Date of approval.
Year
Month
Date
Ashuravir softgels instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Potential Hepatotoxicity: Patients on an asuravir-containing regimen require frequent monitoring of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and bilirubin until completion of therapy (see [Precautions]). Discontinue acrivir immediately and do not use again if the patient develops: an elevated ALT level of 10 x ULN or greater during therapy, or an elevated ALT level of > 5 x ULN and elevated total bilirubin> 2 x ULN during therapy; elevated liver enzymes and bilirubin observed in clinical trials that are reversible after discontinuation of therapy.
Drug Name
Generic name: Asuravir Softgels
Trade name: AsunaprevirTM (SUNVEPRATM)
English Name: Asunaprevir Soft Capsules
Hanyu Pinyin: Ashuruiwei Ruanjiaonang
Ingredients
The active ingredient of this product is Ashuruiwei
Chemical Name.
tert-butyl {(2S)-1-[(2S,4R)-4-({7-chloro-4-methoxyisoquinolin-1-yl}oxy)-2-({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-vinylcyclopropyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate
Chemical structure formula.
Molecular formula: C35H46ClN5O9S
Molecular weight: 748.29
【Properties】.
This product is white to slightly yellow oval opaque soft capsule, the first line is printed with “BMS” in black, the second line is printed with “711” in black, the contents are clear solution.
Indications
Asuravir soft capsule is used in combination with Dalatavir Hydrochloride tablets for the treatment of adult genotype 1b chronic hepatitis C (non-cirrhotic or compensated cirrhosis).
Specification
100mg
Dosage]
Recommended Dosage
Oral administration, either before or after meals.
The recommended dose is 100mg twice daily. For the treatment of genotype 1b chronic hepatitis C, Asuravir softgels should be given in combination with Dalatavir Hydrochloride tablets for 24 weeks. Refer to its instructions for the recommended dose of Dalatavir Hydrochloride Tablets.
Dose Adjustment and Suspension of Dosing
No dose adjustment of Asulpride Softgels or Daclatasvir Hydrochloride Tablets is recommended and suspension of dosing should be avoided. However, if dosing suspension is required due to adverse reactions, neither Asulpride Softgels nor Dalatavir Hydrochloride Tablets should be administered alone. If restarting treatment is considered, the risks and benefits should be carefully assessed (see [Precautions]). For regimens of Asulpride softgels in combination with daclatasvir hydrochloride tablets, both drugs must be restarted at the same time.
Discontinuation of Dosing
Hepatitis C virus ribonucleic acid (HCV RNA) levels should be monitored during treatment. Patients with incomplete virologic response during treatment are less likely to achieve sustained virologic response (SVR) and may develop resistance-associated substitution. Patients are advised to discontinue therapy once a confirmed virologic breakthrough (HCV RNA elevation greater than 1 log10 IU/mL from nadir) occurs (see [Precautions]).
Missed Doses
In the case of a missed dose of Asuravir Softgel, patients should be instructed to make up the dose as soon as possible if it is within 8 hours of the scheduled dosing time; if it is beyond 8 hours, no further doses should be made up and the next dose should be continued at the scheduled time.
Renal impairment
For patients with severe renal impairment [creatinine clearance (CrCl) <30 mL/min] who are not receiving hemodialysis, the recommended dose of Asuravir softgels is 100 mg once daily. Dose adjustment of Asuravir Softgels is not required in most patients with renal impairment, including those on hemodialysis or with mild or moderate renal impairment (CrCl ≥30 mL/min) (see [Pharmacokinetics]).
Hepatic Impairment
Asuravir softgels are contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C with a score of 7 or greater) and in patients with decompensated liver disease. Dose adjustment of Asuravir Softgels is not required in patients with mild liver impairment/compensated cirrhosis (Child-Pugh A, score 5-6) (see [Contraindications] and [Pharmacokinetics]).
[Adverse Reactions].
Clinical Study Experience
Clinical studies in China
The HALLMARK ASIA (AI447036) study evaluated the asuravir softgel 100 mg twice daily regimen in combination with daclatasvir hydrochloride tablets in 159 Asian patients with genotype 1b chronic hepatitis C, 127 of whom were from mainland China. The safety profile of 24 weeks of treatment with asuravir softgels in combination with daclatasvir hydrochloride tablets in this study was consistent with that observed in global studies. The most common adverse reactions (≥5%) are shown in Table 1. there was one non-treatment related death. Serious adverse events occurred in 5 subjects (3.1%) and 2 subjects (1.3%) discontinued treatment due to adverse events. The majority of events were mild to moderate in severity. The safety profile of asuravir softgels in combination with daltegravir hydrochloride tablets was similar in patients with compensated cirrhosis and non-cirrhotic liver disease.
Table 1: Systematic organ classification/incidence of adverse reactions reported in the HALLMARK ASIA (AI447036) study of asulpride softgels in combination with daclatasvir hydrochloride tabletsa
Adverse reactionsb
n=159 Blood and lymphatic system disorders Thrombocytopenia (5.0%) Common laboratory tests Monocyte count reduction (5.7%) Commona Incidence classified as very common (≥1/10) as well as 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 the HALLMARK ASIA (AI447036) study with the application of asuravir softgels in combination with daltegravir hydrochloride tablets.
Global Clinical Studies
The safety of acriflavine softgels 100 mg twice daily in combination with daclatasvir hydrochloride tablets was evaluated in 1059 patients with chronic hepatitis C in five global Phase 2/3 studies (see [Clinical Trials] Table 7). The duration of treatment in the study was 24 weeks. The most common adverse reactions (incidence ≥10%) included headache (14%) and fatigue (12%). The majority of adverse reactions were mild to moderate in severity. 6% of patients experienced serious adverse events. 3% of patients discontinued the drug due to adverse events; the most common adverse events leading to discontinuation were elevated alanine aminotransferase (ALT) and elevated aspartate aminotransferase (AST). The incidence of adverse reactions was similar between the placebo group and the asuravir softgels combined with daltegravir hydrochloride tablets treatment group during the initial 12 weeks of treatment in HALLMARK DUAL (AI447028). In addition, the safety profile of asuravir softgels in combination with daclatasvir hydrochloride tablets was similar in patients with and without cirrhosis.
Adverse reactions reported in patients treated with asulavir softgels in combination with daclatasvir hydrochloride tablets are listed in Table 2.
Table 2.
Adverse reactions reported in global clinical trials of asuravir softgels in combination with daclatasvir hydrochloride tablets
System organ classification/incidencea Adverse reactionsb,c
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.
Events in the pooled data of the HALLMARK DUAL (AI447028), HALLMARK NIPPON (AI447026), AI447031, AI447017, and AI447011 studies that were potentially relevant (in the judgment of the investigator) to the study drug and had an incidence of at least 5%. A number of other adverse reactions with an incidence of less than 5% in clinical studies are also listed based on an assessment of potential causality between severity and dosing regimen.
Potential Hepatotoxicity
Elevated ALT and AST were observed in Phase 2 and Phase 3 clinical studies of the asuravir-containing softgel regimen (see Table 3). In some cases, elevated ALT/AST was associated with hepatic dysfunction with or without fever or eosinophilia. Severe drug-induced liver injury may occur with treatment with regimens containing Asulpride softgels (see [Precautions]).
Postmarketing Experience
The following events have been reported in the post-marketing clinical use of Asulprideve Softgels in combination with Dalatavir Hydrochloride Tablets. The incidence cannot be assessed as it was spontaneously reported and the population size is unknown.
Skin and subcutaneous tissue disorders: erythema multiforme.
Laboratory findings
Clinical studies in China
The specific grade 3-4 laboratory test abnormalities observed in patients with chronic hepatitis C treated with asulprideve softgels in combination with daltegravir hydrochloride tablets in HALLMARK ASIA (AI447036) are listed in Table 3.
Table 3: Specific grade 3-4 laboratory test abnormalities in the HALLMARK ASIA (AI447036) clinical study of asulpride softgels in combination with daclatasvir hydrochloride tabletsa Incidence of parameter abnormalities asulpride softgels in combination with daclatasvir hydrochloride tablets
n = 159 ALT elevation (³5.1 x ULN)1% AST elevation (³5.1 x ULN)2% Total bilirubin elevation (³2.6 x ULN)<1%a Grade 3/4 platelet reduction during treatment occurred in 13 (8.2%) subjects. However, all of these subjects had grade 2 platelet reductions at baseline. None of these patients developed concomitant clinical symptoms and none discontinued study treatment due to thrombocytopenia. The platelet count changes observed in this study were not considered to be clinically relevant, but were correlated with the baseline characteristics of the enrolled subjects.
Clinical studies worldwide
The specific grade 3-4 laboratory test abnormalities observed in patients with chronic hepatitis C treated with asuravir softgels in combination with daltegravir hydrochloride tablets are listed in Table 4.
Table 4.
Specific Grade 3-4 Laboratory Test Abnormalities in Global Clinical Studies of Asulprasvir Softgels in Combination with Dalatavir Hydrochloride Tablets
Incidence of abnormalities Asuravir softgels in combination with daclatasvir hydrochloride tablets Parameter 1059a Elevated ALT (≥5.1 x ULN) 5% Elevated AST (≥5.1 x ULN) 3% Elevated total bilirubin (≥2.6 x ULN) <1% HALLMARK DUAL (AI447028), HALLMARK NIPPON (AI447026 ), AI447031, AI447017, and AI447011 studies for pooled data. (See [Clinical Trials])
[Contraindication].
When this product is used in combination with Dalatavir Hydrochloride Tablets, the same contraindications of Dalatavir Hydrochloride Tablets apply to this product (see Dalatavir Hydrochloride Tablets instructions).
This product is contraindicated in patients with prior hypersensitivity to acepromazine or any of the components of this product.
This product is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score 7 or greater) and in patients with decompensated liver disease (see [Pharmacokinetics]).
The combination of this product with the following drugs is prohibited.
Thioridazine, the clearance of which is highly dependent on cytochrome P450 enzyme 2D6 (CYP2D6), and elevated plasma concentrations have been associated with severe ventricular arrhythmias and sudden death.
Drugs that potently or moderately induce cytochrome P450 enzyme 3A (CYP3A) may result in reduced exposure and lack of efficacy of this product.
Drugs that potently or moderately inhibit CYP3A may lead to increased exposure and toxicity.
Drugs that potently inhibit organic anion transporting polypeptide (OATP) 1B1 may result in decreased hepatic concentrations and lack of efficacy.
Contraindicated drugs include, but are not limited to, those listed in Table 5 (see [Drug Interactions]).
Table 5:
Drugs prohibited in combination with Asuravir Softgels
Clinical Review of Interaction Mechanisms Drugs prohibited in combination with Asuravir Softgelsa Increased CYP2D6 inhibition by Asuravir may lead to arrhythmias or sudden death Antipsychotics
Combination of drugs with thioridazine potent or moderate induction of CYP3A may result in a lack of virologic response to asulpride softgels Anticonvulsants
Phenytoin sodium, carbamazepine, oxcarbazepine, phenobarbital
Anti-infective drugs
Rifampin, rifabutin, rifapentine, nefcillin
Endothelin receptor antagonists
Bosentan
Systemic glucocorticoids
Dexamethasone
Chinese medicine
St John’s wort (Guan Ye Lian Qiao)
HIV non-nucleoside reverse transcriptase inhibitors
Efavirenz, etravirine, nevirapine
Oxytocics
Modafinil combination drugs potent or moderate inhibitors of CYP3A acepromazine softgels elevated concentrations may increase the likelihood and severity of liver-related adverse events antifungals
Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
Anti-infective agents
Clarithromycin, erythromycin, telithromycin
Calcium channel blockers
Diltiazem, verapamil
HIV protease inhibitors
Atazanavir, dirinavir/ritonavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir
Pharmacokinetic enhancers
Cobicistat or Cobicistat-containing dosing regimens potent inhibition of OATP 1B1 may result in a lack of virologic response to asulpride softgels Antituberculous mycobacterial agents
Rifampin
Immunosuppressants
Cyclosporine
Lipid-lowering agents
Gemfibezila This table is not a complete list of all potent or moderately potent CYP3A inducers/inhibitors or potent inhibitors of OATP 1B1.
[Precautions].
General Precautions
Asuravir softgels should not be used as monotherapy (see [Indications] and [Dosage]). When Asuravir Softgels are used in combination with Dalatavir Hydrochloride Tablets, the same warnings and precautions for Dalatavir Hydrochloride Tablets apply.
Potential Hepatotoxicity
Patients treated with a regimen containing Asuravir softgels should be monitored for liver enzymes at least every 2 weeks for the first 12 weeks and every 4 weeks thereafter until completion of therapy. Any trend toward elevated ALT and AST levels will require more frequent monitoring. If ALT levels increase ≥10-fold ULN during treatment, treatment should be discontinued immediately and not used again.
Elevated ALT and AST have been observed in Phase 2 and Phase 3 clinical studies of treatment regimens containing Asulpride softgels. In some cases, elevated ALT/AST is associated with hepatic impairment (suggested by an increase in total bilirubin), with or without fever or eosinophilia. Severe drug-induced liver injury may occur with treatment with regimens containing asulpride softgels. In a clinical trial of the combination of asuravir, daltegravir hydrochloride and Beclabuvir (a non-nucleoside HCV NS5B inhibitor), a grade 4 ALT elevation with elevated bilirubin and hepatic encephalopathy was observed in one subject with cirrhosis at week 6 of treatment.
The incidence of ALT and AST elevations up to at least 5-fold ULN was 4% and 3%, respectively, and the incidence of bilirubin elevations up to at least 2.6-fold ULN was <1% in global clinical studies of treatment with Asuravir Soft Capsules in combination with Dalatavir Hydrochloride Tablets (see [Adverse Reactions]). In the HALLMARK ASIA (AI447036) study in the Asian population (China, Korea and Taiwan), only 1.3% of subjects had ALT above 5 times ULN, and all of these subjects had reversible liver enzyme elevations. The incidence of ALT/AST elevation was higher in the clinical study of asuravir softgels in combination with daltegravir hydrochloride tablets conducted in Japan than in the global clinical study or the Chinese study using this dosing regimen. In the HALLMARK NIPPON (AI447026) and AI447031 studies conducted in Japan, 7% and 12.6% of patients had ALT above 5 times ULN, respectively, while in the global clinical study HALLMARK DUAL (AI447028), 2% of patients had ALT above 5 times ULN. The median time to ALT/AST elevation in the clinical study was 13 weeks after treatment initiation (range: 4-24 weeks), and in most cases, the elevation returned to the normal range with continued drug therapy. These liver enzyme elevations were also reversible in patients who discontinued treatment. 16 of the 19 patients treated with asulprideve softgels in combination with daltegravir hydrochloride tablets who discontinued study treatment due to elevated transaminases achieved SVR.
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
Drugs that are contraindicated in combination with Ashuravir Softgel due to potential life-threatening adverse events, significant drug interactions, or loss of virologic activity are listed in [Contraindications]. For identified interactions with other potentially important drugs see [Drug Interactions]. For information on drug interactions with Dalatavir Hydrochloride Tablets refer to their instructions. The most conservative recommendations should be followed.
Retreatment with Asuravir Soft Capsules
Asuravir Softgel has not been studied in patients who have failed prior treatment regimens including Asuravir Softgel or other HCV NS3/4A protease inhibitors.
Cirrhosis of the liver
Of the more than 1,300 patients from five clinical studies of the combination therapy with Asulpride softgels, 322 patients had compensated cirrhosis (Child-Pugh A). No overall differences in safety or efficacy were observed between patients with and without cirrhosis (see [Contraindications] and [Pharmacokinetics]).
Organ Transplant Patients
The safety and efficacy of Asuravir Softgel for the treatment of chronic hepatitis C have not been established in patients before, during, or after liver transplantation or other organ transplantation.
HCV/HIV (human immunodeficiency virus) co-infection
The safety and efficacy of Asuravir Softgels in the treatment of chronic hepatitis C in patients co-infected with HIV has not been established.
HCV/HBV (hepatitis B virus) co-infection
The safety and efficacy of Asuravir Softgel in the treatment of chronic hepatitis C in patients co-infected with HBV has not been established (see [PRECAUTIONS], Potential Risk of Hepatitis B Virus Reactivation).
Effects on the ability to drive and use machines
The effect of Asuravir Softgels on the ability to drive and use machines has not been studied.
Other
Do not use if the inner package is opened or broken.
For Pregnant and Lactating Women
There are no data on the use of Asuravir Softgels in pregnant women. Animal studies have not shown harmful reproductive toxicity of Asulpride (see animal study data for Asulpride below). Asuravir Softgels combined with Dalatavir Hydrochloride Tablets should not be given during pregnancy or in women of childbearing age who are not using contraception (see instructions for Dalatavir Hydrochloride Tablets). For patients using oral contraceptives, a high dose of oral contraceptives (containing at least 30 µg ethinyl estradiol combined with norethindrone acetate/norethindrone) is recommended (see [Drug Interactions]).
Animal Study Data for Asuravir
Administration to pregnant rats or rabbits during organogenesis showed no selective developmental toxicity observed with maternal acepromazine doses up to an area under the curve (AUC) value of 472 times the recommended human dose (RHD) (mice) and 1.2 times the RHD (rabbits). In a rat prenatal and postnatal developmental study, no developmental toxicity was observed at doses up to 125 mg/kg/day and AUC values 76 times the recommended human dose. Maternal and developmental toxicity was observed at the highest dose level evaluated (400 mg/kg/day). Developmental toxicity manifested itself in the form of reduced survival and weight loss that persisted into adulthood with reduced food intake. This dose level corresponds to an AUC value 193 times the recommended human dose.
Lactation
It is not known if acepromazine is secreted into human breast milk. Animal pharmacokinetic data indicate secretion of acepromazine/metabolites into breast milk. Mothers who are using Asuravir Softgels should be instructed that they should not breastfeed. Also refer to the prescribing information for other drugs in the regimen.
[Pediatric Dosage].
The safety and efficacy of Asuravir Softgels have not been established in pediatric patients.
Geriatric Use]
No overall differences in safety or efficacy have been observed between patients 65 years of age and older and younger patients. No dose adjustment of Asuravir Softgels is required in elderly patients.
Drug Interactions]
Possible effects of other drugs on Asuravir Softgels
CYP3A is involved in the elimination process of Asulprasvir. Therefore, moderate or potent CYP3A inducers may decrease plasma concentrations of Asulpride and moderate or potent CYP3A inhibitors may increase plasma concentrations of Asulpride (see [Contraindications]). Asuravir is also a P-glycoprotein transporter (P-gp) substrate, but the combination of drugs that alter P-gp activity alone (without CYP3A synergy) is unlikely to have a clinically meaningful effect on asuravir exposure.OATP 1B1 (to a lesser extent) and 2B1 (to a lesser extent) are involved in the hepatic distribution of asuravir. Therefore, inhibitors of OATP-mediated transport may increase the plasma concentration of asulpride and may diminish its therapeutic effect by reducing hepatic distribution (see [Contraindications]).
Possible effects of Asuravir Softgels on other drugs
Asuravir is a moderately potent CYP2D6 inhibitor (see [Contraindications]), an inhibitor of OATP 1B1/1B3- and P-gp-mediated transport, and a weak CYP3A inducer. Asuravir softgels should be used with caution in combination with substrates of these enzymes or transport proteins and should be closely monitored for therapeutic effects and adverse reactions. In vitro, acitretin does not inhibit (IC50>40 µM) CYP1A2, CYP2C9 or CYP2C19. in vitro, acitretin is an inhibitor of renal uptake of transporter proteins, organic anion transporter proteins (OAT) 1 and 3, and organic cation transporter protein (OCT) 1, but no clinically meaningful effects on the pharmacokinetics of these transporter substrates are expected. clinically meaningful effects on these transporter substrates.
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 6 provides drug interaction study information for Asuravir softgels, 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 6 were conducted in healthy adult subjects.
Table 6: Drug Interaction Information for Asuravir Softgels with Other Drugs
Drug Interactions in Different Therapeutic Areas Recommendations for Combinations Antivirals, HCV Dalatasvir hydrochloride 30 mg once daily
(Asuravir* 200 mg twice daily)
*Non-marketed softgel formulation↔ Asuravir
AUC*: 0.87 (0.73,1.04)
Cmax*: 0.58 (0.45,0.76)
Cmin*:1.76 (1.42, 2.17)
↔ Daclatasvir hydrochloride
AUC**: 1.20 (1.11, 1.30)
Cmax**:1.07 (0.97,1.18)
Cmin:**1.33(1.22, 1.45)
*Results are dose normalized to 600 mg dose
**Results are dose normalized to 60 mg dose does not require adjustment of the dose of Asulprasvir Softgels or Dalatavir Hydrochloride Tablets. pegylated interferon alpha 180 µg once weekly and ribavirin 1000 or 1200 mg/day administered in 2 divided doses (500 mg or 600 mg twice daily)*
(Asuravir tablets** 200 mg twice daily)
*Study conducted in patients with chronic hepatitis C
**Asuravir tablets (not available) 200 mg, administered with food, had similar bioavailability to Asuravir softgels 100 mg. ↔ Asuravir.
AUC: ↔*
Cmax: ↔*
Cmin: ↔*
↔ Polyethylene glycol interferon alpha
AUC: ↔*
Cmax: ↔*
Cmin: ↔*
↔ Ribavirin.
AUC: ↔*
Cmax: ↔*
Cmin: ↔*
* The pharmacokinetic parameters of asuravir when combined with pegylated interferon a and ribavirin in this study were similar to those observed in subjects with chronic hepatitis C administered with asuravir and daltegravir hydrochloride for a 14-day study. The pegylated interferon alfa/ribavirin pharmacokinetic parameters in patients on pegylated interferon alfa, ribavirin and asuravir were similar to those observed in patients on pegylated interferon alfa, ribavirin and placebo. No adjustment of the dose of asuravir softgels, pegylated interferon alfa or ribavirin was required.
Table 6: Information on drug-drug interactions between Asuravir softgels and other drugs
Drug-drug interactions in different therapeutic areas Recommendations for co-administration of the acid inhibitor proton pump inhibitor omeprazole 40 mg single dose
(Asuravir tablets* 200 mg twice daily)
*Asuravir tablets (not available)
200 mg, administered with food, is biologically similar to Asulpride
Softgels 100 mg have similar bioavailability. ↔ Omeprazole.
AUC:0.80 (0.69, 0.94)
Cmax:0.96 (0.79, 1.16) No dose adjustment of omeprazole or other CYP2C19 substrates is required. Based on the route of clearance of acepromazine and the known pharmacokinetic profile of omeprazole, coadministration should have no clinically meaningful effect on acepromazine pharmacokinetics. No interactions have been studied with the anticoagulant dabigatran.
Because of the inhibition of P-gp by asulavir, it is expected that.
↑ Close clinical monitoring is recommended when initiating treatment with Asuravir softgels in patients receiving dabigatran or other enteric P-gp substrates (narrow therapeutic range). Antidepressant selective pentazocine reuptake inhibitor etaprepitant 10 mg once daily
(Asuravir softgels 100 mg twice daily)↔ Asuravir
AUC: 0.92 (0.76, 1.12)
Cmax: 0.87 (0.65, 1.18)
↔ Etaprepitant
AUC: 0.95 (0.91, 0.98)
Cmax: 0.97 (0.92, 1.02) No dose adjustment of acepromazine softgels or etaprepitant is required. Sertraline 50 mg once daily
(Asuravir softgels 100 mg twice daily)↔ Asuravir
AUC: 0.88 (0.70, 1.11)
Cmax: 0.94 (0.70, 1.28)
↔ Sertraline.
AUC: 0.79 (0.67, 0.94)
Cmax: 0.81 (0.67,0.97) No dose adjustment of Asulpride softgels or sertraline was required. Table 6: Information on drug interactions between Asuravir Softgels and other drugs
Drug interactions in different therapeutic areas Recommendations on co-administration Tricyclic amitriptyline
Promethazine
Nortriptyline Interactions not studied
Due to the inhibition of CYP2D6 by acutrevir, it is expected that
↑ amitriptyline
↑ Promethazine
↑ Close clinical monitoring is recommended when nortriptyline treats a narrow range of CYP2D6-sensitive substrates, including certain tricyclic antidepressants (TCAs), in combination with asuravir softgels. Monitoring of TCA plasma concentrations and dose reduction of TCA may be required (see [Contraindications]). Antifungal Ketoconazole 200 mg every 12 hours
(Asuravir Tablets* 200 mg every 12 hours)
*Asuravir tablets (not available) 200 mg, administered with food, had similar bioavailability to asuravir softgels 100 mg. ↑ Asuravir
AUC: 9.65 (8.64, 10.77)
Cmax: 6.92 (5.92, 8.09)
Cmin: 9.35 (8.31, 10.53)
Inhibition of CYP3A and P-gp by ketoconazole prohibits the use of acriflavine softgels in combination with ketoconazole and other potent or moderately potent CYP3A inhibitors. Fluconazole
Itraconazole
Posaconazole
Voriconazole Interactions have not been studied.
Because antifungals inhibit CYP3A4, it is expected that.
↑ Asuravir anti-hypertensive drug cloxacin 25 mg single dose
(Asuravir tablets* 200 mg twice daily)
*Asuravir tablets (not available) 200 mg, administered with food, have similar bioavailability to asuravir softgels 100 mg. ↔ Cloxacin.
AUC: 0.89 (0.81, 0.98)
Cmax:1.63 (1.35, 1.97)
Unknown mechanism does not require dose adjustment of cloxacin or other CYP2C9 substrates. Based on the route of clearance of aculpride and the known pharmacokinetic profile of losartan and other angiotensin 2 receptor blockers, coadministration should have no clinically meaningful effect on the pharmacokinetics of aculpride. No interactions have been studied with irbesartan.
Expected.
↔ Irbesartan Table 6: Information on drug interactions between Asulpride Softgels and other drugs
Drug-drug interactions in different therapeutic areas Recommendations for co-administration Anti-mycobacterium tuberculosis drug Rifampicin 600 mg Single dose
(Asuravir tablets* 200 mg given as a single dose with food fasting)
Rifampicin 600 mg once daily (asuravir tablets* 600 mg twice daily)
*Asuraprevir tablets (not available) 200 mg have similar bioavailability to asuraprevir softgels 100 mg ↑ Asuravir
AUC: 14.81 (11.22, 19.53)
Cmax: 21.11 (14.27, 31.24)
Rifampicin inhibits OATP 1B1
↓ Asulpride
AUC: 0.79 (0.56, 1.09)
Cmax: 0.95 (0.60, 1.50)
Rifampicin induces CYP3A and also inhibits OATP1B1. acepromazine softgels are prohibited in combination with rifampicin, rifabutin, rifapentine and other potent OATP inhibitors or moderate/strong CYP3A inducers. Rifabutin
Rifapentine has not been studied for interaction.
Due to induction of CYP3A by antituberculous mycobacterial agents, it is expected that.
↓ Asuravir cough suppressant dextromethorphan 30 mg single dose
(Asuravir tablets* 200 mg twice daily)
*Asuravir tablets (not available) 200 mg administered with food had similar bioavailability to asuravir softgels 100 mg. ↑Dextromethorphan
AUC: 3.94 (3.09, 5.03)
Cmax: 2.72 (2.10, 3.53)
Asuravir inhibits CYP2D6. close clinical monitoring is recommended when dextromethorphan or other CYP2D6 substrates are combined with Asuravir softgels. Dose reduction of CYP2D6-sensitive substrates should be considered (see [Contraindications]).
Table 6: Drug Interaction Information for Asulpride Softgels with Other Drugs
Drug interactions in different therapeutic areas Recommendations for coadministration Cardiovascular drugs Antiarrhythmic drugs Digoxin 0.5 mg Single dose
(Asuravir tablets* 200 mg twice daily)
Single dose 0.25 mg
(Asuravir 100 mg twice daily and Dalatasvir hydrochloride 60 mg once daily)
*Asuravir tablets (not available) 200 mg administered with food had similar bioavailability to asuravir softgels 100 mg. ↑Digoxin
AUC: 1.30 (1.21, 1.40)
Cmax: 1.09 (0.97, 1.22)
AUC: 1.29 (1.20, 1.39)
Cmax: 1.77 (1.50, 2.07)
Asuravir inhibits P-gp. Digoxin and other P-gp substrates with a narrow therapeutic window should be used with caution in combination with Asuravir softgels. The lowest dose of digoxin should be prescribed for initial administration. Serum digoxin concentrations should be monitored and digoxin should be administered in a dose-escalation approach to achieve the desired clinical effect. Flecainide
Propafenone has not been studied for interaction.
Due to the inhibition of CYP2D6 by axorivir, it is expected that
↑ flecainide
↑ Close clinical monitoring is recommended when combining axuravir softgels with CYP2D6-sensitive substrates with a narrow therapeutic window (e.g., flecainide or propafenone). Dose reduction of CYP2D6-sensitive substrates should be considered (see [Contraindications]). Hormonal contraceptives ethinyl estradiol 35 μg once daily + norgestimate 0.180/0.215/0.250 mg once daily for 7/7/7 days
(Asuravir tablets* 600 mg twice daily)
* Asuravir tablets (not available) 200 mg administered with food had similar bioavailability to Asuravir softgels 100 mg. ↓ ethinyl estradiol
AUC: 0.72 (0.67, 0.78)
Cmax: 0.75 (0.67, 0.85)
↓norgestrel
AUC: 0.66 (0.62, 0.70)
Cmax: 0.71 (0.65, 0.77)
Ethinylestradiol: acepromazine induces CYP3A.
Norethindrone: unknown mechanism. High-dose oral contraceptives (containing at least 30 µg ethinylestradiol combined with norethindrone acetate/norethindrone) are recommended for patients on oral contraceptives during treatment with acepromazine softgels.
The combination should have no clinically meaningful effect on the pharmacokinetics of acepromazine based on the route of clearance of acepromazine and the known pharmacokinetic profile of oral contraceptives. Table 6: Information on drug interactions between Asulprasvir softgels and other drugs
Drug Therapeutic Area Interactions Recommendations for co-administration ethinyl estradiol 30 μg once daily / norethindrone acetate 1.5 mg once daily (high-dose contraceptive)
(acepromazine 100 mg twice daily and daclatasvir hydrochloride 60 mg once daily) ↔ ethinyl estradiol
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)*
** Pharmacokinetics of ethinyl estradiol/norethindrone when high-dose oral contraceptives are combined with acepromazine and daltegravir hydrochloride compared with the pharmacokinetics of ethinyl estradiol/norethindrone when low-dose oral contraceptives (ethinyl estradiol 20 μg once daily/norethindrone 1 mg once daily) are administered alone. Lipid-lowering agent HMG-CoA reductase inhibitor resulvastatin 10 mg single dose (asuravir tablets* 200 mg twice daily)
*Asuravir tablets (not available) 200 mg, administered with food had similar bioavailability to asuravir softgels 100 mg. ↑Risulvastatin
AUC: 1.41 (1.26, 1.57)
Cmax: 1.95 (1.47, 2.58)
Asulpride
Inhibition of OATP1B1/1B3. when Rosuvastatin and other OATP1B1/1B3 substrates are combined with Asuravir softgels, Rosuvastatin and other OATP1B1/1B3 substrates may be started at the recommended dose. Close clinical monitoring of both desired treatment outcomes and side effects of OATP substrates is recommended. Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Simvastatin
Interactions have not been studied.
Due to the inhibition of OATP 1B1 by acrivir, it is expected that
↑ statin concentrations Table 6: Information on drug interactions of Asuravir softgels with other drugs
Drug therapeutic area interactions Recommendations for coadministration Opioid buprenorphine/naloxone, stable maintenance 8/2 mg-24/6 mg once daily
(Asuravir 100 mg twice daily) ↔ Buprenorphine
AUC: 0.97 (0.73, 1.30)
Cmax: 0.85 (0.71, 1.01)
Cmin: 1.01 (0.71, 1.43)
↔ Norbuprenorphine
AUC: 1.10 (1.70, 1.68)
Cmax: 1.17 (0.96, 1.42)
Cmin: 1.13 (0.75, 1.71) No buprenorphine/naloxone dose adjustment is required when starting a combination of acepromazine softgels. Methadone, stable maintenance 40-120 mg once daily
(Asuravir 100 mg twice daily) ↔ Total methadone
AUC: 0.94 (0.84, 1.05)
Cmax: 1.00 (0.89, 1.12)
Cmin: 0.91 (0.80, 1.03)
↔ R-Methadone
AUC: 0.91 (0.82, 1.01)
Cmax: 0.97 (0.86, 1.08)
Cmin: 0.88 (0.80, 0.98) No methadone dose adjustment is required when starting coadministration of Asuravir softgels. Sedative benzodiazepine midazolam 5 mg single dose
(Asuravir tablets* 200 mg twice daily)
* Asuravir tablets (not available) 200 mg administered with food has similar bioavailability to asuravir softgels 100 mg. ↓ Midazolam
AUC: 0.71 (0.67, 0.75)
Cmax: 0.79 (0.73, 0.87)
Asulpride induces CYP3A Asulpride Softgels should be used with caution in combination with midazolam and other drugs that are highly dependent on CYP3A elimination and where a decrease in plasma concentrations may be associated with reduced efficacy. Stimulant caffeine 200 mg single dose
(Asuravir tablets* 200 mg twice daily)
* Asuravir Tablets (not available) 200 mg administered with food has similar bioavailability to Asuravir Softgels 100 mg. ↔ Caffeine.
AUC: 0.96 (0.89, 1.04)
Cmax:0.95 (0.91, 1.00) No dose adjustment of caffeine or other CYP1A2 substrates is required.
No clinically significant interactions are expected with the following drugs in combination: nucleoside/nucleotide reverse transcriptase inhibitors (NRTI, e.g., tenofovir, lamivudine), rilpivirine, raltegravir, dolutegravir, enfuvirtide, maraviroc, azithromycin, warfarin, phosphodiesterase type 5 (PDE-5) inhibitors (e.g., sildenafil), ang angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril), amiodarone, propyzamide, quinidine, famotidine or antacids.
Overdose]
There is limited clinical experience with overdose with Asuravir softgels. in phase 1 clinical studies, no unintended adverse events were observed in healthy subjects administered doses up to 300 mg twice daily (gelatin capsules) for 10 days. Clinical studies with higher than recommended doses of asuravir were associated with elevated liver enzymes.
There is no known antidote to an asuravir softgel overdose. Treatment of an asuravir softgel overdose should include general supportive measures (including vital signs monitoring) and observation of the patient’s clinical status. Dialysis is unlikely to significantly reduce drug plasma concentrations due to the high degree of protein binding (>99%) and molecular weights above 700 of acepromazine.
[Clinical Trials].
The efficacy and safety of asuravir softgels in combination with daltegravir hydrochloride tablets in the treatment of patients with genotype 1b chronic hepatitis C was evaluated in four phase 3 studies (see Table 7). HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV assay (version 2.0) (using a highly sensitive method). SVR (virological cure) was defined as HCV RNA below the LLOQ at 12 or 24 weeks after drug discontinuation. 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 HCV RNA ³LLOQ after mid-treatment), non-responders with detectable HCV RNA or missing HCV RNA data at the end of treatment, and non-responders who were not tested for HCV RNA because they took a non-study anti-HCV drug during treatment Patients who were counted as non-responders because they took non-investigational anti-HCV drugs during treatment and were not tested for HCV RNA. Relapse was defined as confirmation of HCV RNA during the visit among patients with non-detectable HCV RNA at the end of treatment ³ LLOQ. 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 7: Clinical Study of Ashuravir Softgels in Combination with Dalatavir Hydrochloride Tablets in Subjects with Chronic Hepatitis C
Clinical study patient population study subgroup
(number of subjects treated) HALLMARK ASIA (AI447036) Interferon alpha treatment intolerant or unsuitable for genotype 1b chronic hepatitis C compensated liver disease (including cirrhosis) Asian subjects Asulprideve Softgels + Dalatavir Hydrochloride Tablets, 24 weeks
(n = 159) HALLMARK DUAL (AI447028) Primary, non-responsive or partially responsive to pegylated interferon alfa and ribavirin therapy; or genotype 1b chronic hepatitis C compensated liver disease (including cirrhosis) subjects intolerant or unsuitable for interferon therapy asuravir softgels + daclatasvir hydrochloride tablets, 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, intolerance or unsuitability for interferon therapy Asuravir Softgels + Dalatavir Hydrochloride Tablets, 24 weeks (n = 222) AI447031 Genotype Type 1b chronic hepatitis C compensated liver disease (including cirrhosis) primary treatment Japanese subjects with asulpride viva softgels + daclatasvir hydrochloride tablets for 24 weeks (n = 119)
Telaprevir + interferon alfa-2b + ribavirin for 24 weeks (n = 111)
Telaprevir softgels in combination with Dalatavir hydrochloride tablets in patients with genotype 1b chronic hepatitis C
Clinical study in China
HALLMARK ASIA (Study AI447036) is an open study evaluating asuravir softgels in combination with daclatasvir hydrochloride tablets (DUAL) for 24 weeks of continuous treatment in subjects with genotype 1b chronic hepatitis C who were intolerant or unfit for interferon a therapy (with or without ribavirin).
A total of 159 subjects with genotype 1b chronic hepatitis C who were intolerant/unsuitable for interferon a treatment were treated in this open study: 127 (80%) from mainland China, 15 (9%) from Taiwan, and 17 (11%) from Korea. The median age of treated subjects was 56.0 years, and 35% were male subjects. 32.7% of subjects 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, pegylated interferon alfa/ribavirin treatment 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 viral relapse after undetectable HCV RNA at the end of treatment. Table 8 summarizes the SVR rates by country/region in the HALLMARK ASIA (AI447036) study and the outcomes of patients who did not achieve SVR. 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 according to baseline NS5A resistance associated polymorphisms summarizes the SVR rate. Epidemiologic information on these polymorphisms is available in [Pharmacologic Toxicology].
Table 8: HALLMARK ASIA (AI447036) study: treatment outcomes in patients with genotype 1b hepatitis C with the application of asulpride viva softgels in combination with daclatasvir hydrochloride tablets 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% without Y93H or L31F/I/M/Va (2/10)
98 % (114/116) 67% (2/3) 100.0 % (14/14) 67% (4/6) 100.0% (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 for patients without SVR On-treatment virologic failure 9% (11/127) 6% (1/17) 0 8% (12/159) Relapse 0 0 13% (2/15) 1% (2/147) a Patients with baseline NS5A sequence data were included in the analysis.
Global clinical studies.
HALLMARK DUAL (Study AI447028) was a global study that included patients with genotype 1b chronic hepatitis C and compensated liver disease who were primary treatment, pegylated interferon alpha/ribavirin non-responders or partial responders, or patients who were intolerant or unsuitable for interferon-based therapy. Patients in the primary treatment cohort were randomized 2:1 to receive either asuravir softgels 100 mg twice daily in combination with daltegravir hydrochloride tablets 60 mg once daily for 24 weeks or placebo for 12 weeks (placebo patients were subsequently enrolled in another study and received asuravir softgels in combination with daltegravir hydrochloride tablets for 24 weeks). Non-responders or partial responders and patients in the intolerant/unsuitable cohort received asuravir softgels 100 mg twice daily in combination with daclatasvir hydrochloride tablets 60 mg once 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 asuravir softgels in combination with daclatasvir hydrochloride tablets. 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 asulisvir softgels in combination with daltegravir hydrochloride tablets.
SVR12 (primary endpoint) results and patient outcomes without SVR in HALLMARK DUAL (AI447028) are presented by patient population in Table 9. 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 9: Treatment outcomes in patients with genotype 1b hepatitis C infection in HALLMARK DUAL (AI447028) with the application of asuravir softgels in combination with daclatasvir hydrochloride tablets
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 prior partial responders and 119 prior 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 were intolerant/unsuitable for interferon-based therapy. Patients in the poor responders and intolerant/unfit cohort were given asuravir softgels 100 mg twice daily in combination with daltegravir hydrochloride tablets 60 mg once 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.
SVR outcomes from the HALLMARK NIPPON (AI447026) study and outcomes for patients who did not achieve SVR are presented by patient population in Table 10. The table also summarizes the SVR rates of patients based on baseline NS5A resistance-associated polymorphisms. Information on the incidence of these polymorphisms is presented in [Pharmacology and Toxicology].
Table 10: Treatment Outcomes in Patients with Genotype 1b Chronic Hepatitis C in HALLMARK NIPPON (AI447026) with Asulavir Softgels in Combination with Dalatavir Hydrochloride Tablets
Treatment outcome Previous treatment failure
(partial responders and non-responders)
n=87Interferon intolerance/unsuitability
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 and 81% of prior non-responders achieved SVR. 94% of intolerant patients and 86% of unfit patients in the intolerant/unfit cohort achieved SVR. virologic response 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 asuravir softgels in combination with daclatasvir hydrochloride tablets or with the combination of telaprevir + pegylated interferon a-2b/ribavirin for 24 weeks of continuous treatment. The SVR12 rates were 89 % (106/119) and 62 % (69/111) in the asulisvir softgels combined with daltavir hydrochloride tablets and the Telaprevir+polyethylene glycol interferon+ribavirin groups, respectively. SVR rates with aprevir softgels combined with daltegravir hydrochloride tablets were influenced by the presence of baseline NS5A gene polymorphisms (see Table 11).
Also in this study, patients with chronic hepatitis C who had relapsed on a previous interferon-containing regimen received asuravir softgels in combination with daclatasvir hydrochloride tablets for 24 weeks of continuous treatment. The SVR12 rate for those who relapsed was 96% (21/22).
Table 11: Treatment outcomes in patients with chronic hepatitis C with genotype 1b in AI447031 treated with asulprideve softgels in combination with daclatasvir hydrochloride tablets Treatment outcome 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 study of 24-week treatment of patients with genotype 1 chronic hepatitis C (previously non-responsive to pegylated interferon alpha + ribavirin) with asulavir softgels in combination with daltegravir hydrochloride tablets, HCV RNA was not detected in 2 of 9 patients (22%) with genotype 1a chronic hepatitis C at week 24 post-treatment.
Long-term follow-up
There are limited data from ongoing follow-up studies to assess response durability up to 3 years after treatment with asulisvir softgels in combination with daclatasvir hydrochloride tablets. Of the 224 patients treated with asuravir softgels in combination with daclatasvir hydrochloride tablets who obtained SVR12 (median duration of follow-up after obtaining SVR12 was approximately 8.5 months), 1 (<1%) developed relapse.
[Pharmacology and Toxicology].
Mechanism of action
Asuravir is an HCV NS3/4A serine protease complex inhibitor. The NS3/4A enzyme complex is responsible for the production of HCV polyproteins, which form the mature viral proteins required for viral replication. In biochemical analyses, acrivir inhibited the NS3/4A protease complex (genotypes 1a, 1b, 4a, 5a and 6a HCV) most strongly with IC50 [concentration of half inhibition] values ranging from 0.7 to 1.8 nM, 0.3 nM, 1.6 nM, 1.7 nM and 0.9 nM, respectively. genotype 2 (2a IC50 value = 15 nM. 2b IC50 value = 78 nM) and genotype 3 (3a IC50 value = 320 nM) were observed to be reduced inhibition.
Antiviral activity
In cell-based HCV replicon studies, the effective concentration (EC50) values for suppression of genotype 1a (H77 strain) and type 1b (Con1 strain) HCV were 4 nM and 1.2 nM, respectively. the EC50 values for suppression of genotype 2a replicons and hybrid replicons encoding the NS3 protease structural domain of HCV genotypes 2b and 3a were The EC50 values observed for the hybrid replicon targeting the NS3 protease structural domain of HCV gene type 4a ranged from 1.8 nM to 7.6 nM.
Two-drug combination or three-drug combination studies using HCV replicon based systems have shown superimposed and/or synergistic effects of acitretin in combination with pegylated interferon alpha, daltegravir hydrochloride, HCV NS5B active site or metabolic inhibitors targeting either NS5B thumb-1 or palm domains, and ribavirin.
Pharmacodynamics
The effect of acriflavine on the QTc interval was evaluated in a randomized, double-blind, positive-controlled, placebo-controlled, parallel-group, nested crossover study in 120 healthy subjects. The effect of asuravir 300 mg twice daily (supratherapeutic dose level) compared to placebo on QTc (using Fridericia correction) was evaluated on days 3 and 10 of positive dosing. No statistically significant effect of asuravir on placebo-corrected changes in QTc was observed, and no significant relationship between plasma concentrations and changes in QTc was observed.
Drug resistance
Cell culture
Cell cultures were screened for genotype 1a and genotype 1b HCV replicons with reduced susceptibility to acriflavine, exhibiting both genotypic and phenotypic resistance to acriflavine. Amino acid substitutions of the NS3 protease sequence that emerged after treatment were introduced into the respective replicon subjects to evaluate resistance to acitretin. The main variants detected in the genotype 1a HCV asuravir-associated resistance replicons were amino acids R155K, D168G and I170T. recombinant replicons containing these amino acid substitutions identified their role in asuravir resistance (5-21 fold reduction in susceptibility to asuravir).
The main variant detected in HCV genotype 1b acrivir-associated resistant replicons was amino acids D168A/G/H/V/Y. Recombinant replicons containing these variants identified their role in acrivir resistance (16-280-fold reduction in susceptibility to acrivir).
Cross-resistance
There may be cross-resistance between acitretinide and other NS3/4A protease inhibitors. In clinical studies, the most frequently observed variants associated with acitretin resistance are located at the R155 and D168 sites on NS3. HCV replicons containing the asuravir resistance variants remain fully susceptible to interferon alpha and ribavirin, as well as other direct antivirals with different mechanisms of action, such as HCV NS5B polymerase inhibitors.
Clinical studies
Impact of baseline HCV polymorphisms on treatment response
A pooled analysis of phase 2/3 global clinical studies (n=1045) of primary and treated genotype 1b chronic hepatitis C patients with available NS5A sequence data showed that eight (<1%) patients had viral detection of NS3-D168E at baseline. 3% (4/152) of patients who failed treatment and had NS3 sequence data had this polymorphism at baseline.
Reduced efficacy of asuravir softgels in combination with daclatasvir hydrochloride tablets in patients with chronic hepatitis C virus infection of genotype 1b with baseline viral detection of the HCV NS5A polymorphism at the L31 (F, I, M, or V) or Y93 (H) loci. The prevalence of NS5A gene polymorphisms was 14% (142/992) in 992 primary and treated genotype 1b chronic hepatitis C patients who participated in the phase 2/3 global clinical study with available NS5A sequence data. The overall SVR rate was 42% (59/142) in patients with the presence of the L31F/I/M/V or Y93H variants and 93% (792/850) in patients in whom the L31F/I/M/V or Y93H polymorphisms were not observed (see [Clinical Trials]).
Asuravir softgels in combination with daltegravir hydrochloride tablets: 12% (19/159) incidence of NS5A polymorphisms at the L31F/I/M/V or Y93H loci at baseline in 159 patients with genotype 1b chronic C infection who had NS5A sequence data and were intolerant or unfit for interferon alpha in the phase 3 clinical study HALLMARK ASIA (AI447036) ; <1% (1/159 patients) had L31M-containing, Y93H-free virus, and 11% (18/159) had Y93H-containing, L31M-free virus. 13 subjects with virologic failure who had baseline NS5A sequence data, 8% (1/13) 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 SVR rate was 42% (8/19) in patients with viral L31M or Y93H polymorphisms, compared with an overall SVR rate of 99% (137/139) in patients without observed L31M or Y93H polymorphisms , see [clinical trial].
Resistance-associated variants that emerged after treatment in patients who did not obtain SVR
Dalatavir hydrochloride tablets in combination with asuravir softgels
Analysis of the phase 3 clinical study HALLMARK ASIA (AI447036) in patients with genotype 1b chronic hepatitis C virus infection who were intolerant or unsuitable for interferon alpha therapy treated with asuravir softgels in combination with daclatasvir hydrochloride tablets showed that all patients who developed virologic failure and had resistance data (100%, 13/13) had variants at the viral NS5A amino acid loci L31 and/or Y93 and NS3 amino acid site D168 had on-treatment substitutions.
Table 12: On-treatment NS5A amino acid substitution in the HALLMARK ASIA (AI447036) study: patients with SVR24 not obtained with the application of Asulprideve softgels in combination with daclatasvir hydrochloride tablets Asulprideve softgels in combination with daclatasvir hydrochloride tablets Classification (%, n) Genotype 1b
n = 13* Subjects with NS5A and NS3 sequence data13 NS5A locus 31, NS5A substitution in treatment at 93 100% (13/13) L31: F, M, V 92% (12/13) Y93H 23% (3/13) L31F/V and Y93H 15% (2/13) NS3 locus 56, 155, 168 NS3 Displacement.
100% (13/13) Y56: H 23% (3/13) R155: Q 8% (1/13) D168: A, E, N, T, V, Y 100% (13/13) *One 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 virus infection treated with asuravir softgels in combination with daclatasvir hydrochloride tablets [from the AI447011, AI447017, AI447031, HALLMARK NIPPON (AI447026), and HALLMARK DUAL (AI447028) studies] showed that in 95% ( 131/138) of patients with virologic failure and available resistance data had detectable NS5A amino acid substitutions (see Table 13). The majority of these patients (89%, 123/138) had an on-treatment amino acid substitution at the NS3 D168 site. 80% (108) of 135 treatment-naïve patients with available NS3 and NS5A resistance data had a combined substitution at the NS3 D168 site and the NS5A L31+Y93H site.
Table 13 Post-treatment NS3 amino acid substitutions in pooled data from patients without SVR12 in phase 2 and phase 3 clinical studies of asuravir softgels in combination with daclatasvir hydrochloride tablets.
Classification (%, n) Asuravir softgels combined with Dalatavir hydrochloride tablets genotype 1b
Subjects with NS3 sequence data at and after baseline n=138 Substitutions occurring on treatment were located in NS3’s 36, 54, 56H/L, 77, 80, 122, 155, 168, and/or 170A/M/T 91% (126/138) D168Xa 89% (123/138) D168V 37% (51/138) D168E 19% (26/138) V36G/M, T54S, N77S, Q80K/L/R or S122D/G/I/N/T, R155Q less than 10% X may contain NS3 D168 replacement A, E, F, H, N, T, V or Y.
Persistence of drug resistance-related substitutions
Patients who failed treatment after receiving a regimen containing asuravir softgels in a phase 2/3 global clinical study were monitored over time for the persistence of NS3 resistance-associated substitutions that occurred after treatment. Among patients with genotype 1b who developed NS3 resistance-associated variants after treatment with asuravir softgels in combination with daclatasvir hydrochloride tablets, only 26 of 46 patients monitored to 24 weeks post-discontinuation and 1 of 9 patients monitored to 36 weeks or more post-discontinuation had consistently detectable variants.
The absence of resistance-associated variants does not confirm the absence of resistant viral strains. The long-term clinical impact of post-treatment emergence of acriflavine resistance-associated variant viral strains is unknown.
Oncogenicity, Mutagenicity, Fertility Impairment
Asulpride is not carcinogenic at AUC values up to 350 times the recommended human dose AUC in mice or 54 times the recommended human dose AUC in rats. No evidence of mutagenicity or chromosome breakage was observed in an in vitro mutagenicity (Ames) assay, a mammalian mutation assay in Chinese hamster ovary cells, or an in vivo oral micronucleus study in rats.
There was no effect of acepromazine on fertility in male or female rats at any of the dose levels studied. The highest AUC values that were not affected were 105 and 101 times the recommended human dose AUC for males and females, respectively.
Animal Toxicology
The toxicity profile in juvenile rats administered with acepromazine for 10 weeks was similar to that observed in adult rats. abdominal distention and changes in body weight and food intake at 400 mg/kg/day (the highest dose tested) were considered adverse effects. The AUC for the no observed adverse effect level (NOAEL) in juvenile rats was 98 times the AUC of the recommended human dose.
Pharmacokinetics]
The pharmacokinetic profile of acriflavine was evaluated in healthy adult subjects and in subjects with chronic hepatitis C virus infection. In subjects with chronic hepatitis C virus infection, the steady-state geometric mean (CV%) Cmax of asulpride 100 mg twice daily in combination with multiple doses of daltegravir hydrochloride
was 642 (64.2) ng/mL, AUC0-12h was 1910 (76.3) ng-h/mL, and Cmin was 45 (83.3) ng/mL.
Absorption and bioavailability
In subjects with chronic hepatitis C virus infection, acepromazine reached peak plasma concentrations between 1 and 4 hours. The Cmax, AUC, and Cmin of acutrevir increase in an approximately dose-proportional manner. Healthy subjects were dosed twice daily and reached steady state after 7 days. In vitro studies using human Caco-2 cells have shown that asuravir is a P-gp substrate. The absolute oral bioavailability of Asuravir softgels was 9.3%.
Effect of food on oral absorption
The absorption of asulpride 100 mg softgels administered to healthy subjects eating a high-fat meal (approximately 1000 kcal, approximately 50% from fat) increased (relative to the fasted condition), but had no clinically meaningful effect on the overall bioavailability of asulpride, with a 34% and 20% increase in Cmax and AUC, respectively. The Tmax for concomitant food administration of acepromazine was 1.5 hours post-dose, compared to 2.5 hours for fasted administration.
Distribution
Within the dose range studied (200-600 mg twice daily), the protein binding rate of asulpride in subjects with chronic hepatitis C virus infection was >99% and was not dose dependent.
In vitro studies using HEK-293 cells have shown that acitretin is a substrate for the hepatic uptake transport proteins OATP 1B1 and 2B1. Subjects were administered 100 mg of asulpride softgels orally followed by 100 μg of 14C-asulpride intravenously, with an estimated volume of distribution of 194 L at steady state.
Metabolism
In vitro studies demonstrated that acepromazine is primarily metabolized via CYP3A-mediated oxidation.
Elimination
After a single oral dose of 14C-asulpride in healthy subjects, 84% of the total radioactivity (mainly metabolites) was recovered in feces and less than 1% in urine (mainly metabolites). The major route of elimination of asulpride is metabolism. Prototype acriflavine in fecal recovery accounted for 7.5% of the dose. The majority of radioactivity in human circulating plasma is the prototype asuravir, with a small amount of minor metabolites detectable in human plasma (less than 10% of total asuravir and metabolite exposure after repeated dosing). Asuravir and its metabolites were detected in human bile. The terminal elimination half-life ranges from 17 to 23 hours after multiple doses of acutrevir in healthy subjects. The estimated total clearance of acriflavine was 49.5 L/h for subjects receiving 100 mg of acriflavine softgels orally followed by 100 µg of 14C-asulpride intravenously.
Special Populations
Renal impairment
As one of the 3 components of a fixed-dose combination tablet (asuravir/daltegravir hydrochloride/ Beclabuvir) in non-chronic hepatitis C virus-infected subjects with normal renal function (CrCL>90 mL/min, determined using the Cockcroft-Gault CrCL formula), mild (CrCL 60 to<90 mL/min ), moderate (CrCL 30 to <60 mL/min), or severe (CrCL<30 mL/min) renal impairment in subjects not on hemodialysis, and end-stage renal disease (ESRD) subjects receiving hemodialysis were studied for the pharmacokinetic profile of multiple doses of acitretinoin. Compared to normal renal function subjects, the estimated asulpride Cmax was 29%, 65%, and 88% higher and the asulpride AUC was 33%, 76%, and 103% higher in subjects with mild, moderate, and severe renal impairment, respectively. Estimated unconjugated asuravir Cmax was 37%, 87%, and 119% higher and unconjugated asuravir AUC was 41%, 99%, and 137% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Compared to subjects with normal renal function, ESRD subjects requiring hemodialysis had 11% lower asuravir Cmax and 16% lower AUC shortly after hemodialysis. Unconjugated asuravir Cmax and AUC were reduced by 2% and 6%, respectively, shortly after dialysis in ESRD subjects requiring dialysis compared to subjects with normal renal function. See [DOSAGE AND ADMINISTRATION].
Liver damage
The pharmacokinetic profile of asuravir was evaluated in non-chronic hepatitis C virus-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) liver impairment compared to subjects without liver impairment. Subjects received asuravir 200 mg (unlisted hard capsules) twice daily for 7 days. Mild hepatic impairment had a slight effect on the pharmacokinetics of asulpride. Steady-state exposures (Cmax, AUCTAU, and Cmin) were significantly higher for asulpride in subjects with moderate liver impairment (5.0, 9.8, and 32.9-fold, respectively) or severe liver impairment (22.9, 32.1, and 76.5-fold, respectively) compared to subjects without liver impairment. The appropriate dose of asulpride for patients with moderate or severe liver impairment has not been determined (see [DOSAGE AND ADMINISTRATION] and [CONTRAINDICATIONS]).
Geriatric
Population pharmacokinetic analysis of data from clinical studies of asulpride softgels indicated that age was a statistically significant covariate for apparent oral clearance (CL/F) of asulpride, but the extent to which age affected asulpride exposure was not clinically significant (see [Geriatric Use]).
Children and Adolescents
The pharmacokinetics of Asulprasvir Softgels have not been evaluated in pediatric patients (see [Pediatric Dosing]).
Gender
Population pharmacokinetic analysis of clinical study data for Asulpride Softgel Capsules indicated that gender was a statistically significant covariate for the apparent volume of distribution (Vc/F) of Asulpride, but the extent to which gender influenced Asulpride exposure was not clinically significant.
Race
Population pharmacokinetic analysis of clinical study data for asulpride softgels showed that race was a statistically significant covariate for asulpride CL/F, with Japanese and non-Japanese Asian subjects having higher asulpride exposure compared to white subjects. However, there was no clinically meaningful effect of race on the pharmacokinetics of asuravir.
Storage]
Store below 25°C away from light in the original packaging
Package
Aluminum-plastic blister packaging, boxed, 14 capsules/box, 28 capsules/box
Expiration date
24 months
Execution standard
To be determined
Approval number
TBD
Manufacturer
Manufacturing facility: Catalent Pharma Solutions LLC
2725 Scherer Drive St Petersburg FL 33716-1016 USA UNITED STATES (USA)
Packing House: AndersonBrecon Incorporated
4545 Assembly Drive Rockford, 61109, USA UNITED STATES (USA)
In China, please contact: Bristol-Myers Squibb (China) Investment Co.
Address: 17/F, Wheelock International Plaza, 1717 West Nanjing Road, Shanghai, China
Postal Code: 200040
Tel: 021-23218100
Fax: 021-53862127
Medical consultation telephone number: 800 820 8790 (landline) 400821 8790 (mobile) Monday to Friday 9:00-17:00 (except holidays)
Website: www.bms.com.cn