96% (21/22).
Table 17: Treatment Outcomes in Patients with Genotype 1b Chronic Hepatitis C in AI447031 with Dalatavir Hydrochloride Tablets in Combination with Asulpride Softgels Treatment Outcomes Primary Patients
n=119 Relapsers
n=22 SVR12
All 89% (106/119) 96% (21/22) With Y93H or L31F/I/M/V
Without Y93H or L31F/I/M/V 52% (11/21)
97% (95/98) 50% (1/2)
100% (20/20) Cirrhosisa
Non-cirrhotic 100% (6/6)
88% (91/104) N/A
N/A Outcome for patients without SVR On-treatment virologic failure
Relapse 3% (4/119)
8% (6/115) 0
5% (1/22) a Fibrotest score indicating advanced fibrosis/cirrhosis (METAVIR F4) genotype 1a chronic hepatitis C
In a 24-week study of dalactavir hydrochloride tablets in combination with softscale asuravir in patients with chronic genotype 1 chronic hepatitis C (no response to prior pegylated interferon alpha + ribavirin therapy), HCV RNA was not detected in 2 of 9 patients (22%) with genotype 1a chronic hepatitis C at week 24 post-treatment.
Dalatavir hydrochloride tablets in combination with sofosbuvir
The AI444040 study enrolled 211 patients with genotype 1, 2, or 3 chronic hepatitis C without cirrhosis who received daclatasvir hydrochloride tablets 60 mg once daily and sofosbuvir 400 mg once daily with or without ribavirin for 12 or 24 weeks. of the 167 patients with genotype 1 chronic hepatitis C, 126 were primary patients and 41 were on a protease inhibitor (PI) regimen (Boceprevir or Telaprevir) treatment failure patients. The median age of the 211 patients was 54 years (range: 20-70); 53% were male; 83% were white; 12% were black; and 2% were Asian. 82 patients with primary treatment for genotype 1 chronic hepatitis C were treated for 12 weeks, and the other 129 patients (primary treatment for genotype 1, 2, or 3) were treated for 12 weeks. The duration of treatment was 24 weeks for the other 129 patients (patients with genotype 1, 2 or 3 primary treatment and patients with genotype 1 prior PI treatment failure), and all patients were observed until 48 weeks post-treatment. The mean FibroTest score (a validated non-invasive diagnostic method to assess liver fibrosis status) for all 211 patients was 0.460 (range: 0.03 to 0.89). type 2 or 3 patients) had F3 or more severe liver fibrosis. The majority of patients in this study were IL-28B rs12979860 non-CC genotypes (71%, of which 98% were patients who had failed prior PI therapy).
SVR was achieved in 99% of genotype 1 chronic hepatitis C patients, 96% of genotype 2 patients, and 89% of genotype 3 patients. rapid response (more than 97% of patients achieved HCV RNA<LLOQ at week 4) and was unaffected by chronic hepatitis C subtype (1a/1b), IL28B genotype, or ribavirin use. Patients with primary treatment of genotype 1 chronic hepatitis C who received 12 weeks of treatment had similar response rates to those who received 24 weeks of treatment.
SVR outcomes in the AI444040 study and outcomes for patients who did not obtain SVR are presented by patient population in Table 18.
Table 18: Treatment Outcomes for Patients with Genotype 1, 2, or 3 Chronic Hepatitis C Daclatasvir Hydrochloride Tablets + Sofosbuvir (with or without Ribavirin) Treatment Outcomes Genotype 1 Genotype 2 Genotype 3 Primary Treatment
n=126 Prior Telaprevir or Boceprevir treatment failure
n=41 primary treatment
n=26 primary treatment
n=18 SVRa99% (125/126) 100% (41/41) 96% (25/26) 89% (16/18) ³ F3 liver fibrosis 100% (41/41) 100% (20/20) 100% (8/8) 100% (5/5) Outcome for patients without SVR Virologic breakthrough 0 0 0 6% (1/18) Relapse 0 0 0 6% (1/16) Missing post-treatment data 1% (1/126) 0 4% (1/26) 0 a In the AI444040 study, 31 subjects received a 7-day introduction period of sofosbuvir monotherapy. Excluding these subjects, SVR rates in primary subjects were 99% (110/111) for genotype 1 chronic hepatitis C, 94% (16/17) for genotype 2 chronic hepatitis C, and 100% (11/11) for genotype 3 chronic hepatitis C.
ALLY-3 (study AI444218) was an open trial of dalactavir hydrochloride tablets in combination with sofosbuvir that included 152 primary (n=101) or treated (n=51) patients with genotype 3 chronic hepatitis C compensated liver disease. Most of the treated patients were prior pegylated interferon/ribavirin treatment failures, but 7 patients were previously treated with sofosbuvir regimens and 2 patients were treated with the investigational cyclosporine-containing inhibitor alisporivir regimen. Patients received daclatasvir hydrochloride tablets 60 mg and sofosbuvir 400 mg once daily for 12 weeks and were observed up to 24 weeks after treatment.
The median age of the 152 treated patients in ALLY-3 (AI444218) was 55 years (range: 24-73); 59% were male; 90% were white, 5% were Asian, and 4% were black. The majority of patients (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 21% had compensated cirrhosis, 20% had stage F4 fibrosis (according to FibroTest results), and 40% were IL28B rs12979860 CC genotype.
The SVR results in study ALLY-3 and patient outcomes without SVR are presented by patient population in Table 19.
Table 19: Treatment outcomes in patients with chronic hepatitis C in ALLY-3 (AI444218) genotype 3 treated with daclatasvir hydrochloride tablets in combination with sofosbuvir Treatment outcomes Primary n=101 Treated n=51 Total n=152SVR12 All 90% (91/101) 86% (44/51) 89% (135/152) Cirrhosisa 58% (11/19) 69% (9/13) 63% (20/32) Non-cirrhotica 97% (73/75) 94% (32/34) 96% (105/109) Outcomes for subjects without SVR12 Virologic failure on treatmentb1% (1/101) 0 0.7% (1/152) Relapse 9% (9/100) 14% (7/51) 11% (16/151 ) a 11 patients with missing or indeterminate cirrhosis status.
b HCV RNA was detectable at the end of treatment in 1 patient.
SVR12 rates were comparable in patients of different ages, races, genders, IL28B allele status, or baseline levels of HCV RNA.
ALLY-2 (study AI444216) was an open trial including 153 HCV/HIV co-infected patients treated with daclatasvir hydrochloride tablets and sofosbuvir for 12 weeks. Patients with genotype 1, 2, 3, 4, 5, or 6 chronic hepatitis C were eligible for enrollment, including patients with primary chronic hepatitis C (n=101) and patients with treated chronic hepatitis C (n=52). The dose of daltegravir hydrochloride was 60 mg once daily (with dose adjustment based on the combination of antiretroviral drugs) and the dose of sofosbuvir was 400 mg once daily.
The median age of the 153 treated patients was 53 years (range: 24-71); 88% were male; 63% were white, 33% were black, and 1% were Asian. 68% of patients had genotype 1a chronic hepatitis C, 15% had genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most patients (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 16% had compensated cirrhosis, and 27% were IL28B rs12979860 CC genotype. Combined HIV treatment included PI-based regimens (dirinavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) in 46% of patients, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine) in 26%, integrase inhibitor-based regimens (raltegravir or dolutegravir) in 26% Two patients were not treated with combination HIV therapy.
The SVR outcomes in ALLY-2 (AI444216) and patient outcomes without SVR are presented by patient population in Table 20.
Table 20: Outcomes of patients with genotype 3 chronic hepatitis C in ALLY-2 (AI444216) treated with daclatasvir hydrochloride tablets in combination with sofosbuvir Primary treatment
n=101 Treateda
n=52 SVR12 97% (98/101)98% (51/52)cirrhoticb, c89% (8/9)93% (14/15)non-cirrhoticc98% (88/90)100% (34/34)genotype 196% (80/83 )98% (43/44) 1a
1b96% (68/71)
100% (12/12) 97% (32/33)
100% (11/11 )genotype 2100% (11/11)100% (2/2)genotype 3100% (6/6 )100% (4/4)genotype 4100% (1/1)100% (2/2)Outcomes for subjects without SVR12 on-treatment virologic failured1% (1/101)0 relapse1% (1/100)2% (1/52 ) Missing data after treatment1% (1/101)0a Previous treatment was interferon in 49 patients and sofosbuvir and ribavirin in 3 patients
b 22/127 of patients with genotype 1 chronic hepatitis C with cirrhosis, 1/13 of patients with genotype 2 chronic hepatitis C with cirrhosis, 1/10 of patients with genotype 3 chronic hepatitis C with cirrhosis, and no patients with genotype 4 with cirrhosis.
c The cirrhotic status of 5 patients was not determined.
d HCV RNA was measurable in 1 patient at the end of treatment.
SVR12 rates were high regardless of the combination antiretroviral therapy (CART) applied. SVR12 was 98% in patients with primary chronic hepatitis C receiving PI-based regimens (46/47), 100% in patients receiving NNRTI-based regimens (28/28), 92% in patients receiving integrase inhibitor-based regimens (23/25), and 1 patient receiving no combination antiretroviral therapy who obtained SVR. patients receiving PI-based SVR was achieved in 96% (22/23) of treated patients with chronic hepatitis C receiving PI-based regimens, 100% (12/12) of patients receiving NNRTI-based regimens, and 100% (14/14) of patients receiving integrase inhibitor-based regimens, while two patients receiving nucleoside analogs only and one patient not on combination antiretroviral therapy achieved SVR.
SVR rates were comparable among patients of different ages, races, genders, IL28B allele status, or baseline HCV RNA levels.
ALLY-1 (AI444215) was an open trial of daclatasvir hydrochloride tablets, sofosbuvir, and ribavirin that included 113 patients with advanced cirrhosis (n=60) or chronic hepatitis C relapse after liver transplantation (n=53) with chronic hepatitis C. Patients with genotype 1, 2, 3, 4, 5, or 6 chronic hepatitis C were enrolled. Patients received daltegravir hydrochloride tablets 60 mg once daily, sofosbuvir 400 mg once daily and ribavirin for 12 weeks of continuous treatment and were followed up to 24 weeks after treatment. The recommended initial dose of ribavirin is 600 mg daily with food, adjusted based on hemoglobin and creatinine clearance assays. If tolerated, the dose of ribavirin can be increased to 1000 mg/day. Patients who relapsed during the follow-up period received DAKLINZA, sofosbuvir and ribavirin again for 24 weeks, followed by an additional 24 weeks of follow-up.
The median age of the 113 treated patients in the ALLY-1 (AI444215) study was 59 years (range: 19-82); 67% of patients were male; 96% were white, 4% were black and 1% were Asian. Most patients (59%) were treated, and most patients (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL. 58% of patients had genotype 1a chronic hepatitis C, 19% had genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6. In the cohort of 60 patients with cirrhosis, 20% were Child-Pugh class A, 53% were Child-Pugh class B, and 27% were Child-Pugh class C. The median advanced liver disease score (MELD) for the cirrhotic patient cohort was 13 (range: 8 to 27). the majority (55%) of the 53 post-transplant patients cohort had F3 or F4 fibrosis (according to FibroTest results). Seventy-seven percent of all 113 patients were IL28B rs12979860 non–CC genotype.
The SVR results in ALLY-1 (AI444215) and patient outcomes without SVR are presented by patient population in Table 21.
Table 21: Treatment outcomes in patients with advanced cirrhosis or chronic hepatitis C relapse after liver transplantation in ALLY-1 (AI444215) treated with daclatasvir hydrochloride tablets + sofosbuvir + ribavirin Treatment outcomes Advanced cirrhosis
n=60 post-transplant n=53 SVR12 all 83% (50/60) 94% (50/53) Child-Pugh A 92% (11/12) Child-Pugh B 94% (30/32) Child-Pugh C 56% (9/16) MELD score ³15 <1567% (14/21) 87% ( 34/39) Genotype 1a, b 82% (37/45) 95% (39/41) Genotype 2 80% (4/5) – Genotype 3 83% (5/6) 91% (10/11) Genotype 4 100% (4/4) – Genotype 6- 100% (1/1) Outcome in subjects without SVR Virologic failure on treatmentc2% (1/60) 0 Relapse 16% (9/58) 6% (3/53) a Genotype 1a: 76% (26/34) in patients with advanced cirrhosis and 97% (30/31) in patients after transplantation. Genotype 1b: 100% (11/11) in patients with advanced cirrhosis and 90% (9/10) in post-transplant patients.
b 91% (10/11) of patients with Child-Pugh A, 92% (22/24) of patients with Child-Pugh B, and 50% (5/10) of patients with Child-Pugh C who had advanced cirrhosis with genotype 1 chronic hepatitis C obtained SVR12.
c HCV RNA was detectable at the end of treatment in 1 patient.
SVR rates were comparable in patients of different ages, races, genders, IL28B allele status, or baseline HCV RNA levels. Four patients with hepatocellular carcinoma in the cirrhosis cohort underwent liver transplantation after 1 to 71 days of treatment; three of the four patients received extended treatment after 12 weeks of transplantation and one patient was treated for 23 days before transplantation and did not receive extended treatment. SVR12 was obtained in all 4 patients.
Dalatavir hydrochloride tablets in combination with pegylated interferon alpha and ribavirin
The COMMAND study evaluated the efficacy and safety of daclatasvir hydrochloride tablets in combination with pegylated interferon/ribavirin for the treatment of patients with chronic hepatitis C in adult patients with genotype 1 (COMMAND-3, AI444052) and genotype 4 (COMMAND-4, AI444042) primary hepatitis C. The COMMAND study applied daclatasvir hydrochloride tablets in combination with pegylated interferon/ribavirin according to a response-guided protocol. The COMMAND study applied daltegravir hydrochloride tablets in combination with pegylated interferon/ribavirin for 24 or 48 weeks of continuous treatment according to a response-guided regimen. Patients received 24 weeks of daclatasvir hydrochloride tablets/pegIFN/RBV. patients who achieved HCV RNA undetectable (eRVR) at both 4 and 12 weeks of treatment completed treatment at week 24. Patients who did not achieve HCV RNA non-detectable at both 4 and 12 weeks of treatment received an additional 24 weeks of pegIFN/RBV.
COMMAND-3 (study AI444052) was a patient treatment study with either daclatasvir hydrochloride tablets 60 mg once daily (n=402) or telaprevir 750 mg three times daily (n=200) + pegIFN/RBV.
The median age of the 602 treated patients was 48 years (range: 18 to 71); 92% were white; 5% were black/African American; and 1% were Asian. 33% of patients had genotype 1a chronic hepatitis C and 67% had genotype 1b chronic hepatitis C; 11% had compensated cirrhosis and 76% had IL-28B rs12979860 non-CC genotype. In different subgroups (including age, sex, baseline viral load, cirrhosis status and IL28B genotype), SVR12 was higher in patients with genotype 1b chronic hepatitis C treated with daclatasvir hydrochloride tablets + pegIFN/RBV than in patients treated with telaprevir + pegIFN/RBV (see Table 22).
Table 22.
Results of treatment with dalactavir hydrochloride tablets combined with pegIFN/ribavirin in patients with genotype 1 chronic hepatitis C primed in COMMAND-3 (AI444052 study) relative to telaprevir combined with pegIFN/ribavirin treatment outcome parameters genotype 1b chronic hepatitis C genotype 1a chronic hepatitis C dalactavir hydrochloride tablets + pegIFN/RBV
n=268 Telaprevir + pegIFN/RBV
n=134 Dalatavir hydrochloride tablets + pegIFN/RBV
n=134Telaprevir + pegIFN/RBV
n=66SVRa 85% (228/268) 81% (109/134) 65 % (87/134) 70% (46/66)
Cirrhosis 77% (20/26) 67% (10/15) 56% (9/16) 56% (5/9)
Non-cirrhotic 86% (208/242) 83% (99/119) 66% (78/118) 72% (41/57)
Acquired eRVR94% (189/201) 88% (86/98) 90% (65/72) 86% (31/36)
No eRVR obtained 58% (39/67) 64% (23/36) 36% (22/62) 50% (15/30) Virological failure On-treatment virological failure 8% (21/268) 2% (3/268) 22% (29/268) 15% (10/268) Relapse 5% (12/244) 15% (20/131) 9% (9/ 102) 6% (3/53) Missing data at week 12 post-treatment 3% (7/244) 2% (2/131) 9% (9/102) 13% (7/53) a Modified intention-to-treat analysis (patients with missing data at week 12 post-treatment were considered treatment failures). Difference in SVR rate (95% confidence interval) for gene 1b chronic hepatitis C (daclatasvir hydrochloride tablets/pegIFN/RBV – telaprevir/pegIFN/RBV) (primary endpoint): 4.3% (-3.3, 11.9)]. The lower limit of the 95% confidence interval for the difference was greater than -12% indicating non-inferiority.
The median age of patients treated in COMMAND-4 (study AI444042) was 49 years (range: 20 to 71); 77% were white; 19% were black/African American. 10% had compensated cirrhosis and 75% had IL-28B rs12979860 non-CC genotype. see Table 23 for treatment outcomes in study AI444042. il -28B CC genotype patients had higher SVR12 than non-CC genotype patients, and for patients with baseline HCV RNA below 800,000 IU/ml, SVR12 was higher in all subgroups of patients treated with daclatasvir hydrochloride tablets than in placebo-treated patients.
Table 23: Results of treatment with dalactavir hydrochloride combined with pegylated interferon alfa/ribavirin in genotype 4 chronic hepatitis C primed patients in the COMMAND-4 (AI444042 study) Dalactavir hydrochloride tablets, pegylated interferon alfa and ribavirin
n=82Polyethylene glycol interferon alpha and ribavirin
n=42SVR12
Cirrhosis
Non-cirrhotic 82% (67/82)
78% (7/9)b
81% (56/69)b43% (18/42)
25% (1/4)
45% (17/28) Virological failure on treatment Virological failure on treatmentc
Relapse 10% (8/82)
3% (2/74) 36% (15/42)
30% (8/27) a Patients with missing data at week 12 of follow-up were considered responders if their next available HCV RNA value<LLOQ
b Four patients in the daltegravir hydrochloride tablets + pegylated interferon alpha/ribavirin group did not report cirrhotic status.
Long-term follow-up
There are limited data from ongoing follow-up studies evaluating response durability up to 3 years after the end of treatment with daclatasvir hydrochloride tablets in Phase 2 and Phase 3 studies. Of the 224 patients treated with daclatasvir hydrochloride tablets in combination with softspray capsules who obtained SVR12 (median time to follow-up after obtaining SVR12 was approximately 8.5 months), 1 (<1%) developed relapse. No relapses occurred in the 28 patients who obtained SVR12 with daclatasvir hydrochloride tablets in combination with sofosbuvir (± ribavirin), and the median time to follow-up after obtaining SVR12 was approximately 14.5 months. Daclatasvir hydrochloride tablets combined with pegylated interferon alpha/ribavirin resulted in relapse in 4 (2%) of the 194 patients who obtained SVR12, with a median follow-up time of approximately 22 months after obtaining SVR12.
[Pharmacology and Toxicology
Mechanism of action
Dalatavir hydrochloride is an inhibitor of NS5A, a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir hydrochloride inhibits viral RNA replication and viral particle assembly. In vitro and computer modeling data suggest that dalactavir hydrochloride interacts with the N-terminus within protein region 1, which can lead to structural distortion that interferes with NS5A function.
Antiviral activity
Dalatavir hydrochloride is an inhibitor of the full-length/chimeric replicon of the NS5A sequence encoding a clinical isolate from HCV genotype 1-6. For genotype 1a, 1b, 2, 3 and 4 subject-derived NS5A sequence heterozygous replicons without detectable polymorphisms at amino acid sites 28, 30, 31 or 93 in NS5A associated with daltavir hydrochloride resistance, the median EC50 values for daltavir hydrochloride inhibition were 0.008 nM (range 0.002-0.03 nM, n=35), 0.002 nM (range 0.00070.006 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). For subject-derived replicas of genes type 1a, 1b, 2, 3 and 4 containing polymorphisms at amino acid loci 28, 30, 31 or 93 associated with drug resistance, daltegravir hydrochloride inhibitory activity was reduced with median EC50 values of 76 nM (range 4.6-2409 nM, n=5), 0.05 nM (range 0.00210 nM, n=12), respectively 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).
For genotype 5 subject-derived NS5A hybrid replicons, the median EC50 value for daltegravir hydrochloride was 0.004 nM (range 0.003-0.019 nM, n=3), whereas the EC50 value for inhibition of a single HCV genotype 6-derived replicon was 0.054 nM.
In a cell culture-based combination antiviral activity study using an HCV replicon system, daltegravir hydrochloride showed superimposed synergy with interferon alpha, HCV NS3 protease inhibitor, HCV NS5B nucleoside analog, and HCV NS5B non-nucleoside inhibitor.
Pharmacodynamics
The effects of daltegravir hydrochloride 60 mg and 180 mg on the QTc interval were evaluated in a randomized, partially blinded, placebo-controlled, positive-controlled, complete QT study in 56 healthy subjects. Single doses of daltavir hydrochloride 60 mg or 180 mg did not produce clinically meaningful effects on the QTc interval (corrected by the Fridericia method (QTcF)). There was no meaningful relationship between increased plasma concentrations of daclatasvir hydrochloride and changes in the QTc interval. The 180 mg dose of dalactavir hydrochloride is expected to achieve the highest clinically expected plasma concentrations.
Drug Resistance
Cell Culture
Amino acid substitutions associated with daclatasvir hydrochloride resistance in HCV genotypes 1-6 were selected in a cell-based replication subsystem and were observed in the N-terminal 100 amino acid region of NS5A. Phenotypic analysis of stable genotype 1a replicon cell lines showed that replicons of genotype 1a variants containing M28T, Q30H, Q30R, L31V, and Y93C substitutions were ≥500-fold less susceptible to daclatasvir hydrochloride. Genotype 1b with combined L31M/Y93H and L31V/Y93H substitutions had reduced sensitivity to daclatasvir hydrochloride >8000-fold. Gene type 2a with F28S, C92R, and Y93H substitutions had ≥470-fold reduced sensitivity to daclatasvir hydrochloride; and gene type 3a with Y93H substitutions had 2738-fold reduced sensitivity to daclatasvir hydrochloride. Gene type 4a replicons with R30G/S or L30H/R or Y93H/R were ≥143-fold less susceptible to daclatasvir hydrochloride. Genotype 5a with combined L31F/K56R and L31V/K56R substitutions had a reduced sensitivity to daclatasvir hydrochloride >6000-fold. Gene type 6a with L31M, P32L, P32S and T58N substitutions had ≥382-fold reduced susceptibility to daclatasvir hydrochloride.
Cross-resistance
HCV replicons containing daclatasvir hydrochloride associated resistance variants remain fully susceptible to interferon alpha and other anti-HCV drugs with different mechanisms of action, such as NS3 protease and NS5B polymerase inhibitors (nucleoside and non-nucleoside).
Clinical studies
Impact of baseline HCV polymorphisms on treatment response
Exploratory analyses were conducted to assess the relationship between naturally occurring baseline NS5A amino acid substitutions (polymorphisms) and treatment outcomes. the effect of NS5A polymorphisms was protocol specific.
Dalatavir Hydrochloride Tablets in Combination with Asuravir Softgels
The incidence of NS5A polymorphisms at the L31F/I/M/V or Y93H loci at baseline was 12% (19/159) in 159 patients with genotype 1b HCV infection who had NS5A sequence data and were intolerant or unfit for interferon alpha in the HALLMARK ASIA (AI447036) phase 3 clinical study (AI447036); <1% (1/159) of patients had virus containing L31M without Y93H and 11% (18/159) of patients had virus containing Y93H without L31M. 8% (1/13) of the 13 subjects with virologic failure and baseline NS5A sequence data had L31M alone and 77% (10/13) had Y93H alone.
In patients with baseline detectable NS5A polymorphisms at the viral L31(M) or Y93(H) loci, the efficacy of asuravir softgels and daclatasvir hydrochloride tablets was reduced: the overall SVR rate was 42% (8/19) in patients with viral L31M or Y93H polymorphisms, compared with 99% (137/ 139), see [clinical trial].
A pooled analysis of phase 2/3 global clinical studies in patients with primary and treated genotype 1b HCV infection showed reduced efficacy of daltegravir hydrochloride tablets in combination with asuravir softgels in patients with NS5A polymorphisms detected at the L31 (F, I, M, or V) or Y93 (H) loci of the virus at baseline. phase 2/3 global clinical studies in which the virus had the L31F/I/M/V or Y93H polymorphisms was 42% (59/142) compared to 93% (792/850) for patients without the observed L31F/I/M/V and Y93H polymorphisms, see [Clinical Trials].
Among the 992 patients with genotype 1b HCV infection who participated in the phase 2/3 global clinical study with available NS5A sequence data, the incidence of NS5A polymorphisms with L31F/I/M/V or Y93H at baseline was 14% (142/992); 4% of patients (38/992) had L31F/I/M/V without Y93H and 10% (99/992) patients had Y93H without L31F/I/M/V, and 0.5% (5/992) had the combined L31F/I/M/V+Y93H variant. Of 141 patients with virologic failure who had baseline NS5A sequence data, 15% (21/141) had L31F/I/M/V only, 41% (58/141) had Y93H only, and 3% (4/141) had L31F/I/M/V+Y93H.
Dalatavir hydrochloride tablets in combination with sofosbuvir
Pooled analysis of phase 2 and phase 3 studies showed that (patients treated with daclatasvir hydrochloride tablets and sofosbuvir with or without ribavirin for 12 or 24 weeks of continuous treatment) in 19% (116/605) of patients with available baseline NS5A sequences (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), NS5A polymorphisms at the baseline daclatasvir hydrochloride tablet resistance-associated amino acid loci (28, 30, 31 or 93) were detected. 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; and M28V, A30E/K/S/T/ in patients with genotype 3. V, L31M or Y93H in patients with genotype 4; L28M or L30R in patients with genotype 6; and F28M/V and R30S in patients with genotype 6.
Overall, the SVR12 rate was 88% (102/116) and 96% (469/489) in patients with and without baseline NS5A polymorphisms at loci 28, 30, 31, or 93, respectively (see Table 24). SVR12 rates were higher in non-cirrhotic patients with and without baseline NS5A polymorphisms: 95% (83/87) and 99% (350/353), respectively. The SVR12 rates in patients with and without baseline NS5A polymorphisms in cirrhotic patients were 53% (11/21) and 85% (77/91), respectively. 10 patients with failed cirrhosis had baseline NS5A polymorphisms: M28T (n=1), L31M (n=2, both Child-Pugh B) and Y93N (n=1) in patients with genotype 1a; A30K (n=1) in patients with genotype 3 were A30K (n=1), Y93H (n=3) and A30T (n=1); genotype 2 patients were L31M (n=1, Child-Pugh C). All described genotype 1a, genotype 2, and genotype 3 NS5A region substitutions in vitro caused more than 100-fold reduction in daltegravir hydrochloride activity, except for A30T, which was detected only at baseline and not at failure. 6 of 14 patients with undetectable baseline NS5A polymorphism in cirrhosis at failure were Child-Pugh Class C.
Based on sequencing of all populations, sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence in all patients in the phase 2 or 3 studies.
Table 24: Effect of baseline NS5A polymorphisms (amino acid amino sites 28, 30, 31, or 93) on SVR12 response in patients with/without baseline cirrhosis treated with daltegravir hydrochloride tablets + sofosbuvir with or without ribavirin for 12 or 24 weeks The rate of SVR12 in patients with NS5A sequences Baseline NS5A polymorphisms detecteda No baseline NS5A polymorphisms Totala 88% (104/118) 96% (469/489) Patients with cirrhosis 57% (13/23) 85% (77/91) Genotype 1a 33% (2/6) 88% (42/48) Genotype 1b 0100% (12/12) Genotype 2 83% (5/6)0 Genotype 3 29% (3/8)a 73% (22/30) Genotype 4 100% (3/3)a100% (1/1) Patients without cirrhosis95% (83/87)99% (350/353)genotype 1a
100% (24/24)100% (186/186)genotype 1b
100% (11/11)100% (42/42)Genotype 2 100% (27/27)100% (3/3)Genotype 3 83% (19/23)98% (118/121)Genotype 4 100% (2/2)100% (1/1)For 53 liver transplant recipients treated with daclatasvir hydrochloride tablets + sofosbuvir with or without ribavirin for 12 weeks post-transplant patients, the presence of baseline NS5A polymorphisms (28, 30, 31, or 93) did not affect response rates because all patients with these polymorphisms (n=8) obtained SVR12. This patient population was included in the table totals but not in patients with and without cirrhosis.
Dalatavir hydrochloride tablets, pegylated interferon alpha and ribavirin
Pretreatment NS5A polymorphisms known to cause decreased sensitivity of dalactavir hydrochloride tablets in vitro were observed in 7% (9/125) of genotype 1a HCV, 16% (8/50) of genotype 1b HCV, and 63% (59/94) of genotype 4 primed patients (genotype 1a: M28T, Q30H/R, L31M/V, Y93H/N; genotype 1b : L31M, Y93C/H; genotype 4: L28M, L30C/R, M31V). The majority of patients with these pretreatment NS5A resistance-associated polymorphisms acquired SVR [56% (5/9) genotype 1a, 75% (6/8) genotype 1b, and 83% (49/59) genotype 4].
Resistance-associated variants that emerged after treatment in patients who did not acquire SVR
Daclatasvir hydrochloride tablets in combination with asuravir softgels
Analysis of patients with interferon alpha treatment-intolerant or inappropriate genotype 1b HCV infection treated with dalactavir hydrochloride tablets in combination with the application of asuravir softgels in the phase 3 clinical HALLMARK (AI447036 study) showed that 13/13 (100%) patients who developed virologic failure had detectable on-treatment viral NS5A amino acid substitutions and had resistance data (see Table 25). All of these patients (13/13, 100%) had on-treatment viral NS5A amino acid substitutions at viral NS5A amino acid sites L31 and/or Y93 and NS3 amino acid site D168.
Table 25: On-treatment amino acid substitutions in the HALLMARK ASIA (AI447036) study: daclatasvir hydrochloride tablets + asuravir softgels in patients who did not obtain SVR24 Classification of daclatasvir hydrochloride tablets + asuravir softgels (%, n) Genotype 1b
n = 13* Subjects without SVR24 and with NS5A and NS3 sequence data13 NS5A substitution at NS5A loci 31, 93 100% (13/13) L31: F, M, V 92% (12/13) Y93H 23% (3/13) L31F/V and Y93H 15% (2/13) NS3 loci 56, 155, 168 NS3 replacement in treatment at 168.
100% (13/13) Y56: H 23% (3/13) R155: Q 8% (1/13) D168: A, E, N, T, V, Y 100% (13/13) *1 patient died on day 25 due to a serious adverse event (Adams-Stokes syndrome, arrhythmia and coronary artery disease). This patient was considered a non-virologic failure and was not included in the resistance analysis.
A pooled analysis of patients with genotype 1b chronic hepatitis C treated with daclatasvir hydrochloride tablets in combination with asuravir softgels [from the AI447011, AI447017, AI447031, HALLMARK NIPPON (AI447026), and HALLMARK DUAL (AI447028) studies] showed that 132 patients presenting with virologic failure and available resistance data 131 (99%) of patients with detectable post-treatment emergence of NS5A amino acid substitution (see Table 26). The majority of these patients (119/132, 90%) had post-treatment amino acid substitutions at the NS5A L31 and/or Y93 sites. 108 (80%) of the 135 patients with available NS5A and NS3 resistance data had detectable combined substitutions at the D168 site on NS3 and the L31 plus Y93 site on NS5A.
Table 26 Post-treatment NS5A amino acid substitutions in pooled data from patients without SVR12 in phase 2 and phase 3 clinical studies of Dalatavir hydrochloride tablets + Asuravir softgels.
Classification (%, n) Dalatavir Hydrochloride Tablets + Asuravir Softgels Genotype 1b
Subjects who did not obtain SVR12 and had NS5A sequence data at baseline and treatment failure n=132 Substitutions at sites 28, 29, 30, 31, 32, 58, 62, 93 on NS5A 98% (130/132) L31: F, I, L, M, V 69% (91/132) Y93: C, H, N 48% (64/132) Y93H 46% (61/132) L31X and Y93X a27% (36/132) L28M/T, P29S/Δb, R30G/H/P/Q, Q54H/Y, P32F/L/Δb, P58A/G/S or Q62D/Ec less than 10% X for L31F, I, M or V and Y93H or N.
Δ represents a deletion of a specific amino acid.
The incidence of NS5A M28T substitution during treatment in subjects with gene type 1a is less than 10%.
Dalatavir hydrochloride tablets in combination with sofosbuvir
In the pooled analysis of phase 2 or 3 studies (629 patients treated with daclatasvir hydrochloride tablets in combination with sofosbuvir with or without ribavirin for 12 or 24 weeks), 36 of these patients were analyzed for resistance due to virologic failure or early termination of the study and HCV RNA values greater than 1,000 IU/ml. Table 27 reports the observed treatment-associated substitutions for NS5A resistance.
Table 27: Summary of new HCV NS5A substitutions in treatment or during follow-up in HCV-infected subjects with genotype 1 to 3 who did not obtain SVR12 Classification/replacement, n (%) Genotype 1a Genotype 1b Genotype 2 Genotype 3 n=301 n=79 n=44 n=197 Non-responders (did not obtain SVR12) 14*1 2*21** with baseline and post-baseline sequences 12 1 1 20 Emergence of NS5A RAVs*** 83% (10/12) 100% (1/1) 0 80% (16/20) M28: T 17% (2/12) — 0 Q30: H, K, R 75% (9/12) — — — L31: I, M, V 17% (2/12) 0 0 5% (1/20) P32-deleted 0 100% (1/1) 0 0 H58: D, P 17% (2/12) — — S62: L — — 10% (2/20) Y93: C, H, N 17% (2/10) 0 0 55% (11/20) * One patient missed
** One patient considered for failure of dosing regimen to obtain SVR (non-SVR)
*** Monitoring of NS5A RAVs at amino acid loci 28, 29, 30, 31, 32, 58, 62, 92, and 93
Only 1 patient with non-SVR12 genotype 3 HCV infection developed replacement S282T associated with sofosbuvir resistance.
Dalatavir hydrochloride tablets in combination with pegylated interferon alpha and ribavirin
Among the 210 (153 genotype 1a and 57 genotype 1b) primary treatment patients and prior non-responders who failed treatment, most developed NS5A resistance-associated substitutions (91% [139/153] genotype 1a and 86% [49/57] genotype 1b). The most frequently detected NS5A substitution sites included Q30E or Q30R in combination with L31M. NS5A substitution was detected at Q30 in most genotype 1a failures (91%, 127/139 patients) and at L31 (76%, 37/49) and/or Y93H (69%, 34/49) in most genotype 1b failures. NS5A combination mutations were detected in 74% (36/49) of patients at the time of treatment failure: both L31M/V-Y93H were present during treatment in 69% (25/36) of patients, and substitutions at one locus were present during treatment in 31% (11/36) of patients, while substitutions at the other locus were present before treatment.
Persistence of drug resistance-related substitutions
An ongoing observational long-term follow-up study is evaluating the durability of resistance substitution with daltegravir hydrochloride tablets, and to date, there has been only one interim analysis of daltegravir hydrochloride tablets in combination with pegylated interferon/ribavirin and/or the NS3 protease inhibitor, asuravir softgels. Resistance-associated replacement of NS5A was observed for all genotypes up to >2 years after treatment, however, partial substitution of NS5A resistance-associated replacement was also observed. The long-term clinical impact of the presence of daclatasvir hydrochloride resistant variants of the virus is unknown.
Oncogenicity, mutagenicity, and fertility impairment
Daclatasvir hydrochloride is not carcinogenic at AUC values up to 8.7 times the recommended human dose AUC value in mice or 4.7 times the recommended human dose AUC value in rats. No evidence of mutagenicity or chromosome breakage was observed in an in vitro mutagenicity (Ames) assay, in a mammalian mutation assay in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats.
Daclatasvir hydrochloride at any of the dose levels studied had no effect on fertility in either male or female rats. The highest unaffected AUC value in females was 18 times the recommended human dose AUC. in males, effects on reproductive endpoints were limited to reduced prostate/sperminal vesicle weight and a slight increase in aberrant sperm at the 200 mg/kg/day dose level; however, neither adverse fertility effects nor effects on the number of viable sperm were observed. The AUC at this dose level in males was 19 times the AUC of the recommended human dose.
Animal Toxicology
The toxicity profile in juvenile rats administered daltegravir hydrochloride for 10 weeks was similar to that observed in adult rats. The highest dose level studied was accompanied by adrenal hypertrophy, with an AUC 7.8 times the AUC of the recommended human dose. The AUC value for the no observed adverse effect level (NOAEL) in juvenile rats was 3.1 times the AUC of the recommended human dose.
Pharmacokinetics]
The pharmacokinetic properties of dalactavir hydrochloride were evaluated in healthy adult subjects and subjects with chronic hepatitis C. The geometric mean Cmax (CV%) of dalactavir hydrochloride 60 mg once daily in combination with pegylated interferon alpha/ribavirin in HCV-infected subjects was 1156 (30.4) ng/ml and the AUC0-24h was 12175 (37.2) ng*h/ml and Cmin was 221 (54.4) ng/mL.
Absorption and bioavailability
Daclatasvir hydrochloride tablets are readily absorbed by multiple oral administrations, reaching peak plasma concentrations between 1 and 2 hours. The Cmax, AUC and Cmin of dalactavir hydrochloride increase in a dose-proportional manner. Steady state is reached after 4 days of once daily dosing. Exposure to the 60 mg dose level of dalactavir hydrochloride was similar between healthy subjects and HCV-infected subjects.
In vitro studies in human Caco-2 cells have shown that dalactavir hydrochloride is a P-gp substrate. The absolute bioavailability of the tablet dosage form was 67%.
Effect of food on oral absorption
The Cmax and AUC of daclatasvir hydrochloride decreased by 28% and 23%, respectively, when daclatasvir 60 mg tablets were administered to healthy subjects after a high-fat meal (approximately 1000 kcal, approximately 50% fat-derived) compared to fasting state administration. Administration of dalactavir hydrochloride 60 mg tablets after a light meal (approximately 275 kcal, approximately 15% fat-derived) resulted in no reduction in exposure.
Distribution
At steady state, protein binding of dalactavir hydrochloride in HCV-infected subjects was approximately 99% over the range of doses studied (1 mg to 100 mg), with no dose dependence. The estimated steady-state volume of distribution of [13C,15N]-dalactavir hydrochloride was 47 L. In vitro studies demonstrated active and passive transport of dalactavir hydrochloride into hepatocytes, with active transport predominating. Active transport was mediated by OCT1 and other unidentified uptake transport proteins, but not organic anion transport protein (OAT)2, taurocholate co-transport peptide (NTCP) or OATP.
Metabolism
In vitro studies have shown that daltegravir hydrochloride is a CYP3A substrate and CYP3A4 is the major CYP isoform involved in metabolism. None of the circulating metabolites exceed the parent drug concentration level of 5%.
Elimination
After a single oral administration of 14C-daltegravir hydrochloride to healthy subjects, 88% of the total radioactivity was recovered in the feces (53% was the prototype drug) and 6.6% was excreted in the urine (mainly the prototype drug). the terminal elimination half-life of daltegravir hydrochloride was 12-15 hours after multiple oral administrations of daltegravir hydrochloride to HCV-infected subjects. The total clearance of 100 μg [13C,15N]-dalactavir hydrochloride administered intravenously after oral administration of 60 mg of dalactavir hydrochloride tablets in subjects was 4.24 L/h.
Special Populations
Renal impairment
Compared to non-HCV-infected subjects with normal renal function [creatinine clearance (CrCL) of 90 mL/min, using the Cockcroft-Gault CrCL formula], the estimated AUC of daclatasvir hydrochloride was 26%, 60% and 80% higher in subjects with CrCL values of 60, 30 and 15 mL/min, respectively. The estimated AUC of unconjugated daclatasvir hydrochloride was 18%, 39%, and 51% higher in subjects with CLcr values of 60, 30, and 15 mL/min, respectively, compared to subjects with normal renal function. Subjects with end-stage renal disease requiring hemodialysis had a 27% increase in AUC for daclatasvir hydrochloride and a 20% increase in AUC for unconjugated daclatasvir hydrochloride compared with subjects with normal renal function. In the pharmacokinetic analysis of the population of subjects with mild to moderate renal impairment chronic hepatitis C, CrCL was defined as a statistically significant covariate, with higher exposure in subjects with moderate renal impairment; however, the extent of this effect is unlikely to have a clinically meaningful effect on the pharmacokinetic parameters of daltegravir hydrochloride (see [DOSAGE]).
Liver damage
The pharmacokinetic properties of daltegravir hydrochloride following a single dose of 30 mg were evaluated in non-HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) liver impairment compared to subjects without liver impairment. The Cmax and AUC (free and protein-bound drug) of total daltegravir hydrochloride were lower in subjects with hepatic impairment; however, there was no clinically meaningful effect of hepatic impairment on free blood concentrations of daltegravir hydrochloride (see [Dosage] and [Precautions]).
Older Adults
Pharmacokinetic analysis of clinical study data populations showed no significant effect of age on the pharmacokinetics of daltegravir hydrochloride tablets (see [Geriatric Use]).
Children and Adolescents
The pharmacokinetics of Dalatavir Hydrochloride Tablets have not been evaluated in pediatric patients (see [Pediatric Dosage]).
Gender
Population pharmacokinetic analysis of clinical study data indicates that gender is a statistically significant covariate for apparent oral clearance (CL/F) of daltegravir hydrochloride, with lower CL/F in female subjects, but the extent to which gender affects daltegravir hydrochloride exposure is unlikely to be clinically significant.
Race
Pharmacokinetic analysis of the clinical study data population indicated that race was a statistically significant covariate for apparent oral clearance (CL/F) and apparent volume of distribution (Vc/F), and that exposure was slightly higher in black subjects compared to white subjects, but the extent to which race affected exposure to daclatasvir hydrochloride was not clinically significant.
[Storage].
Store below 30°C
Package
Aluminum-plastic blister packaging, boxed, 7 tablets/box, 14 tablets/box
Expiration date
30 months
Execution Standard
JX20160253
Approval number
Pending
Manufacturer
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